My Biochem Flashcards
Complex II Inhibitors
Carboxin
TTFA
Malonate
Complex 1 inhibitors
Barbiturate
Amytal
Rotenone
Piercidin A
Complex III Inhibitors
Antimycin A
Dimercaprol
Complex IV Inhibitors
Sodium azide
Hydrogen sulfide
Cyanide
Carbon monoxide
Complex v inhibitors
Oligomycin
Uncouplers
Aspirin
Dinitrophenol
Thermogenin
All complex mitochondrial disease
Fatal infantile mitochondrial myopathy
Complex I mitochondrial disease
MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke like episodes)
Complex II mitochondrial disease
Kearns-Sayre syndrome
Complex III mitochondrial disease
Leber’s hereditary optic neuropathy
Complex IV mitochondrial disease
Leigh’s disease
Ragged red muscle fiber disease
Glut transporter for erythrocytes
1
Glut transporter for brain
1 & 3
Glut transporter for kidney
1, 2, 3
Glut transporter for colon
1
Glut transporter for placenta
1 & 3
Glut transporter for liver
2
Glut transporter for pancreatic B cell
2
Glut transporter for small intestine
2, 5
Glut transporter for heart
4
Glut transporter for adipose
4
Glut transporter for skeletal muscle
4
Where does glycolysis occur?
Cytoplasm in all cells
What is the substrate for glycolysis?
Glucose
What is the end product for glycolysis?
Pyruvate or lactate
Rate limiting step for Glycolysis
Fructose-6-Phosphate –(Phosphofructokinase 1)–> F-1,6-Bisphosphate)
Enzyme for energy expenditure step in Glycolysis
Hexokinase or Glucokinase
Energy production enzymes and steps in glycolysis
1,3 Bisphosphoglycerate –(Phosphoglycerate Kinase)–> 3 phosphoglycerate
PEP –(PEP Kinase)–> Pyruvate
Where is glucokinase present?
Liver parenchymal cells and islet cells of the pancreas
Activators for PFK1 vs PFK2
PFK1: Fructose-2,6-BP and AMP
PFK2: Well-fed state ^ Insulin and v Glucagon
Inhibitors for PFK1 vs PFK2
PFK1: ATP and citrate
PFK2: Starved state V insulin ^ Glucagon
Activator for PEP -> Pyruvate
Fructose-1,6-Bisphosphate
NADH2 production in glycolysis
Glyceraldehyde-3-P –(Glyceraldehyde-3-dehydrogenase)–> 1,3-Bisphosphoglycerate
Aerobic glycolysis shuttle used for the liver kidney and heart
Malate-asparte shuttle = 3 ATP
mas Late but mas Astig!
Aerobic glycolysis shuttle used for the skeletal and brain
Glycerol Phosphate shuttle = 2 ATP
needed FASTER thus less output
Major fate of pyruvate in RBCs, lens, cornea, kidney medulla, testes, and WBC
Anaerobic glycolysis
ATP yield for glycolysis in Aerobic vs Anaerobic
2 vs 6-8
How does arsenic poisoning disrupt the glycolytic cycle?
Arsenic:
- Inhibits pyruvate dehydrogenase by binding to lipoic acid
- Competes with inorganic P as a substrate for G-3-P dehydrogenase
Most common enzyme defiency in glycolysis?
Pyruvate kinase deficiency (X-linked recessive) which manifests as chronic hemolytic anemia. Decreased acetyl Coa in the brain causes psychomotor retardation and death.
Treated with Ketogenic diet
Four fates of pyruvate
Lactate, Ethanol, Acetyl CoA, Oxaloacetate
Co-enzymes of pyruvate dehydrogenase
Love Never Fails to Conquer Lipoic Acid NAD FAD Thiamine pyrophosphate Coenzyme A
Where does the TCA cycle occur
In all cells with mitochondria in the mitochondrial matrix except succinate dehydrogenase which occurs in the inner membrane.
Rate limiting step in the TCA cycle
Isocitrate –(isocitrate dehydrogenase)–> a-ketoglutarate
What inhibits the conversion of citrate to isocitrate?
Fluroacetate (rat poison) inhibits aconitase
Where are the NADHs produced in the TCA cycle?
Isocitrate –(Isocitrate dehydrogenase)–> a-ketoglutarate + CO2
a-ketoglytarate –> Succinyl CoA + CO2
Malate -> Oxaloacetate
Where is the FADH2 produced in the TCA cycle?
Succinate –(succinate dehydrogenase)–> Fumarate
Which TCA intermediate could be used for heme synthesis and activation of ketone bodies in extra hepatic tissues?
Succinyl CoA
Which TCA intermediate can be used for gluconeogenesis?
Malate
Which TCA intermediate delivers acetyl CoA to the cytoplasm for Fatty synthesis via a shuttle mechanism?
Citrate
Is there hormonal control and new oxaloacetate production in the TCA cycle?
No
ATP yield for the TCA cycle from pyruvate? from Acetyl CoA?
From pyruvate: 15
From Acetyl Coa: 12
Where does gluconeogenesis occur?
90% liver
10% kidney
During prolonged fasting, the kidneys contribute as much as 40%
Mitochondria and cytoplasm
Rate limiting step for gluconeogenesis
F-1,6-BP –(Fructose 1,6-bisphosphatase)–> F-6-P
Three processes that occur both in the mitochondria and the cytoplasm
Gluconeogenesis
Heme Synthesis
Urea synthesis
What cycle is responsible for the conversion of lactate to glucose?
Cori cycle
Energy expenditure of the Cori cycle
4 ATP
Enzymes required for the conversion of pyruvate to PEP in gluconeogenesis
PEP
^ Pyruvate carboxylase (Requires biotin and ATP)
Oxaloacetate
^ PEP Carboxykinase (Requires GTP)
Pyruvate
What are the 3 Carboxylase reactions? What is the required co-factor in these reactions?
- Pyruvate -> OAA (Pyruvate carboxylase)
- Acetyl CoA -> Malonyl CoA (Acetyl CoA Carboxylase)
- Propionyl CoA -> Succinyl CoA (Propionyl CoA Carboxylase
Where does conversion of Glucose-6-P to Glucose occur? And why?
Liver and kidneys only since the muscle lacks G-6-Phosphatase
Energy expenditure for gluconeogenesis
- Use of 4 ATPs
- use of 2 GTPs
- Oxidizes 2 NADH back to NAD+
Renal blood glucose threshold that leads to glucosuria
9.5-10.0 mmol/L
What are the three reactions that is favored by NADH usually due to alcoholism?
- Pyruvate -> Lactate
- OAA -> Malate
- DHAP -> glycerol-3-phosphate
In pregnancy which hormone is resonsible for hyperinsulinemia? Insulin resistance?
Hyperinsulinemia: Estrogen (fasting hypoglycemia)
IR: HPL (Post prandial hyperglycemia)
Where is glycogen stored?
Liver 100g (6% of liver) and muscle 400g (<1% of muscle) only
Where does glycogenesis occur?
Cytosol of the Liver and the muscle
Substrates for glycogenesis
- UDP Glucose
- ATP and UTP
- Glycogenin: primer protein core
Rate limiting step in glycogenesis
Elongation of glycogen (via glycogen synthase)
Steps in Glycogenesis
- Glucose-6-P to Glucose-1-P (phosphoglucomutase)
- Glucose-1-P to UDP-Glucose
- Elongation of glycogen chains (Glycogen synthase)
- Branching of glycogen (Branching enzyme a transglucosidase)
Where does glycogenolysis occur?
Cytosol of the liver and the muscle
How many glucose residues are there before a branch point or limit dextrin?
Four
Products of glycogenolysis
Glucose-1-P and Free glucose
Liver: Can release free glucose
Muscle: Glucose-6-P limited
Rate limiting step of glycogenolysis
Removal of glucose (Breaking of a[1->4] bonds via glycogen phosphorylase)
Steps in Glycogenolysis
- Removal of glucose by glycogen phosphorylase
- Glucantransferase transfers the a(1->4) -> a(1->4) limit dextrin
- Amylo-a(1->6) removes a free glucose by breaking its bond)
- Conversion of G-1-P to G-6-P via phosphoglucomutase
Glycogen storage disease that is due to G-6-phosphatase deficiency. Findings such as glycogen in liver and renal cells. Hypoglycemia + lactic acidosis and ketosis.
Type I - Von Gierke’s
Glycogen storage disease that is due to acid maltase deficiency. There are findings such as glycogen in lysosomes, cardiomegaly, and heart failure.
Type II - Pompe’s disease
Glycogen storage disease that is due to debranching enzyme deficiency. It is a milder form of type I
Type III - Cori’s
Glycogen storage disease that is due to a skeletal muscle glycogen phosphorylase deficiency leading to glycogen in the muscle, muscle cramps + myoglobinuria but no lactic acidosis.
Type V - McArdle’s
Where are Disaccharidases and trisaccharidases are located in? Can pancreatic amylases hydrolyze the sugars that these enzymes cover?
Brush border of the intestinal epithelium
No, pancreatic amylases cannot
Steps in galactose metabolism
- Galactose -> Galactose-1-P (Galactokinase or hexokinase)
- Formation of UDP-Galactose + Glucose-1-P (Galactose-1-P uridyl transferase)
- UDP-Galactose -> UDP-Glucose
Causes galactosemia and galactosuria
Galactokinase deficiency
Absence of galactose 1-P uridyltransferase, it is autosomal recessive, which leads to galactitol accumulation resulting in cataracts, hepatosplenomegaly and mental retardation
Classic Galactosemia
Important source of fructose
Disaccharide sucrose found in honey and fruits
Sucrose if hydrolyzed by sucrase in the brush border
What sugar has the fastest metabolism and greatest yield of energy?
Fructose
Steps in fructose metabolism
- Phosphorylation of fructose (Fructokinase or hexokinase)
2. Formation of DHAP and glyceraldehyde (Aldolase B)
Which pathways are the two aldolases found?
Aldolase A: Glycolysis
F-1,6-BP -> DHAP + Glycerol-3-P
Aldolase B: Fructose
F-1,6-P -> DHAP + Glyceraldehyde
Symptoms of essential dructosuria
Defect in fructokinase: benign and asymptompatic. Only blood and urine fructose is noted.
An autosomal recessive disease that is due to the deficiency in aldolase B. Symptoms noted are hypoglycemia, jaundice, cirrhosis, and vomiting.
Fructose intolerance leading to fructose 1-P accumulation which leads to decrease in phosphate, glycogenolysis, and gluconeogenesis. Treatment is decrease intake of sucrose and fructose.
Where is sorbitol dehydrogenase found? (Sorbitol -> Fructose)
Seminal vesicles since fructose is fuel for sperm
Where is aldose reductase found? (Glucose-> Sorbitol)
Lens, Schwann cells, liver, kidney, placenta, RBC, ovaries, seminal vesicles
What is the Pentose phosphate pathway for?
- NADPH production
- Ribose-5-phophate production for synthesis of nucleotides
- Metabolic use of 5-carbon sugars
Where does the PPP occur?
Cytoplasm
NADPH provides electrons for
- FA and steroid biosynthesis
- Reduction of glutathione
- Cytochrome P450
- WBC respiratory burst
- Nitric oxide synthesis
Rate limiting step for HMP or PPP?
Glucose-6-P -> 6-phosphogluconate
Glucose-6-P dehydrogenase
Two phases of PPP
Phase 1: Oxidative (Irreversible) producing NADPH and Ribulose-5-P [via G-6-P dehydrogenase]
Phase 2: Non-oxidative (reversible) producing ribose-5-P, Glyceraldehyde-3-P, fructose-5-P [via transketolases requiring Thiamine]
Purpose of glutathione and how is it regenerated?
Reduced glutathione sequesters harmful H2O2 via glutathione peroxidase
Reduced glutathione is recreated using NAGPH via glutathione reductase
Most common disease producing enzyme abnormality in humans which involves decreased NADPH in RBCs and a decrease in glutathione reductase activity causing free radicals and peroxidases to accumulate?
Glucose 6-Phosphate deficiency
Most common precipitating factor for G6PD
Infection
Histologic pathognomonic features of G6PD
Heinz bodies and bite cells
a disease that is noted for its NADPH oxidase deficiency. It leads to severe, persistent and chronic pyogenic infections caused by catalase (+) bacteria
Chronic granulomatous disease
What enzyme activates fatty acid for metabolism use?
Fatty-acyl-CoA synthetase
Cofactor required for fatty acid activation
Vitamin B5 or Panthotenic acid
Energy required to activate fatty acid
2 ATP
What is the product formed in fatty acid synthesis?
Palmitate (16:0)
Where does fatty acid synthesis occur?
Cytosol
Major: Liver and lactating mammary glands
Minor: adipose tissue
Substrates for fatty acid synthesis
1 acetyl CoA
7 malonyl CoA
NADPH
ATP
Rate limiting step in fatty acid synthesis
Acetyl CoA + ATP -> malonyl CoA
Enzyme: acetyl CoA carboxylase
Steps in fatty acid synthesis
- Synthesis of cytoplasmic acetyl CoA (transfer of mitochondrial acetyl CoA to cytoplasm via citrate shuttle)
- Acetyl CoA carboxylation to malonyl CoA (via acetyl CoA carboxylase with biotin) [+ insulin, citrate]
- Assembly of palmitate (via fatty acid synthase and Vit B5)
Steps in palmitate assembly
- Condensation
- Reduction
- Dehydration
- Reduction
What is the fate of Palmitate after its production?
- Further elongation in SER and mitochondria
2. Desaturated in the ER (but not past the 9th carbon)
Main storage form of fatty acids
Triacylglycerols
Where does TAG synthesis occur?
Liver and adipose tissue
Sources of glycerol-3-phosphate
- DHAP from glycolysis (liver and adipose)
2. Phosphorylation of free glycerol (liver)
What enzyme is responsible for the release of free fatty acids from TAGs?
Hormone sensitive lipases
In the bloodstream fatty acids are always bound to?
Albumin
Hormone sensitive lipases can only release what free fatty acids stored in TAG?
C1 & 3 thus resulting in
TAG -> 2 free FA and 2-mono acyl glycerol
Where does B-oxidation of fatty acids occur
Mitochondria of all cells, but the fatty acid activation raft occurs in the Cytosol
Exception: RBC, kidney medulla, neurons, testes
Rate limiting step in B-oxidation
Fatty acyl CoA + carnitine -> fatty acyl carnitine + CoA
Enzyme: carnitine acyl transferase I
Cutoff number of carbons that do not need a shuttle
Less than 12 carbons
Steps in the carnitine shuttle
- Fatty acyl synthase activates the fatty acid
- Carnitine acyl transferase 1 attaches to fatty acyl to carnitine in the outer mitochondrial membrane
- Fatty acyl-carnitine is shuttle through the inner membrane
- Carnitine acyl transferase-2 transfers fatty acyl group back to a CoA in the mitochondrial matrix
Steps in beta oxidation
- Oxidation
- Hydratiion
- Oxidation
- Thiolysis
Beta oxidation of fatty acids with an odd number of carbon atoms releases?
Propionyl CoA which is converted to methylmalonyl coa (requires B12) then to succinyl CoA
Which is responsible for the conversion of very long chain fatty acids?
Peroxisomes but if unsaturated it requires 3,2 enol-CoA isomerase
Energy yield in ATP of beta oxidation of palmitate
129 ATP
7 NADH= 21
7 FAD= 14
8 acetyl CoA= 96
Activation = -2
Intake of this compound depletes the body’s NAD+ supply leading to accumulation Of fat in the liver
Alcohol
Type of carnitine deficiency which leads to impaired FA oxidation and ketogenesis with hypoglycemia?
CPT-1 deficiency
Type of carnitine deficiency which affects skeletal muscle and when severe the liver
CPT-2 deficiency
It is a disorder school results in decreased fatty acid oxidation. Without the ATP to support gluconeogenesis, hypoglycemia becomes profound which may eventually leads to SIDS. It is prevented by frequent feeding with high carbohydrate and low fat diet.
Medium-chain fatty acyl-CoA dehydrogenase (MCAD) deficiency
Associated with eating unripe fruit of the akee tree which contains hypoglycin thus activating MC and SC acyl CoA dehydrogenase
Jamaican vomiting sickness
Rare neurological disorder which results to the accumulation of phytanic acid found in plant food stuff which blocks Boxidation
Refsum disease
Cerebrohepatorenal syndrome resulting from the absence of peroxisomes in all tissues, it is characterized by liver dysfunction, jaundice, MR, weakness, hypotonia, and craniofacial dimorphism
Zellweger syndrome
Defect in peroxismal activation of VLCFA thus leading to its accumulation. Ssx: apathy, behavral change, then visual loss spasticity, ataxia. All due to the fact since VLCFA are found in myelin tissue.
X-lied adrenoleukodystrophy
Where does ketogenesis occur?
Liver mitochondria
Products of ketogenesis
Acetoacetate and B-hydroxybutyrate (fuel)
Acetone (cannot be used as fuel)
Rate limiting step of ketogenesis
Acetoacetyl CoA + acetyl CoA –(HMG CoA synthase)–> HMG CoA
What are the initial products that lead to the formation of acetyl CoA in ketogenolysis?
B-hydroxybutyrate -> acetoacetate -> acetyl coa
What peripheral tissues can oxidize ketone bodes?
Those with mitochondria like the renal cortex, brain, and skeletal muscle
Why cant liver convert acetoacetate to acetyl CoA?
It lacks succinyl-CoA acetoacetyl-CoA reductase (thiophorase)
What is the Urine test for ketones? What ketone type does not it detect?
Nitroprusside test
Does not detect b-hydroxybutyrate
Which part of cholesterol can a fatty acid attach to form a cholesteryl ester?
Single hydroxyl group of carbon 3 of the alpha ring
Where does cholesterol synthesis occur?
All cells in the Cytosol and SER majority of which are found in the liver and intestines
Substrates of cholesterol synthesis
Acetyl CoA, NADPH, ATP
Rate limiting step in cholesterol synthesis
HMG CoA –(HMG CoA reductase)–> mevalonate
Steps in Cholestid synthesis
- Biosynthesis of mevalonate
- Formation of isoprenoid units
- Isoprene unit is formed from 6 isoprenoid units
- Formation of lanosterol
- Formation of cholesterol
How is the cholesterol ring eliminated?
Through conversion to bile salts then secretion to bile
Bile acid synthesis, found in the liver and Cytosol, rate limiting enzyme is?
Cholesterol-7-a-hydroxylase
What are the primary bile acids?
Cholic acid
Chenocholic acid
What are the two amino acids used in bile acid conjugation to form bile salts?
Taurine and glycine
What are the secondary bile acids?
Deoxycholic acid
Lithocholic acid
Where does steroid hormone synthesis occur?
SER of the adrenal glands, ovaries and testes, and placenta
What is blocked by the drug aminogluthetimide?
The conversion of cholesterol to pregnenolone by desmolase
The enzyme responsible for the breakdown of TAG to FA and:
A) 2-MAG from diet
B) FREE glycerol from chylomicrons and VLDL
C) 2-MAG from adipose
A) pancreatic lipase
B) Lipoprotein lipase
C) hormone sensitive lipase
Lipoprotein with the largest percentage of TG
Chylomicrons
Lipoprotein with the largest percentage of cholesteryl esters
LDL
Chylomicrons transport TG and cholesterol from where to where?
Intestines to tissues
VLDL transports TG from where to where?
Liver to tissues
What apoprotein activates lipoprotein lipase?
APO-CII
What apolipoprotein uptakes remnants by the liver?
APO E
Apolipoprotein B-48 is used by chylomicrons which are created by the?
Epithelial cells
What apolipoprotein is secreted by the liver for VDL?
B-100
How does IDL become LDL?
By picking up cholesterol from HD!
Which apoprotein delivers cholesterol into cells?
LDL
Which apolipoprotein is used by HDL to activate lecithin cholesterol acyl transferase or LCAT to produce cholesterol esters?
APO-A1
Difference between Type II familial hypercholesterolemia and type IV familial hypertriglyceredemia?
The former has high LDL leader to xanthomas and xanthelasmas with increased risk of atherosclerosis and CHD
The latter has increased VLDL production leading to a triad of
- DM type 2
- CAD
- Obesity
Phospholipid is composed of
DAG
Alcohol
Phosphodiester bond
Most abundant phospholipid which is important in nervous transmission
Phosphatidylcholine
Phospholipid playing a role in apoptosis
Phosphatidyl serine
Phospholipid that is a major component of surfactant?
Dipalmitoylphosphatidylcholine
Phospholipid reservoir for arachidonic acid in the membranes
Phosphatidylinositol
What phospholipid is essential in mitochondrial function which is also used as a non-troponemal test due to its ability to act as an antigen?
Cardiolipin
Composition of these glycolipids: Ceramide Cerebroside Globoside Ganglioside Sulfatide
Ceramide: sphingosine + FA
Ceramide + \_\_\_\_\_\_\_\_ Glucose or galactose = Cerebroside Oligosacchardide = Globoside N-acetylneuramic acid = Ganglioside Sulfated galactose = Sulfatide
Hexosaminidase a ficiency leading to Ssx like cherry red macula, MR, hypotonia
Tay-Sachs disease
A-galactosidase deficiency leading to 3Rs: recessive x-linked, rash, renal failure
Fabrys disease
B-glucosidase deficiency leading to hepatosplenomegaly and erosion of long bones
Gauchers dissease
Sphingomyelinase deficiency leading to hepatosplenomegaly
Nieman-pick disease
The set of all proteins expressed by an individual at a particular time
Proteome
Aims to identify the entire complement of proteins elaborated by a cell under diverse conditions
Proteomics
What amino acid is needed to form ALA in heme synthesis?
Glycine combined with succinyl CoA
Which amino acid carries nitrogen from the liver?
Alanine
Which amino acids are implicated in maple syrup disease
valine, lucine, isoleucine
What enzyme is responsible for the buildup of phenyl lactate, phenyl acetate, and phenylpyruvate?
Phenylalanine hydroxylase
What amino acid is the precursor for niacin, serotonin, and melatonin?
Serotonin
What is the amino acid precursor for homocysteine?
Methionine
What amino acid contributes to the fibrous structure of collagen and interrupts a-helices in globular proteins?
Proline
Increase of the combination of this Amino acid is responsible for the curly hair of people?
Cysteine + cysteine = cystine
Amino acids with sites for O-linked glycosylation in the Golgi apparatus?
Serine and threonine
Site for n-linked glycosylation in the ER
Asparagine
Amino acid deaminated by an enzyme which results in the formation of ammonia. This is the major carrier of nitrogen to the liver from peripheral tissues,
Glutaminase deaminates glutamine
Amino acid used in the determination for Folic acid deficiency. What is the test called?
Histidine used in the N-forminoglutamate excretion test
Increased amounts of FIGu in urine by Folic acid deficient individuals after histindine intake
Precursor amino acid for creatinine, urea, nitric oxide
Arginine
Essential amino acids that cannot be synthesized by the body and must come from the diet
PVT TIM HALL always ARGues and never TYRes
Phenylalanine, valine, tryptophan, threonine’ isoleucine, methionine, histidine, argenine, Leucine, Lysine
Heme is a complex of?
Protoporphorin IX and heme
What is the Bohr effect?
HBO2 + H+ HbH + O2
What is an oxidized for of HB (Fe 3+) that does not bind O2 readily which could lead to chocolate cyanosis ? It is treated with oral methylene blue or ascorbic acid up to IV methylene blue.
Methemoglobin
Hemoglobin bound to carbon monoxide instead of O2 leading to a cherry pink color.
Carboxyhemoglobin
HB bound to carbon dioxide is called
Carbaminohenoglobin
Classification of alpha and beta thalassemia
Alpha: silent carrier, a-thalassemia trait, Hb H disease, hydrops fetalis
Beta: B-thalassemia minor and major
Most frequently affected collagen in Ehler Danlos syndrome leading to hyper extensible skin, tendency to bleed, hyper mobile joints, and increased risk for berry aneurysms.
Collagen type 3
Collagen I mutation leading to bendable and easily fractured bones. Accompanied with blue sclerae, hearing loss, and dental imperfections.
Osteogenesis imperfecta
Vitamin C deficiency leading to decreased hydroxylation of collagen. This leads to sore spongy gums, loose teeth, poor wound healing, and petecchiae on skin and mucous membranes.
Scurvy
Type IV collagen defect leading to hematuria and ESRD
Alpert syndrome
Collagen defect leading to kinky hair due to a deficiency of copper required by lysyl oxidase to strengthen collagen fibers.
Menke syndrome
Skin breaking and blisters as a result for minor trauma. This disease is due to a defect in collage VII.
Epidermolysis bullosa
Like collagen elastin has pro line and Lysine but has little and no?
Hydroxyproline
Hydroxylysine
Protein degradation mechanisms of nitrogen
Energy dependent ubiquitin-proteosome mechanism
Non-energy dependent degradation enzyme
Phases in amino acid catabolism
First phase: removal of a-amino group forming ammonia and a corresponding ketoacid
Second phase: carbon skeletons of a-ketoacids are converted to common intermediates of energy producing metabolic pathwas
Two main steps in nitrogen removal from AA
- Transamination
2. Oxidative deamination
Where does transamination occur?
All cells of the body
All but two amino acids transfer their amino groups to a-ketoglutarate except?
Lysine and threonine
What is the coenzyme for the two aminotransferases?
Pyridoxal phosphate (vitamin B6)
Oxidative deamination occurs where and for which amino acid only?
Liver and kidney
Only glutamate
Glutamate is oxidized by glutamate dehydrogenases and deaminated to form ?
free ammonia which is used to make urea
What does the conversion of glutamate to a-ketoglutarate yield? What about vice versa?
Glutamate -> a ketoglutarate NH3 + NADH
A ketoglutarate -> glutamate NADP+ + NH3
How is excess nitrogen removal from peripheral tissues removed?
- Glutamine: via glutamate + ammonia (through Flutamide synthaetase)
- Alanine: via glucose -> pyruvate + glutamate -> alanine cycle
Glutaminase deaminates glutamine to produce ammonium ion which is excreted from the body. Where are the two tissues this enzyme could be located?
Kidneys and small intestines
Another name for urea cycle
Ornithine cycle or krebs-henseleit cycle
What are the donors of the urea molecule?
- NH3 from free ammonia
- NH3 from aspartate
- 1C and 1O from CO2
Reactions in the urea cycle
- Formation of carbamoyl phosphate (via carbamoyl phosphate synthetase I)
- Formation of citrulline (via Ornithine transcarbamoylase)
- Synthesis of arginosuccinate (arginosuccinate synthetase)
- Cleavage of arginosuccinate to form arginine (Arginosuccinase)
- Arginine cleavage to yield urea and Ornithine (arginase)
Rate limiting step of urea cycle
Carbamoyl phosphate synthetase I
Energy requirement of urea cycle
4 ATP
Co factors of urea cycle
N-acetylglutamate
Biotin
Hereditary hyperammonemia produces symptoms such as
Hyperammonemia, elevated blood glutamine, decreased BUN
Parents with lethargy, vomiting, hyperventilation, convulsions, cerebral edema, coma, and death
Treatment for hereditary hyperammonemia
Low protein diet
Administration of sodium benzoate or phenylpyruvate to capture and excrete excess nitrogen
Ketogenic carbon skeletons of AA
Leucine
Lysine
Yields acetoacetate or acetyl-coa/ acetoacetyl-coa
Ketogenic and glucogenic carbon skeletons of AA
WIFY Phenylalanine Isoleucine Tryptophan Tyrosine
Yields Ketogenic and glucose or glycogen by products
This amino acid acts as a raw material in the biosynthesis of Heme, purines, creatine
Glycine
This amino acid acts as a raw material in the biosynthesis of phospholipid, sphingolipid, purines, thymine
Serine
This amino acid acts as a raw material in the biosynthesis of GABA
Glutamate
This amino acid acts as a raw material in the biosynthesis of creatine, polyamines, nitric oxide
Arginine
This amino acid acts as a raw material in the biosynthesis of serotonin, NAD+, NADP+, melatonin
Tryptophan
This amino acid acts as a raw material in the biosynthesis of catecholamines, thyroid hormones, melanin
Tyrosine
3 hormones dependent on tyrosine
Thyroid hormones
Melanin
Catecholamines
Deficiency of homogenistic acid oxidase in the degrative pathway of tyrosine which results in urine turning to black on standing with dark connective tissues (ochronosis)
Alkaptonuria
Congenital deficiency due tyrosinase deficieny or defective tyrosine transporters which leads to an increased risk for skin cancer.
Albinism
Autosomal recessive disorder that may either be due to decreased methionine, increased cysteine, B6, and folate or decreased affinity for cystathione synthase. This results in mental retardation, osteoporosis, tall stature, lens subluxation, and atherosclerosis.
Homocystinuria
Common inherited defect of renal tubular amino acid transporter for its parent compound, Ornithine, Lysine, and arginine, in the PCT of the kidneys. It eventually precipitates and cause staghorn caliculi. What is its treatment?
Cystinuria is treated with acetazolamide to alkalinize the urine
The initial and last three steps of heme synthesis occurs in?
The mitochondria
Heme synthesis summary
- Formation of ALA (via ALA synthase and B6)
- Formation of porphobilinogen
- Formation of uroporphyrinogen
- Formation of heme
Lead inhibits what two steps in heme synthesis?
- Introduction of Fe 2+ into protoporphyrin IX via ferrochelatase
- Condensation of two ALA molecules by zinc containing ALA dehydratase
Where is B6 a cofactors of?
- Heme synthesis
- Synthesis of cystathionine from homocysteine
- Transamination between alanine and a-ketoglutarate
Most common porphyria
Porphyria cutanea tarda
Which part of heme synthesis do these symptoms appear?
- Photosensitivity
- Neuropsychiatric symptoms
- After ring formation
2. Before ring formation
Pyridoxine ficiency associated with isoniazid therapy results in this histopathologic finding
Sideroblastic anemia with ringed sideroblast
Poisoning due to this heavy metal leads to coar basophilic stippling of RBC, peripheral neuropathy, lines in gums, increas in urinary ALA and free erythrocytes porphorin
lead poisoning
Microcytic hypo chromic anemia is found in
IDA
Thalassemia
Lead poisoning
Megaloblastic anemia is found in
Folate or B12 deficiency
Pernicious anemia
Normoyctic normochromic anemia is found in
Anemia of chronic kidney disease
Blood loss
Increase in MCHC is found in
Hereditary spherocytosis
Summary of heme degradation
- Formation of bilirubin
- Uptake of bilirubin by the liver
- Formation of bilirubin diglucoronide
- Secretion of bilirubin into bile
- Formation of urobilins in the intestine
Colors of biliverdin, bilirubin, urobilinogen, stercolin, urobilin
Biliverdin: green Bilirubin: red orange Urobilinogen: colorless Stercolin: brown orange red Urobilin: yellow
Examples of unconjugated hyperbilirubinemia
Hemolytic anemia Physiologic jaundice Crigler-najjar syndrome types I and II Gilbert syndrome Toxic hyperbilirubinemia
Examples of conjugated hyperbilirubinemia
Biliary tree obstruction
Dubin-Johnson syndrome
Rotor syndrome
What reaction measures total and direct bilirubin?
Van den bergs reaction
What enzyme activates fatty acid for metabolism use?
Fatty-acyl-CoA synthetase
Cofactor required for fatty acid activation
Vitamin B5 or Panthotenic acid
Energy required to activate fatty acid
2 ATP
What is the product formed in fatty acid synthesis?
Palmitate (16:0)
Where does fatty acid synthesis occur?
Cytosol
Major: Liver and lactating mammary glands
Minor: adipose tissue
Substrates for fatty acid synthesis
1 acetyl CoA
7 malonyl CoA
NADPH
ATP
Rate limiting step in fatty acid synthesis
Acetyl CoA + ATP -> malonyl CoA
Enzyme: acetyl CoA carboxylase
Steps in fatty acid synthesis
- Synthesis of cytoplasmic acetyl CoA (transfer of mitochondrial acetyl CoA to cytoplasm via citrate shuttle)
- Acetyl CoA carboxylation to malonyl CoA (via acetyl CoA carboxylase with biotin) [+ insulin, citrate]
- Assembly of palmitate (via fatty acid synthase and Vit B5)
Steps in palmitate assembly
- Condensation
- Reduction
- Dehydration
- Reduction
What is the fate of Palmitate after its production?
- Further elongation in SER and mitochondria
2. Desaturated in the ER (but not past the 9th carbon)
Main storage form of fatty acids
Triacylglycerols
Where does TAG synthesis occur?
Liver and adipose tissue
Sources of glycerol-3-phosphate
- DHAP from glycolysis (liver and adipose)
2. Phosphorylation of free glycerol (liver)
What enzyme is responsible for the release of free fatty acids from TAGs?
Hormone sensitive lipases
In the bloodstream fatty acids are always bound to?
Albumin
Hormone sensitive lipases can only release what free fatty acids stored in TAG?
C1 & 3 thus resulting in
TAG -> 2 free FA and 2-mono acyl glycerol
Where does B-oxidation of fatty acids occur
Mitochondria of all cells, but the fatty acid activation raft occurs in the Cytosol
Exception: RBC, kidney medulla, neurons, testes
Rate limiting step in B-oxidation
Fatty acyl CoA + carnitine -> fatty acyl carnitine + CoA
Enzyme: carnitine acyl transferase I
Cutoff number of carbons that do not need a shuttle
Less than 12 carbons
Steps in the carnitine shuttle
- Fatty acyl synthase activates the fatty acid
- Carnitine acyl transferase 1 attaches to fatty acyl to carnitine in the outer mitochondrial membrane
- Fatty acyl-carnitine is shuttle through the inner membrane
- Carnitine acyl transferase-2 transfers fatty acyl group back to a CoA in the mitochondrial matrix
Steps in beta oxidation
- Oxidation
- Hydratiion
- Oxidation
- Thiolysis
Beta oxidation of fatty acids with an odd number of carbon atoms releases?
Propionyl CoA which is converted to methylmalonyl coa (requires B12) then to succinyl CoA
Which is responsible for the conversion of very long chain fatty acids?
Peroxisomes but if unsaturated it requires 3,2 enol-CoA isomerase
Energy yield in ATP of beta oxidation of palmitate
129 ATP
7 NADH= 21
7 FAD= 14
8 acetyl CoA= 96
Activation = -2
Intake of this compound depletes the body’s NAD+ supply leading to accumulation Of fat in the liver
Alcohol
Type of carnitine deficiency which leads to impaired FA oxidation and ketogenesis with hypoglycemia?
CPT-1 deficiency
Type of carnitine deficiency which affects skeletal muscle and when severe the liver
CPT-2 deficiency
It is a disorder school results in decreased fatty acid oxidation. Without the ATP to support gluconeogenesis, hypoglycemia becomes profound which may eventually leads to SIDS. It is prevented by frequent feeding with high carbohydrate and low fat diet.
Medium-chain fatty acyl-CoA dehydrogenase (MCAD) deficiency
Associated with eating unripe fruit of the akee tree which contains hypoglycin thus activating MC and SC acyl CoA dehydrogenase
Jamaican vomiting sickness
Rare neurological disorder which results to the accumulation of phytanic acid found in plant food stuff which blocks Boxidation
Refsum disease
Cerebrohepatorenal syndrome resulting from the absence of peroxisomes in all tissues, it is characterized by liver dysfunction, jaundice, MR, weakness, hypotonia, and craniofacial dimorphism
Zellweger syndrome
Defect in peroxismal activation of VLCFA thus leading to its accumulation. Ssx: apathy, behavral change, then visual loss spasticity, ataxia. All due to the fact since VLCFA are found in myelin tissue.
X-lied adrenoleukodystrophy
Where does ketogenesis occur?
Liver mitochondria
Products of ketogenesis
Acetoacetate and B-hydroxybutyrate (fuel)
Acetone (cannot be used as fuel)
Rate limiting step of ketogenesis
Acetoacetyl CoA + acetyl CoA –(HMG CoA synthase)–> HMG CoA
What are the initial products that lead to the formation of acetyl CoA in ketogenolysis?
B-hydroxybutyrate -> acetoacetate -> acetyl coa
What peripheral tissues can oxidize ketone bodes?
Those with mitochondria like the renal cortex, brain, and skeletal muscle
Why cant liver convert acetoacetate to acetyl CoA?
It lacks succinyl-CoA acetoacetyl-CoA reductase (thiophorase)
What is the Urine test for ketones? What ketone type does not it detect?
Nitroprusside test
Does not detect b-hydroxybutyrate
Which part of cholesterol can a fatty acid attach to form a cholesteryl ester?
Single hydroxyl group of carbon 3 of the alpha ring
Where does cholesterol synthesis occur?
All cells in the Cytosol and SER majority of which are found in the liver and intestines
Substrates of cholesterol synthesis
Acetyl CoA, NADPH, ATP
Rate limiting step in cholesterol synthesis
HMG CoA –(HMG CoA reductase)–> mevalonate
Steps in Cholestid synthesis
- Biosynthesis of mevalonate
- Formation of isoprenoid units
- Isoprene unit is formed from 6 isoprenoid units
- Formation of lanosterol
- Formation of cholesterol
How is the cholesterol ring eliminated?
Through conversion to bile salts then secretion to bile
Bile acid synthesis, found in the liver and Cytosol, rate limiting enzyme is?
Cholesterol-7-a-hydroxylase
What are the primary bile acids?
Cholic acid
Chenocholic acid
What are the two amino acids used in bile acid conjugation to form bile salts?
Taurine and glycine
What are the secondary bile acids?
Deoxycholic acid
Lithocholic acid
Where does steroid hormone synthesis occur?
SER of the adrenal glands, ovaries and testes, and placenta
What is blocked by the drug aminogluthetimide?
The conversion of cholesterol to pregnenolone by desmolase
The enzyme responsible for the breakdown of TAG to FA and:
A) 2-MAG from diet
B) FREE glycerol from chylomicrons and VLDL
C) 2-MAG from adipose
A) pancreatic lipase
B) Lipoprotein lipase
C) hormone sensitive lipase
Lipoprotein with the largest percentage of TG
Chylomicrons
Lipoprotein with the largest percentage of cholesteryl esters
LDL
Chylomicrons transport TG and cholesterol from where to where?
Intestines to tissues
VLDL transports TG from where to where?
Liver to tissues
What apoprotein activates lipoprotein lipase?
APO-CII
What apolipoprotein uptakes remnants by the liver?
APO E
Apolipoprotein B-48 is used by chylomicrons which are created by the?
Epithelial cells
What apolipoprotein is secreted by the liver for VDL?
B-100
How does IDL become LDL?
By picking up cholesterol from HD!
Which apoprotein delivers cholesterol into cells?
LDL
Which apolipoprotein is used by HDL to activate lecithin cholesterol acyl transferase or LCAT to produce cholesterol esters?
APO-A1
Difference between Type II familial hypercholesterolemia and type IV familial hypertriglyceredemia?
The former has high LDL leader to xanthomas and xanthelasmas with increased risk of atherosclerosis and CHD
The latter has increased VLDL production leading to a triad of
- DM type 2
- CAD
- Obesity
Phospholipid is composed of
DAG
Alcohol
Phosphodiester bond
Most abundant phospholipid which is important in nervous transmission
Phosphatidylcholine
Phospholipid playing a role in apoptosis
Phosphatidyl serine
Phospholipid that is a major component of surfactant?
Dipalmitoylphosphatidylcholine
Phospholipid reservoir for arachidonic acid in the membranes
Phosphatidylinositol
What phospholipid is essential in mitochondrial function which is also used as a non-troponemal test due to its ability to act as an antigen?
Cardiolipin
Composition of these glycolipids: Ceramide Cerebroside Globoside Ganglioside Sulfatide
Ceramide: sphingosine + FA
Ceramide + \_\_\_\_\_\_\_\_ Glucose or galactose = Cerebroside Oligosacchardide = Globoside N-acetylneuramic acid = Ganglioside Sulfated galactose = Sulfatide
Hexosaminidase a ficiency leading to Ssx like cherry red macula, MR, hypotonia
Tay-Sachs disease
A-galactosidase deficiency leading to 3Rs: recessive x-linked, rash, renal failure
Fabrys disease
B-glucosidase deficiency leading to hepatosplenomegaly and erosion of long bones
Gauchers dissease
Sphingomyelinase deficiency leading to hepatosplenomegaly
Nieman-pick disease
The set of all proteins expressed by an individual at a particular time
Proteome
Aims to identify the entire complement of proteins elaborated by a cell under diverse conditions
Proteomics
What amino acid is needed to form ALA in heme synthesis?
Glycine combined with succinyl CoA
Which amino acid carries nitrogen from the liver?
Alanine
Which amino acids are implicated in maple syrup disease
valine, lucine, isoleucine
What enzyme is responsible for the buildup of phenyl lactate, phenyl acetate, and phenylpyruvate?
Phenylalanine hydroxylase
What amino acid is the precursor for niacin, serotonin, and melatonin?
Serotonin
What is the amino acid precursor for homocysteine?
Methionine
What amino acid contributes to the fibrous structure of collagen and interrupts a-helices in globular proteins?
Proline
Increase of the combination of this Amino acid is responsible for the curly hair of people?
Cysteine + cysteine = cystine
Amino acids with sites for O-linked glycosylation in the Golgi apparatus?
Serine and threonine
Site for n-linked glycosylation in the ER
Asparagine
Amino acid deaminated by an enzyme which results in the formation of ammonia. This is the major carrier of nitrogen to the liver from peripheral tissues,
Glutaminase deaminates glutamine
Amino acid used in the determination for Folic acid deficiency. What is the test called?
Histidine used in the N-forminoglutamate excretion test
Increased amounts of FIGu in urine by Folic acid deficient individuals after histindine intake
Precursor amino acid for creatinine, urea, nitric oxide
Arginine
Essential amino acids that cannot be synthesized by the body and must come from the diet
PVT TIM HALL always ARGues and never TYRes
Phenylalanine, valine, tryptophan, threonine’ isoleucine, methionine, histidine, argenine, Leucine, Lysine
Heme is a complex of?
Protoporphorin IX and heme
What is the Bohr effect?
HBO2 + H+ HbH + O2
What is an oxidized for of HB (Fe 3+) that does not bind O2 readily which could lead to chocolate cyanosis ? It is treated with oral methylene blue or ascorbic acid up to IV methylene blue.
Methemoglobin
Hemoglobin bound to carbon monoxide instead of O2 leading to a cherry pink color.
Carboxyhemoglobin
HB bound to carbon dioxide is called
Carbaminohenoglobin
Classification of alpha and beta thalassemia
Alpha: silent carrier, a-thalassemia trait, Hb H disease, hydrops fetalis
Beta: B-thalassemia minor and major
Most frequently affected collagen in Ehler Danlos syndrome leading to hyper extensible skin, tendency to bleed, hyper mobile joints, and increased risk for berry aneurysms.
Collagen type 3
Collagen I mutation leading to bendable and easily fractured bones. Accompanied with blue sclerae, hearing loss, and dental imperfections.
Osteogenesis imperfecta
Vitamin C deficiency leading to decreased hydroxylation of collagen. This leads to sore spongy gums, loose teeth, poor wound healing, and petecchiae on skin and mucous membranes.
Scurvy
Type IV collagen defect leading to hematuria and ESRD
Alpert syndrome
Collagen defect leading to kinky hair due to a deficiency of copper required by lysyl oxidase to strengthen collagen fibers.
Menke syndrome
Skin breaking and blisters as a result for minor trauma. This disease is due to a defect in collage VII.
Epidermolysis bullosa
Like collagen elastin has pro line and Lysine but has little and no?
Hydroxyproline
Hydroxylysine
Protein degradation mechanisms of nitrogen
Energy dependent ubiquitin-proteosome mechanism
Non-energy dependent degradation enzyme
Phases in amino acid catabolism
First phase: removal of a-amino group forming ammonia and a corresponding ketoacid
Second phase: carbon skeletons of a-ketoacids are converted to common intermediates of energy producing metabolic pathwas
Two main steps in nitrogen removal from AA
- Transamination
2. Oxidative deamination
Where does transamination occur?
All cells of the body
All but two amino acids transfer their amino groups to a-ketoglutarate except?
Lysine and threonine
What is the coenzyme for the two aminotransferases?
Pyridoxal phosphate (vitamin B6)
Oxidative deamination occurs where and for which amino acid only?
Liver and kidney
Only glutamate
Glutamate is oxidized by glutamate dehydrogenases and deaminated to form ?
free ammonia which is used to make urea
What does the conversion of glutamate to a-ketoglutarate yield? What about vice versa?
Glutamate -> a ketoglutarate NH3 + NADH
A ketoglutarate -> glutamate NADP+ + NH3
How is excess nitrogen removal from peripheral tissues removed?
- Glutamine: via glutamate + ammonia (through Flutamide synthaetase)
- Alanine: via glucose -> pyruvate + glutamate -> alanine cycle
Glutaminase deaminates glutamine to produce ammonium ion which is excreted from the body. Where are the two tissues this enzyme could be located?
Kidneys and small intestines
Another name for urea cycle
Ornithine cycle or krebs-henseleit cycle
What are the donors of the urea molecule?
- NH3 from free ammonia
- NH3 from aspartate
- 1C and 1O from CO2
Reactions in the urea cycle
- Formation of carbamoyl phosphate (via carbamoyl phosphate synthetase I)
- Formation of citrulline (via Ornithine transcarbamoylase)
- Synthesis of arginosuccinate (arginosuccinate synthetase)
- Cleavage of arginosuccinate to form arginine (Arginosuccinase)
- Arginine cleavage to yield urea and Ornithine (arginase)
Rate limiting step of urea cycle
Carbamoyl phosphate synthetase I
Energy requirement of urea cycle
4 ATP
Co factors of urea cycle
N-acetylglutamate
Biotin
Hereditary hyperammonemia produces symptoms such as
Hyperammonemia, elevated blood glutamine, decreased BUN
Parents with lethargy, vomiting, hyperventilation, convulsions, cerebral edema, coma, and death
Treatment for hereditary hyperammonemia
Low protein diet
Administration of sodium benzoate or phenylpyruvate to capture and excrete excess nitrogen
What reaction measures total and direct bilirubin?
Van den bergs reaction
Examples of conjugated hyperbilirubinemia
Biliary tree obstruction
Dubin-Johnson syndrome
Rotor syndrome
Examples of unconjugated hyperbilirubinemia
Hemolytic anemia Physiologic jaundice Crigler-najjar syndrome types I and II Gilbert syndrome Toxic hyperbilirubinemia
Colors of biliverdin, bilirubin, urobilinogen, stercolin, urobilin
Biliverdin: green Bilirubin: red orange Urobilinogen: colorless Stercolin: brown orange red Urobilin: yellow
Summary of heme degradation
- Formation of bilirubin
- Uptake of bilirubin by the liver
- Formation of bilirubin diglucoronide
- Secretion of bilirubin into bile
- Formation of urobilins in the intestine
Increase in MCHC is found in
Hereditary spherocytosis
Normoyctic normochromic anemia is found in
Anemia of chronic kidney disease
Blood loss
Megaloblastic anemia is found in
Folate or B12 deficiency
Pernicious anemia
Microcytic hypo chromic anemia is found in
IDA
Thalassemia
Lead poisoning
Poisoning due to this heavy metal leads to coar basophilic stippling of RBC, peripheral neuropathy, lines in gums, increas in urinary ALA and free erythrocytes porphorin
lead poisoning
Pyridoxine ficiency associated with isoniazid therapy results in this histopathologic finding
Sideroblastic anemia with ringed sideroblast
Which part of heme synthesis do these symptoms appear?
- Photosensitivity
- Neuropsychiatric symptoms
- After ring formation
2. Before ring formation
Most common porphyria
Porphyria cutanea tarda
Where is B6 a cofactors of?
- Heme synthesis
- Synthesis of cystathionine from homocysteine
- Transamination between alanine and a-ketoglutarate
Lead inhibits what two steps in heme synthesis?
- Introduction of Fe 2+ into protoporphyrin IX via ferrochelatase
- Condensation of two ALA molecules by zinc containing ALA dehydratase
Heme synthesis summary
- Formation of ALA (via ALA synthase and B6)
- Formation of porphobilinogen
- Formation of uroporphyrinogen
- Formation of heme
The initial and last three steps of heme synthesis occurs in?
The mitochondria
Common inherited defect of renal tubular amino acid transporter for its parent compound, Ornithine, Lysine, and arginine, in the PCT of the kidneys. It eventually precipitates and cause staghorn caliculi. What is its treatment?
Cystinuria is treated with acetazolamide to alkalinize the urine
Autosomal recessive disorder that may either be due to decreased methionine, increased cysteine, B6, and folate or decreased affinity for cystathione synthase. This results in mental retardation, osteoporosis, tall stature, lens subluxation, and atherosclerosis.
Homocystinuria
Congenital deficiency due tyrosinase deficieny or defective tyrosine transporters which leads to an increased risk for skin cancer.
Albinism
Deficiency of homogenistic acid oxidase in the degrative pathway of tyrosine which results in urine turning to black on standing with dark connective tissues (ochronosis)
Alkaptonuria
3 hormones dependent on tyrosine
Thyroid hormones
Melanin
Catecholamines
This amino acid acts as a raw material in the biosynthesis of catecholamines, thyroid hormones, melanin
Tyrosine
This amino acid acts as a raw material in the biosynthesis of serotonin, NAD+, NADP+, melatonin
Tryptophan
This amino acid acts as a raw material in the biosynthesis of creatine, polyamines, nitric oxide
Arginine
This amino acid acts as a raw material in the biosynthesis of GABA
Glutamate
This amino acid acts as a raw material in the biosynthesis of phospholipid, sphingolipid, purines, thymine
Serine
This amino acid acts as a raw material in the biosynthesis of Heme, purines, creatine
Glycine
Ketogenic and glucogenic carbon skeletons of AA
WIFY Phenylalanine Isoleucine Tryptophan Tyrosine
Yields Ketogenic and glucose or glycogen by products
Ketogenic carbon skeletons of AA
Leucine
Lysine
Yields acetoacetate or acetyl-coa/ acetoacetyl-coa
What enzyme activates fatty acid for metabolism use?
Fatty-acyl-CoA synthetase
Cofactor required for fatty acid activation
Vitamin B5 or Panthotenic acid
Energy required to activate fatty acid
2 ATP
What is the product formed in fatty acid synthesis?
Palmitate (16:0)
Where does fatty acid synthesis occur?
Cytosol
Major: Liver and lactating mammary glands
Minor: adipose tissue
Substrates for fatty acid synthesis
1 acetyl CoA
7 malonyl CoA
NADPH
ATP
Rate limiting step in fatty acid synthesis
Acetyl CoA + ATP -> malonyl CoA
Enzyme: acetyl CoA carboxylase
Steps in fatty acid synthesis
- Synthesis of cytoplasmic acetyl CoA (transfer of mitochondrial acetyl CoA to cytoplasm via citrate shuttle)
- Acetyl CoA carboxylation to malonyl CoA (via acetyl CoA carboxylase with biotin) [+ insulin, citrate]
- Assembly of palmitate (via fatty acid synthase and Vit B5)
Steps in palmitate assembly
- Condensation
- Reduction
- Dehydration
- Reduction
What is the fate of Palmitate after its production?
- Further elongation in SER and mitochondria
2. Desaturated in the ER (but not past the 9th carbon)
Main storage form of fatty acids
Triacylglycerols
Where does TAG synthesis occur?
Liver and adipose tissue
Sources of glycerol-3-phosphate
- DHAP from glycolysis (liver and adipose)
2. Phosphorylation of free glycerol (liver)
What enzyme is responsible for the release of free fatty acids from TAGs?
Hormone sensitive lipases
In the bloodstream fatty acids are always bound to?
Albumin
Hormone sensitive lipases can only release what free fatty acids stored in TAG?
C1 & 3 thus resulting in
TAG -> 2 free FA and 2-mono acyl glycerol
Where does B-oxidation of fatty acids occur
Mitochondria of all cells, but the fatty acid activation raft occurs in the Cytosol
Exception: RBC, kidney medulla, neurons, testes
Rate limiting step in B-oxidation
Fatty acyl CoA + carnitine -> fatty acyl carnitine + CoA
Enzyme: carnitine acyl transferase I
Cutoff number of carbons that do not need a shuttle
Less than 12 carbons
Steps in the carnitine shuttle
- Fatty acyl synthase activates the fatty acid
- Carnitine acyl transferase 1 attaches to fatty acyl to carnitine in the outer mitochondrial membrane
- Fatty acyl-carnitine is shuttle through the inner membrane
- Carnitine acyl transferase-2 transfers fatty acyl group back to a CoA in the mitochondrial matrix
Steps in beta oxidation
- Oxidation
- Hydratiion
- Oxidation
- Thiolysis
Beta oxidation of fatty acids with an odd number of carbon atoms releases?
Propionyl CoA which is converted to methylmalonyl coa (requires B12) then to succinyl CoA
Which is responsible for the conversion of very long chain fatty acids?
Peroxisomes but if unsaturated it requires 3,2 enol-CoA isomerase
Energy yield in ATP of beta oxidation of palmitate
129 ATP
7 NADH= 21
7 FAD= 14
8 acetyl CoA= 96
Activation = -2
Intake of this compound depletes the body’s NAD+ supply leading to accumulation Of fat in the liver
Alcohol
Type of carnitine deficiency which leads to impaired FA oxidation and ketogenesis with hypoglycemia?
CPT-1 deficiency
Type of carnitine deficiency which affects skeletal muscle and when severe the liver
CPT-2 deficiency
It is a disorder school results in decreased fatty acid oxidation. Without the ATP to support gluconeogenesis, hypoglycemia becomes profound which may eventually leads to SIDS. It is prevented by frequent feeding with high carbohydrate and low fat diet.
Medium-chain fatty acyl-CoA dehydrogenase (MCAD) deficiency
Associated with eating unripe fruit of the akee tree which contains hypoglycin thus activating MC and SC acyl CoA dehydrogenase
Jamaican vomiting sickness
Rare neurological disorder which results to the accumulation of phytanic acid found in plant food stuff which blocks Boxidation
Refsum disease
Cerebrohepatorenal syndrome resulting from the absence of peroxisomes in all tissues, it is characterized by liver dysfunction, jaundice, MR, weakness, hypotonia, and craniofacial dimorphism
Zellweger syndrome
Defect in peroxismal activation of VLCFA thus leading to its accumulation. Ssx: apathy, behavral change, then visual loss spasticity, ataxia. All due to the fact since VLCFA are found in myelin tissue.
X-lied adrenoleukodystrophy
Where does ketogenesis occur?
Liver mitochondria
Products of ketogenesis
Acetoacetate and B-hydroxybutyrate (fuel)
Acetone (cannot be used as fuel)
Rate limiting step of ketogenesis
Acetoacetyl CoA + acetyl CoA –(HMG CoA synthase)–> HMG CoA
What are the initial products that lead to the formation of acetyl CoA in ketogenolysis?
B-hydroxybutyrate -> acetoacetate -> acetyl coa
What peripheral tissues can oxidize ketone bodes?
Those with mitochondria like the renal cortex, brain, and skeletal muscle
Why cant liver convert acetoacetate to acetyl CoA?
It lacks succinyl-CoA acetoacetyl-CoA reductase (thiophorase)
What is the Urine test for ketones? What ketone type does not it detect?
Nitroprusside test
Does not detect b-hydroxybutyrate
Which part of cholesterol can a fatty acid attach to form a cholesteryl ester?
Single hydroxyl group of carbon 3 of the alpha ring
Where does cholesterol synthesis occur?
All cells in the Cytosol and SER majority of which are found in the liver and intestines
Substrates of cholesterol synthesis
Acetyl CoA, NADPH, ATP
Rate limiting step in cholesterol synthesis
HMG CoA –(HMG CoA reductase)–> mevalonate
Steps in Cholestid synthesis
- Biosynthesis of mevalonate
- Formation of isoprenoid units
- Isoprene unit is formed from 6 isoprenoid units
- Formation of lanosterol
- Formation of cholesterol
How is the cholesterol ring eliminated?
Through conversion to bile salts then secretion to bile
Bile acid synthesis, found in the liver and Cytosol, rate limiting enzyme is?
Cholesterol-7-a-hydroxylase
What are the primary bile acids?
Cholic acid
Chenocholic acid
What are the two amino acids used in bile acid conjugation to form bile salts?
Taurine and glycine
What are the secondary bile acids?
Deoxycholic acid
Lithocholic acid
Where does steroid hormone synthesis occur?
SER of the adrenal glands, ovaries and testes, and placenta
What is blocked by the drug aminogluthetimide?
The conversion of cholesterol to pregnenolone by desmolase
The enzyme responsible for the breakdown of TAG to FA and:
A) 2-MAG from diet
B) FREE glycerol from chylomicrons and VLDL
C) 2-MAG from adipose
A) pancreatic lipase
B) Lipoprotein lipase
C) hormone sensitive lipase
Lipoprotein with the largest percentage of TG
Chylomicrons
Lipoprotein with the largest percentage of cholesteryl esters
LDL
Chylomicrons transport TG and cholesterol from where to where?
Intestines to tissues
VLDL transports TG from where to where?
Liver to tissues
What apoprotein activates lipoprotein lipase?
APO-CII
What apolipoprotein uptakes remnants by the liver?
APO E
Apolipoprotein B-48 is used by chylomicrons which are created by the?
Epithelial cells
What apolipoprotein is secreted by the liver for VDL?
B-100
How does IDL become LDL?
By picking up cholesterol from HD!
Which apoprotein delivers cholesterol into cells?
LDL
Which apolipoprotein is used by HDL to activate lecithin cholesterol acyl transferase or LCAT to produce cholesterol esters?
APO-A1
Difference between Type II familial hypercholesterolemia and type IV familial hypertriglyceredemia?
The former has high LDL leader to xanthomas and xanthelasmas with increased risk of atherosclerosis and CHD
The latter has increased VLDL production leading to a triad of
- DM type 2
- CAD
- Obesity
Phospholipid is composed of
DAG
Alcohol
Phosphodiester bond
Most abundant phospholipid which is important in nervous transmission
Phosphatidylcholine
Phospholipid playing a role in apoptosis
Phosphatidyl serine
Phospholipid that is a major component of surfactant?
Dipalmitoylphosphatidylcholine
Phospholipid reservoir for arachidonic acid in the membranes
Phosphatidylinositol
What phospholipid is essential in mitochondrial function which is also used as a non-troponemal test due to its ability to act as an antigen?
Cardiolipin
Composition of these glycolipids: Ceramide Cerebroside Globoside Ganglioside Sulfatide
Ceramide: sphingosine + FA
Ceramide + \_\_\_\_\_\_\_\_ Glucose or galactose = Cerebroside Oligosacchardide = Globoside N-acetylneuramic acid = Ganglioside Sulfated galactose = Sulfatide
Hexosaminidase a ficiency leading to Ssx like cherry red macula, MR, hypotonia
Tay-Sachs disease
A-galactosidase deficiency leading to 3Rs: recessive x-linked, rash, renal failure
Fabrys disease
B-glucosidase deficiency leading to hepatosplenomegaly and erosion of long bones
Gauchers dissease
Sphingomyelinase deficiency leading to hepatosplenomegaly
Nieman-pick disease
The set of all proteins expressed by an individual at a particular time
Proteome
Aims to identify the entire complement of proteins elaborated by a cell under diverse conditions
Proteomics
What amino acid is needed to form ALA in heme synthesis?
Glycine combined with succinyl CoA
Which amino acid carries nitrogen from the liver?
Alanine
Which amino acids are implicated in maple syrup disease
valine, lucine, isoleucine
What enzyme is responsible for the buildup of phenyl lactate, phenyl acetate, and phenylpyruvate?
Phenylalanine hydroxylase
What amino acid is the precursor for niacin, serotonin, and melatonin?
Serotonin
What is the amino acid precursor for homocysteine?
Methionine
What amino acid contributes to the fibrous structure of collagen and interrupts a-helices in globular proteins?
Proline
Increase of the combination of this Amino acid is responsible for the curly hair of people?
Cysteine + cysteine = cystine
Amino acids with sites for O-linked glycosylation in the Golgi apparatus?
Serine and threonine
Site for n-linked glycosylation in the ER
Asparagine
Amino acid deaminated by an enzyme which results in the formation of ammonia. This is the major carrier of nitrogen to the liver from peripheral tissues,
Glutaminase deaminates glutamine
Amino acid used in the determination for Folic acid deficiency. What is the test called?
Histidine used in the N-forminoglutamate excretion test
Increased amounts of FIGu in urine by Folic acid deficient individuals after histindine intake
Precursor amino acid for creatinine, urea, nitric oxide
Arginine
Essential amino acids that cannot be synthesized by the body and must come from the diet
PVT TIM HALL always ARGues and never TYRes
Phenylalanine, valine, tryptophan, threonine’ isoleucine, methionine, histidine, argenine, Leucine, Lysine
Heme is a complex of?
Protoporphorin IX and heme
What is the Bohr effect?
HBO2 + H+ HbH + O2
What is an oxidized for of HB (Fe 3+) that does not bind O2 readily which could lead to chocolate cyanosis ? It is treated with oral methylene blue or ascorbic acid up to IV methylene blue.
Methemoglobin
Hemoglobin bound to carbon monoxide instead of O2 leading to a cherry pink color.
Carboxyhemoglobin
HB bound to carbon dioxide is called
Carbaminohenoglobin
Classification of alpha and beta thalassemia
Alpha: silent carrier, a-thalassemia trait, Hb H disease, hydrops fetalis
Beta: B-thalassemia minor and major
Most frequently affected collagen in Ehler Danlos syndrome leading to hyper extensible skin, tendency to bleed, hyper mobile joints, and increased risk for berry aneurysms.
Collagen type 3
Collagen I mutation leading to bendable and easily fractured bones. Accompanied with blue sclerae, hearing loss, and dental imperfections.
Osteogenesis imperfecta
Vitamin C deficiency leading to decreased hydroxylation of collagen. This leads to sore spongy gums, loose teeth, poor wound healing, and petecchiae on skin and mucous membranes.
Scurvy
Type IV collagen defect leading to hematuria and ESRD
Alpert syndrome
Collagen defect leading to kinky hair due to a deficiency of copper required by lysyl oxidase to strengthen collagen fibers.
Menke syndrome
Skin breaking and blisters as a result for minor trauma. This disease is due to a defect in collage VII.
Epidermolysis bullosa
Like collagen elastin has pro line and Lysine but has little and no?
Hydroxyproline
Hydroxylysine
Protein degradation mechanisms of nitrogen
Energy dependent ubiquitin-proteosome mechanism
Non-energy dependent degradation enzyme
Phases in amino acid catabolism
First phase: removal of a-amino group forming ammonia and a corresponding ketoacid
Second phase: carbon skeletons of a-ketoacids are converted to common intermediates of energy producing metabolic pathwas
Two main steps in nitrogen removal from AA
- Transamination
2. Oxidative deamination
Where does transamination occur?
All cells of the body
All but two amino acids transfer their amino groups to a-ketoglutarate except?
Lysine and threonine
What is the coenzyme for the two aminotransferases?
Pyridoxal phosphate (vitamin B6)
Oxidative deamination occurs where and for which amino acid only?
Liver and kidney
Only glutamate
Glutamate is oxidized by glutamate dehydrogenases and deaminated to form ?
free ammonia which is used to make urea
What does the conversion of glutamate to a-ketoglutarate yield? What about vice versa?
Glutamate -> a ketoglutarate NH3 + NADH
A ketoglutarate -> glutamate NADP+ + NH3
How is excess nitrogen removal from peripheral tissues removed?
- Glutamine: via glutamate + ammonia (through Flutamide synthaetase)
- Alanine: via glucose -> pyruvate + glutamate -> alanine cycle
Glutaminase deaminates glutamine to produce ammonium ion which is excreted from the body. Where are the two tissues this enzyme could be located?
Kidneys and small intestines
Another name for urea cycle
Ornithine cycle or krebs-henseleit cycle
What are the donors of the urea molecule?
- NH3 from free ammonia
- NH3 from aspartate
- 1C and 1O from CO2
Reactions in the urea cycle
- Formation of carbamoyl phosphate (via carbamoyl phosphate synthetase I)
- Formation of citrulline (via Ornithine transcarbamoylase)
- Synthesis of arginosuccinate (arginosuccinate synthetase)
- Cleavage of arginosuccinate to form arginine (Arginosuccinase)
- Arginine cleavage to yield urea and Ornithine (arginase)
Rate limiting step of urea cycle
Carbamoyl phosphate synthetase I
Energy requirement of urea cycle
4 ATP
Co factors of urea cycle
N-acetylglutamate
Biotin
Hereditary hyperammonemia produces symptoms such as
Hyperammonemia, elevated blood glutamine, decreased BUN
Parents with lethargy, vomiting, hyperventilation, convulsions, cerebral edema, coma, and death
Treatment for hereditary hyperammonemia
Low protein diet
Administration of sodium benzoate or phenylpyruvate to capture and excrete excess nitrogen
Ketogenic carbon skeletons of AA
Leucine
Lysine
Yields acetoacetate or acetyl-coa/ acetoacetyl-coa
Ketogenic and glucogenic carbon skeletons of AA
WIFY Phenylalanine Isoleucine Tryptophan Tyrosine
Yields Ketogenic and glucose or glycogen by products
This amino acid acts as a raw material in the biosynthesis of Heme, purines, creatine
Glycine
This amino acid acts as a raw material in the biosynthesis of phospholipid, sphingolipid, purines, thymine
Serine
This amino acid acts as a raw material in the biosynthesis of GABA
Glutamate
This amino acid acts as a raw material in the biosynthesis of creatine, polyamines, nitric oxide
Arginine
This amino acid acts as a raw material in the biosynthesis of serotonin, NAD+, NADP+, melatonin
Tryptophan
This amino acid acts as a raw material in the biosynthesis of catecholamines, thyroid hormones, melanin
Tyrosine
3 hormones dependent on tyrosine
Thyroid hormones
Melanin
Catecholamines
Deficiency of homogenistic acid oxidase in the degrative pathway of tyrosine which results in urine turning to black on standing with dark connective tissues (ochronosis)
Alkaptonuria
Congenital deficiency due tyrosinase deficieny or defective tyrosine transporters which leads to an increased risk for skin cancer.
Albinism
Autosomal recessive disorder that may either be due to decreased methionine, increased cysteine, B6, and folate or decreased affinity for cystathione synthase. This results in mental retardation, osteoporosis, tall stature, lens subluxation, and atherosclerosis.
Homocystinuria
What reaction measures total and direct bilirubin?
Van den bergs reaction
Examples of conjugated hyperbilirubinemia
Biliary tree obstruction
Dubin-Johnson syndrome
Rotor syndrome
Examples of unconjugated hyperbilirubinemia
Hemolytic anemia Physiologic jaundice Crigler-najjar syndrome types I and II Gilbert syndrome Toxic hyperbilirubinemia
Colors of biliverdin, bilirubin, urobilinogen, stercolin, urobilin
Biliverdin: green Bilirubin: red orange Urobilinogen: colorless Stercolin: brown orange red Urobilin: yellow
Summary of heme degradation
- Formation of bilirubin
- Uptake of bilirubin by the liver
- Formation of bilirubin diglucoronide
- Secretion of bilirubin into bile
- Formation of urobilins in the intestine
Increase in MCHC is found in
Hereditary spherocytosis
Normoyctic normochromic anemia is found in
Anemia of chronic kidney disease
Blood loss
Megaloblastic anemia is found in
Folate or B12 deficiency
Pernicious anemia
Microcytic hypo chromic anemia is found in
IDA
Thalassemia
Lead poisoning
Poisoning due to this heavy metal leads to coar basophilic stippling of RBC, peripheral neuropathy, lines in gums, increas in urinary ALA and free erythrocytes porphorin
lead poisoning
Pyridoxine ficiency associated with isoniazid therapy results in this histopathologic finding
Sideroblastic anemia with ringed sideroblast
Which part of heme synthesis do these symptoms appear?
- Photosensitivity
- Neuropsychiatric symptoms
- After ring formation
2. Before ring formation
Most common porphyria
Porphyria cutanea tarda
Where is B6 a cofactors of?
- Heme synthesis
- Synthesis of cystathionine from homocysteine
- Transamination between alanine and a-ketoglutarate
Lead inhibits what two steps in heme synthesis?
- Introduction of Fe 2+ into protoporphyrin IX via ferrochelatase
- Condensation of two ALA molecules by zinc containing ALA dehydratase
Heme synthesis summary
- Formation of ALA (via ALA synthase and B6)
- Formation of porphobilinogen
- Formation of uroporphyrinogen
- Formation of heme
The initial and last three steps of heme synthesis occurs in?
The mitochondria
Common inherited defect of renal tubular amino acid transporter for its parent compound, Ornithine, Lysine, and arginine, in the PCT of the kidneys. It eventually precipitates and cause staghorn caliculi. What is its treatment?
Cystinuria is treated with acetazolamide to alkalinize the urine
What enzyme activates fatty acid for metabolism use?
Fatty-acyl-CoA synthetase
Cofactor required for fatty acid activation
Vitamin B5 or Panthotenic acid
Energy required to activate fatty acid
2 ATP
What is the product formed in fatty acid synthesis?
Palmitate (16:0)
Where does fatty acid synthesis occur?
Cytosol
Major: Liver and lactating mammary glands
Minor: adipose tissue
Substrates for fatty acid synthesis
1 acetyl CoA
7 malonyl CoA
NADPH
ATP
Rate limiting step in fatty acid synthesis
Acetyl CoA + ATP -> malonyl CoA
Enzyme: acetyl CoA carboxylase
Steps in fatty acid synthesis
- Synthesis of cytoplasmic acetyl CoA (transfer of mitochondrial acetyl CoA to cytoplasm via citrate shuttle)
- Acetyl CoA carboxylation to malonyl CoA (via acetyl CoA carboxylase with biotin) [+ insulin, citrate]
- Assembly of palmitate (via fatty acid synthase and Vit B5)
Steps in palmitate assembly
- Condensation
- Reduction
- Dehydration
- Reduction
What is the fate of Palmitate after its production?
- Further elongation in SER and mitochondria
2. Desaturated in the ER (but not past the 9th carbon)
Main storage form of fatty acids
Triacylglycerols
Where does TAG synthesis occur?
Liver and adipose tissue
Sources of glycerol-3-phosphate
- DHAP from glycolysis (liver and adipose)
2. Phosphorylation of free glycerol (liver)
What enzyme is responsible for the release of free fatty acids from TAGs?
Hormone sensitive lipases
In the bloodstream fatty acids are always bound to?
Albumin
Hormone sensitive lipases can only release what free fatty acids stored in TAG?
C1 & 3 thus resulting in
TAG -> 2 free FA and 2-mono acyl glycerol
Where does B-oxidation of fatty acids occur
Mitochondria of all cells, but the fatty acid activation raft occurs in the Cytosol
Exception: RBC, kidney medulla, neurons, testes
Rate limiting step in B-oxidation
Fatty acyl CoA + carnitine -> fatty acyl carnitine + CoA
Enzyme: carnitine acyl transferase I
Cutoff number of carbons that do not need a shuttle
Less than 12 carbons
Steps in the carnitine shuttle
- Fatty acyl synthase activates the fatty acid
- Carnitine acyl transferase 1 attaches to fatty acyl to carnitine in the outer mitochondrial membrane
- Fatty acyl-carnitine is shuttle through the inner membrane
- Carnitine acyl transferase-2 transfers fatty acyl group back to a CoA in the mitochondrial matrix
Steps in beta oxidation
- Oxidation
- Hydratiion
- Oxidation
- Thiolysis
Beta oxidation of fatty acids with an odd number of carbon atoms releases?
Propionyl CoA which is converted to methylmalonyl coa (requires B12) then to succinyl CoA
Which is responsible for the conversion of very long chain fatty acids?
Peroxisomes but if unsaturated it requires 3,2 enol-CoA isomerase
Energy yield in ATP of beta oxidation of palmitate
129 ATP
7 NADH= 21
7 FAD= 14
8 acetyl CoA= 96
Activation = -2
Intake of this compound depletes the body’s NAD+ supply leading to accumulation Of fat in the liver
Alcohol
Type of carnitine deficiency which leads to impaired FA oxidation and ketogenesis with hypoglycemia?
CPT-1 deficiency
Type of carnitine deficiency which affects skeletal muscle and when severe the liver
CPT-2 deficiency
It is a disorder school results in decreased fatty acid oxidation. Without the ATP to support gluconeogenesis, hypoglycemia becomes profound which may eventually leads to SIDS. It is prevented by frequent feeding with high carbohydrate and low fat diet.
Medium-chain fatty acyl-CoA dehydrogenase (MCAD) deficiency
Associated with eating unripe fruit of the akee tree which contains hypoglycin thus activating MC and SC acyl CoA dehydrogenase
Jamaican vomiting sickness
Rare neurological disorder which results to the accumulation of phytanic acid found in plant food stuff which blocks Boxidation
Refsum disease
Cerebrohepatorenal syndrome resulting from the absence of peroxisomes in all tissues, it is characterized by liver dysfunction, jaundice, MR, weakness, hypotonia, and craniofacial dimorphism
Zellweger syndrome
Defect in peroxismal activation of VLCFA thus leading to its accumulation. Ssx: apathy, behavral change, then visual loss spasticity, ataxia. All due to the fact since VLCFA are found in myelin tissue.
X-lied adrenoleukodystrophy
Where does ketogenesis occur?
Liver mitochondria
Products of ketogenesis
Acetoacetate and B-hydroxybutyrate (fuel)
Acetone (cannot be used as fuel)
Rate limiting step of ketogenesis
Acetoacetyl CoA + acetyl CoA –(HMG CoA synthase)–> HMG CoA
What are the initial products that lead to the formation of acetyl CoA in ketogenolysis?
B-hydroxybutyrate -> acetoacetate -> acetyl coa
What peripheral tissues can oxidize ketone bodes?
Those with mitochondria like the renal cortex, brain, and skeletal muscle
Why cant liver convert acetoacetate to acetyl CoA?
It lacks succinyl-CoA acetoacetyl-CoA reductase (thiophorase)
What is the Urine test for ketones? What ketone type does not it detect?
Nitroprusside test
Does not detect b-hydroxybutyrate
Which part of cholesterol can a fatty acid attach to form a cholesteryl ester?
Single hydroxyl group of carbon 3 of the alpha ring
Where does cholesterol synthesis occur?
All cells in the Cytosol and SER majority of which are found in the liver and intestines
Substrates of cholesterol synthesis
Acetyl CoA, NADPH, ATP
Rate limiting step in cholesterol synthesis
HMG CoA –(HMG CoA reductase)–> mevalonate
Steps in Cholestid synthesis
- Biosynthesis of mevalonate
- Formation of isoprenoid units
- Isoprene unit is formed from 6 isoprenoid units
- Formation of lanosterol
- Formation of cholesterol
How is the cholesterol ring eliminated?
Through conversion to bile salts then secretion to bile
Bile acid synthesis, found in the liver and Cytosol, rate limiting enzyme is?
Cholesterol-7-a-hydroxylase
What are the primary bile acids?
Cholic acid
Chenocholic acid
What are the two amino acids used in bile acid conjugation to form bile salts?
Taurine and glycine
What are the secondary bile acids?
Deoxycholic acid
Lithocholic acid
Where does steroid hormone synthesis occur?
SER of the adrenal glands, ovaries and testes, and placenta
What is blocked by the drug aminogluthetimide?
The conversion of cholesterol to pregnenolone by desmolase
The enzyme responsible for the breakdown of TAG to FA and:
A) 2-MAG from diet
B) FREE glycerol from chylomicrons and VLDL
C) 2-MAG from adipose
A) pancreatic lipase
B) Lipoprotein lipase
C) hormone sensitive lipase
Lipoprotein with the largest percentage of TG
Chylomicrons
Lipoprotein with the largest percentage of cholesteryl esters
LDL
Chylomicrons transport TG and cholesterol from where to where?
Intestines to tissues
VLDL transports TG from where to where?
Liver to tissues
What apoprotein activates lipoprotein lipase?
APO-CII
What apolipoprotein uptakes remnants by the liver?
APO E
Apolipoprotein B-48 is used by chylomicrons which are created by the?
Epithelial cells
What apolipoprotein is secreted by the liver for VDL?
B-100
How does IDL become LDL?
By picking up cholesterol from HD!
Which apoprotein delivers cholesterol into cells?
LDL
Which apolipoprotein is used by HDL to activate lecithin cholesterol acyl transferase or LCAT to produce cholesterol esters?
APO-A1
Difference between Type II familial hypercholesterolemia and type IV familial hypertriglyceredemia?
The former has high LDL leader to xanthomas and xanthelasmas with increased risk of atherosclerosis and CHD
The latter has increased VLDL production leading to a triad of
- DM type 2
- CAD
- Obesity
Phospholipid is composed of
DAG
Alcohol
Phosphodiester bond
Most abundant phospholipid which is important in nervous transmission
Phosphatidylcholine
Phospholipid playing a role in apoptosis
Phosphatidyl serine
Phospholipid that is a major component of surfactant?
Dipalmitoylphosphatidylcholine
Phospholipid reservoir for arachidonic acid in the membranes
Phosphatidylinositol
What phospholipid is essential in mitochondrial function which is also used as a non-troponemal test due to its ability to act as an antigen?
Cardiolipin
Composition of these glycolipids: Ceramide Cerebroside Globoside Ganglioside Sulfatide
Ceramide: sphingosine + FA
Ceramide + \_\_\_\_\_\_\_\_ Glucose or galactose = Cerebroside Oligosacchardide = Globoside N-acetylneuramic acid = Ganglioside Sulfated galactose = Sulfatide
Hexosaminidase a ficiency leading to Ssx like cherry red macula, MR, hypotonia
Tay-Sachs disease
A-galactosidase deficiency leading to 3Rs: recessive x-linked, rash, renal failure
Fabrys disease
B-glucosidase deficiency leading to hepatosplenomegaly and erosion of long bones
Gauchers dissease
Sphingomyelinase deficiency leading to hepatosplenomegaly
Nieman-pick disease
The set of all proteins expressed by an individual at a particular time
Proteome
Aims to identify the entire complement of proteins elaborated by a cell under diverse conditions
Proteomics
What amino acid is needed to form ALA in heme synthesis?
Glycine combined with succinyl CoA
Which amino acid carries nitrogen from the liver?
Alanine
Which amino acids are implicated in maple syrup disease
valine, lucine, isoleucine
What enzyme is responsible for the buildup of phenyl lactate, phenyl acetate, and phenylpyruvate?
Phenylalanine hydroxylase
What amino acid is the precursor for niacin, serotonin, and melatonin?
Serotonin
What is the amino acid precursor for homocysteine?
Methionine
What amino acid contributes to the fibrous structure of collagen and interrupts a-helices in globular proteins?
Proline
Increase of the combination of this Amino acid is responsible for the curly hair of people?
Cysteine + cysteine = cystine
Amino acids with sites for O-linked glycosylation in the Golgi apparatus?
Serine and threonine
Site for n-linked glycosylation in the ER
Asparagine
Amino acid deaminated by an enzyme which results in the formation of ammonia. This is the major carrier of nitrogen to the liver from peripheral tissues,
Glutaminase deaminates glutamine
Amino acid used in the determination for Folic acid deficiency. What is the test called?
Histidine used in the N-forminoglutamate excretion test
Increased amounts of FIGu in urine by Folic acid deficient individuals after histindine intake
Precursor amino acid for creatinine, urea, nitric oxide
Arginine
Essential amino acids that cannot be synthesized by the body and must come from the diet
PVT TIM HALL always ARGues and never TYRes
Phenylalanine, valine, tryptophan, threonine’ isoleucine, methionine, histidine, argenine, Leucine, Lysine
Heme is a complex of?
Protoporphorin IX and heme
What is the Bohr effect?
HBO2 + H+ HbH + O2
What is an oxidized for of HB (Fe 3+) that does not bind O2 readily which could lead to chocolate cyanosis ? It is treated with oral methylene blue or ascorbic acid up to IV methylene blue.
Methemoglobin
Hemoglobin bound to carbon monoxide instead of O2 leading to a cherry pink color.
Carboxyhemoglobin
HB bound to carbon dioxide is called
Carbaminohenoglobin
Classification of alpha and beta thalassemia
Alpha: silent carrier, a-thalassemia trait, Hb H disease, hydrops fetalis
Beta: B-thalassemia minor and major
Most frequently affected collagen in Ehler Danlos syndrome leading to hyper extensible skin, tendency to bleed, hyper mobile joints, and increased risk for berry aneurysms.
Collagen type 3
Collagen I mutation leading to bendable and easily fractured bones. Accompanied with blue sclerae, hearing loss, and dental imperfections.
Osteogenesis imperfecta
Vitamin C deficiency leading to decreased hydroxylation of collagen. This leads to sore spongy gums, loose teeth, poor wound healing, and petecchiae on skin and mucous membranes.
Scurvy
Type IV collagen defect leading to hematuria and ESRD
Alpert syndrome
Collagen defect leading to kinky hair due to a deficiency of copper required by lysyl oxidase to strengthen collagen fibers.
Menke syndrome
Skin breaking and blisters as a result for minor trauma. This disease is due to a defect in collage VII.
Epidermolysis bullosa
Like collagen elastin has pro line and Lysine but has little and no?
Hydroxyproline
Hydroxylysine
Protein degradation mechanisms of nitrogen
Energy dependent ubiquitin-proteosome mechanism
Non-energy dependent degradation enzyme
Phases in amino acid catabolism
First phase: removal of a-amino group forming ammonia and a corresponding ketoacid
Second phase: carbon skeletons of a-ketoacids are converted to common intermediates of energy producing metabolic pathwas
Two main steps in nitrogen removal from AA
- Transamination
2. Oxidative deamination
Where does transamination occur?
All cells of the body
All but two amino acids transfer their amino groups to a-ketoglutarate except?
Lysine and threonine
What is the coenzyme for the two aminotransferases?
Pyridoxal phosphate (vitamin B6)
Oxidative deamination occurs where and for which amino acid only?
Liver and kidney
Only glutamate
Glutamate is oxidized by glutamate dehydrogenases and deaminated to form ?
free ammonia which is used to make urea
What does the conversion of glutamate to a-ketoglutarate yield? What about vice versa?
Glutamate -> a ketoglutarate NH3 + NADH
A ketoglutarate -> glutamate NADP+ + NH3
How is excess nitrogen removal from peripheral tissues removed?
- Glutamine: via glutamate + ammonia (through Flutamide synthaetase)
- Alanine: via glucose -> pyruvate + glutamate -> alanine cycle
Glutaminase deaminates glutamine to produce ammonium ion which is excreted from the body. Where are the two tissues this enzyme could be located?
Kidneys and small intestines
Another name for urea cycle
Ornithine cycle or krebs-henseleit cycle
What are the donors of the urea molecule?
- NH3 from free ammonia
- NH3 from aspartate
- 1C and 1O from CO2
Reactions in the urea cycle
- Formation of carbamoyl phosphate (via carbamoyl phosphate synthetase I)
- Formation of citrulline (via Ornithine transcarbamoylase)
- Synthesis of arginosuccinate (arginosuccinate synthetase)
- Cleavage of arginosuccinate to form arginine (Arginosuccinase)
- Arginine cleavage to yield urea and Ornithine (arginase)
Rate limiting step of urea cycle
Carbamoyl phosphate synthetase I
Energy requirement of urea cycle
4 ATP
Co factors of urea cycle
N-acetylglutamate
Biotin
Hereditary hyperammonemia produces symptoms such as
Hyperammonemia, elevated blood glutamine, decreased BUN
Parents with lethargy, vomiting, hyperventilation, convulsions, cerebral edema, coma, and death
Treatment for hereditary hyperammonemia
Low protein diet
Administration of sodium benzoate or phenylpyruvate to capture and excrete excess nitrogen
Ketogenic carbon skeletons of AA
Leucine
Lysine
Yields acetoacetate or acetyl-coa/ acetoacetyl-coa
Ketogenic and glucogenic carbon skeletons of AA
WIFY Phenylalanine Isoleucine Tryptophan Tyrosine
Yields Ketogenic and glucose or glycogen by products
This amino acid acts as a raw material in the biosynthesis of Heme, purines, creatine
Glycine
This amino acid acts as a raw material in the biosynthesis of phospholipid, sphingolipid, purines, thymine
Serine
This amino acid acts as a raw material in the biosynthesis of GABA
Glutamate
This amino acid acts as a raw material in the biosynthesis of creatine, polyamines, nitric oxide
Arginine
This amino acid acts as a raw material in the biosynthesis of serotonin, NAD+, NADP+, melatonin
Tryptophan
This amino acid acts as a raw material in the biosynthesis of catecholamines, thyroid hormones, melanin
Tyrosine
3 hormones dependent on tyrosine
Thyroid hormones
Melanin
Catecholamines
Deficiency of homogenistic acid oxidase in the degrative pathway of tyrosine which results in urine turning to black on standing with dark connective tissues (ochronosis)
Alkaptonuria
Congenital deficiency due tyrosinase deficieny or defective tyrosine transporters which leads to an increased risk for skin cancer.
Albinism
Autosomal recessive disorder that may either be due to decreased methionine, increased cysteine, B6, and folate or decreased affinity for cystathione synthase. This results in mental retardation, osteoporosis, tall stature, lens subluxation, and atherosclerosis.
Homocystinuria
Common inherited defect of renal tubular amino acid transporter for its parent compound, Ornithine, Lysine, and arginine, in the PCT of the kidneys. It eventually precipitates and cause staghorn caliculi. What is its treatment?
Cystinuria is treated with acetazolamide to alkalinize the urine
The initial and last three steps of heme synthesis occurs in?
The mitochondria
Heme synthesis summary
- Formation of ALA (via ALA synthase and B6)
- Formation of porphobilinogen
- Formation of uroporphyrinogen
- Formation of heme
Lead inhibits what two steps in heme synthesis?
- Introduction of Fe 2+ into protoporphyrin IX via ferrochelatase
- Condensation of two ALA molecules by zinc containing ALA dehydratase
Where is B6 a cofactors of?
- Heme synthesis
- Synthesis of cystathionine from homocysteine
- Transamination between alanine and a-ketoglutarate
Most common porphyria
Porphyria cutanea tarda
Which part of heme synthesis do these symptoms appear?
- Photosensitivity
- Neuropsychiatric symptoms
- After ring formation
2. Before ring formation
Pyridoxine ficiency associated with isoniazid therapy results in this histopathologic finding
Sideroblastic anemia with ringed sideroblast
Poisoning due to this heavy metal leads to coar basophilic stippling of RBC, peripheral neuropathy, lines in gums, increas in urinary ALA and free erythrocytes porphorin
lead poisoning
Microcytic hypo chromic anemia is found in
IDA
Thalassemia
Lead poisoning
Megaloblastic anemia is found in
Folate or B12 deficiency
Pernicious anemia
Normoyctic normochromic anemia is found in
Anemia of chronic kidney disease
Blood loss
Increase in MCHC is found in
Hereditary spherocytosis
Summary of heme degradation
- Formation of bilirubin
- Uptake of bilirubin by the liver
- Formation of bilirubin diglucoronide
- Secretion of bilirubin into bile
- Formation of urobilins in the intestine
Colors of biliverdin, bilirubin, urobilinogen, stercolin, urobilin
Biliverdin: green Bilirubin: red orange Urobilinogen: colorless Stercolin: brown orange red Urobilin: yellow
Examples of unconjugated hyperbilirubinemia
Hemolytic anemia Physiologic jaundice Crigler-najjar syndrome types I and II Gilbert syndrome Toxic hyperbilirubinemia
Examples of conjugated hyperbilirubinemia
Biliary tree obstruction
Dubin-Johnson syndrome
Rotor syndrome
What reaction measures total and direct bilirubin?
Van den bergs reaction
What enzyme activates fatty acid for metabolism use?
Fatty-acyl-CoA synthetase
Cofactor required for fatty acid activation
Vitamin B5 or Panthotenic acid
Energy required to activate fatty acid
2 ATP
What is the product formed in fatty acid synthesis?
Palmitate (16:0)
Where does fatty acid synthesis occur?
Cytosol
Major: Liver and lactating mammary glands
Minor: adipose tissue
Substrates for fatty acid synthesis
1 acetyl CoA
7 malonyl CoA
NADPH
ATP
Rate limiting step in fatty acid synthesis
Acetyl CoA + ATP -> malonyl CoA
Enzyme: acetyl CoA carboxylase
Steps in fatty acid synthesis
- Synthesis of cytoplasmic acetyl CoA (transfer of mitochondrial acetyl CoA to cytoplasm via citrate shuttle)
- Acetyl CoA carboxylation to malonyl CoA (via acetyl CoA carboxylase with biotin) [+ insulin, citrate]
- Assembly of palmitate (via fatty acid synthase and Vit B5)
Steps in palmitate assembly
- Condensation
- Reduction
- Dehydration
- Reduction
What is the fate of Palmitate after its production?
- Further elongation in SER and mitochondria
2. Desaturated in the ER (but not past the 9th carbon)
Main storage form of fatty acids
Triacylglycerols
Where does TAG synthesis occur?
Liver and adipose tissue
Sources of glycerol-3-phosphate
- DHAP from glycolysis (liver and adipose)
2. Phosphorylation of free glycerol (liver)
What enzyme is responsible for the release of free fatty acids from TAGs?
Hormone sensitive lipases
In the bloodstream fatty acids are always bound to?
Albumin
Hormone sensitive lipases can only release what free fatty acids stored in TAG?
C1 & 3 thus resulting in
TAG -> 2 free FA and 2-mono acyl glycerol
Where does B-oxidation of fatty acids occur
Mitochondria of all cells, but the fatty acid activation raft occurs in the Cytosol
Exception: RBC, kidney medulla, neurons, testes
Rate limiting step in B-oxidation
Fatty acyl CoA + carnitine -> fatty acyl carnitine + CoA
Enzyme: carnitine acyl transferase I
Cutoff number of carbons that do not need a shuttle
Less than 12 carbons
Steps in the carnitine shuttle
- Fatty acyl synthase activates the fatty acid
- Carnitine acyl transferase 1 attaches to fatty acyl to carnitine in the outer mitochondrial membrane
- Fatty acyl-carnitine is shuttle through the inner membrane
- Carnitine acyl transferase-2 transfers fatty acyl group back to a CoA in the mitochondrial matrix
Steps in beta oxidation
- Oxidation
- Hydratiion
- Oxidation
- Thiolysis
Beta oxidation of fatty acids with an odd number of carbon atoms releases?
Propionyl CoA which is converted to methylmalonyl coa (requires B12) then to succinyl CoA
Which is responsible for the conversion of very long chain fatty acids?
Peroxisomes but if unsaturated it requires 3,2 enol-CoA isomerase
Energy yield in ATP of beta oxidation of palmitate
129 ATP
7 NADH= 21
7 FAD= 14
8 acetyl CoA= 96
Activation = -2
Intake of this compound depletes the body’s NAD+ supply leading to accumulation Of fat in the liver
Alcohol
Type of carnitine deficiency which leads to impaired FA oxidation and ketogenesis with hypoglycemia?
CPT-1 deficiency
Type of carnitine deficiency which affects skeletal muscle and when severe the liver
CPT-2 deficiency
It is a disorder school results in decreased fatty acid oxidation. Without the ATP to support gluconeogenesis, hypoglycemia becomes profound which may eventually leads to SIDS. It is prevented by frequent feeding with high carbohydrate and low fat diet.
Medium-chain fatty acyl-CoA dehydrogenase (MCAD) deficiency
Associated with eating unripe fruit of the akee tree which contains hypoglycin thus activating MC and SC acyl CoA dehydrogenase
Jamaican vomiting sickness
Rare neurological disorder which results to the accumulation of phytanic acid found in plant food stuff which blocks Boxidation
Refsum disease
Cerebrohepatorenal syndrome resulting from the absence of peroxisomes in all tissues, it is characterized by liver dysfunction, jaundice, MR, weakness, hypotonia, and craniofacial dimorphism
Zellweger syndrome
Defect in peroxismal activation of VLCFA thus leading to its accumulation. Ssx: apathy, behavral change, then visual loss spasticity, ataxia. All due to the fact since VLCFA are found in myelin tissue.
X-lied adrenoleukodystrophy
Where does ketogenesis occur?
Liver mitochondria
Products of ketogenesis
Acetoacetate and B-hydroxybutyrate (fuel)
Acetone (cannot be used as fuel)
Rate limiting step of ketogenesis
Acetoacetyl CoA + acetyl CoA –(HMG CoA synthase)–> HMG CoA
What are the initial products that lead to the formation of acetyl CoA in ketogenolysis?
B-hydroxybutyrate -> acetoacetate -> acetyl coa
What peripheral tissues can oxidize ketone bodes?
Those with mitochondria like the renal cortex, brain, and skeletal muscle
Why cant liver convert acetoacetate to acetyl CoA?
It lacks succinyl-CoA acetoacetyl-CoA reductase (thiophorase)
What is the Urine test for ketones? What ketone type does not it detect?
Nitroprusside test
Does not detect b-hydroxybutyrate
Which part of cholesterol can a fatty acid attach to form a cholesteryl ester?
Single hydroxyl group of carbon 3 of the alpha ring
Where does cholesterol synthesis occur?
All cells in the Cytosol and SER majority of which are found in the liver and intestines
Substrates of cholesterol synthesis
Acetyl CoA, NADPH, ATP
Rate limiting step in cholesterol synthesis
HMG CoA –(HMG CoA reductase)–> mevalonate
Steps in Cholestid synthesis
- Biosynthesis of mevalonate
- Formation of isoprenoid units
- Isoprene unit is formed from 6 isoprenoid units
- Formation of lanosterol
- Formation of cholesterol
How is the cholesterol ring eliminated?
Through conversion to bile salts then secretion to bile
Bile acid synthesis, found in the liver and Cytosol, rate limiting enzyme is?
Cholesterol-7-a-hydroxylase
What are the primary bile acids?
Cholic acid
Chenocholic acid
What are the two amino acids used in bile acid conjugation to form bile salts?
Taurine and glycine
What are the secondary bile acids?
Deoxycholic acid
Lithocholic acid
Where does steroid hormone synthesis occur?
SER of the adrenal glands, ovaries and testes, and placenta
What is blocked by the drug aminogluthetimide?
The conversion of cholesterol to pregnenolone by desmolase
The enzyme responsible for the breakdown of TAG to FA and:
A) 2-MAG from diet
B) FREE glycerol from chylomicrons and VLDL
C) 2-MAG from adipose
A) pancreatic lipase
B) Lipoprotein lipase
C) hormone sensitive lipase
Lipoprotein with the largest percentage of TG
Chylomicrons
Lipoprotein with the largest percentage of cholesteryl esters
LDL
Chylomicrons transport TG and cholesterol from where to where?
Intestines to tissues
VLDL transports TG from where to where?
Liver to tissues
What apoprotein activates lipoprotein lipase?
APO-CII
What apolipoprotein uptakes remnants by the liver?
APO E
Apolipoprotein B-48 is used by chylomicrons which are created by the?
Epithelial cells
What apolipoprotein is secreted by the liver for VDL?
B-100
How does IDL become LDL?
By picking up cholesterol from HD!
Which apoprotein delivers cholesterol into cells?
LDL
Which apolipoprotein is used by HDL to activate lecithin cholesterol acyl transferase or LCAT to produce cholesterol esters?
APO-A1
Difference between Type II familial hypercholesterolemia and type IV familial hypertriglyceredemia?
The former has high LDL leader to xanthomas and xanthelasmas with increased risk of atherosclerosis and CHD
The latter has increased VLDL production leading to a triad of
- DM type 2
- CAD
- Obesity
Phospholipid is composed of
DAG
Alcohol
Phosphodiester bond
Most abundant phospholipid which is important in nervous transmission
Phosphatidylcholine
Phospholipid playing a role in apoptosis
Phosphatidyl serine
Phospholipid that is a major component of surfactant?
Dipalmitoylphosphatidylcholine
Phospholipid reservoir for arachidonic acid in the membranes
Phosphatidylinositol
What phospholipid is essential in mitochondrial function which is also used as a non-troponemal test due to its ability to act as an antigen?
Cardiolipin
Composition of these glycolipids: Ceramide Cerebroside Globoside Ganglioside Sulfatide
Ceramide: sphingosine + FA
Ceramide + \_\_\_\_\_\_\_\_ Glucose or galactose = Cerebroside Oligosacchardide = Globoside N-acetylneuramic acid = Ganglioside Sulfated galactose = Sulfatide
Hexosaminidase a ficiency leading to Ssx like cherry red macula, MR, hypotonia
Tay-Sachs disease
A-galactosidase deficiency leading to 3Rs: recessive x-linked, rash, renal failure
Fabrys disease
B-glucosidase deficiency leading to hepatosplenomegaly and erosion of long bones
Gauchers dissease
Sphingomyelinase deficiency leading to hepatosplenomegaly
Nieman-pick disease
The set of all proteins expressed by an individual at a particular time
Proteome
Aims to identify the entire complement of proteins elaborated by a cell under diverse conditions
Proteomics
What amino acid is needed to form ALA in heme synthesis?
Glycine combined with succinyl CoA
Which amino acid carries nitrogen from the liver?
Alanine
Which amino acids are implicated in maple syrup disease
valine, lucine, isoleucine
What enzyme is responsible for the buildup of phenyl lactate, phenyl acetate, and phenylpyruvate?
Phenylalanine hydroxylase
What amino acid is the precursor for niacin, serotonin, and melatonin?
Serotonin
What is the amino acid precursor for homocysteine?
Methionine
What amino acid contributes to the fibrous structure of collagen and interrupts a-helices in globular proteins?
Proline
Increase of the combination of this Amino acid is responsible for the curly hair of people?
Cysteine + cysteine = cystine
Amino acids with sites for O-linked glycosylation in the Golgi apparatus?
Serine and threonine
Site for n-linked glycosylation in the ER
Asparagine
Amino acid deaminated by an enzyme which results in the formation of ammonia. This is the major carrier of nitrogen to the liver from peripheral tissues,
Glutaminase deaminates glutamine
Amino acid used in the determination for Folic acid deficiency. What is the test called?
Histidine used in the N-forminoglutamate excretion test
Increased amounts of FIGu in urine by Folic acid deficient individuals after histindine intake
Precursor amino acid for creatinine, urea, nitric oxide
Arginine
Essential amino acids that cannot be synthesized by the body and must come from the diet
PVT TIM HALL always ARGues and never TYRes
Phenylalanine, valine, tryptophan, threonine’ isoleucine, methionine, histidine, argenine, Leucine, Lysine
Heme is a complex of?
Protoporphorin IX and heme
What is the Bohr effect?
HBO2 + H+ HbH + O2
What is an oxidized for of HB (Fe 3+) that does not bind O2 readily which could lead to chocolate cyanosis ? It is treated with oral methylene blue or ascorbic acid up to IV methylene blue.
Methemoglobin
Hemoglobin bound to carbon monoxide instead of O2 leading to a cherry pink color.
Carboxyhemoglobin
HB bound to carbon dioxide is called
Carbaminohenoglobin
Classification of alpha and beta thalassemia
Alpha: silent carrier, a-thalassemia trait, Hb H disease, hydrops fetalis
Beta: B-thalassemia minor and major
Most frequently affected collagen in Ehler Danlos syndrome leading to hyper extensible skin, tendency to bleed, hyper mobile joints, and increased risk for berry aneurysms.
Collagen type 3
Collagen I mutation leading to bendable and easily fractured bones. Accompanied with blue sclerae, hearing loss, and dental imperfections.
Osteogenesis imperfecta
Vitamin C deficiency leading to decreased hydroxylation of collagen. This leads to sore spongy gums, loose teeth, poor wound healing, and petecchiae on skin and mucous membranes.
Scurvy
Type IV collagen defect leading to hematuria and ESRD
Alpert syndrome
Collagen defect leading to kinky hair due to a deficiency of copper required by lysyl oxidase to strengthen collagen fibers.
Menke syndrome
Skin breaking and blisters as a result for minor trauma. This disease is due to a defect in collage VII.
Epidermolysis bullosa
Like collagen elastin has pro line and Lysine but has little and no?
Hydroxyproline
Hydroxylysine
Protein degradation mechanisms of nitrogen
Energy dependent ubiquitin-proteosome mechanism
Non-energy dependent degradation enzyme
Phases in amino acid catabolism
First phase: removal of a-amino group forming ammonia and a corresponding ketoacid
Second phase: carbon skeletons of a-ketoacids are converted to common intermediates of energy producing metabolic pathwas
Two main steps in nitrogen removal from AA
- Transamination
2. Oxidative deamination
Where does transamination occur?
All cells of the body
All but two amino acids transfer their amino groups to a-ketoglutarate except?
Lysine and threonine
What is the coenzyme for the two aminotransferases?
Pyridoxal phosphate (vitamin B6)
Oxidative deamination occurs where and for which amino acid only?
Liver and kidney
Only glutamate
Glutamate is oxidized by glutamate dehydrogenases and deaminated to form ?
free ammonia which is used to make urea
What does the conversion of glutamate to a-ketoglutarate yield? What about vice versa?
Glutamate -> a ketoglutarate NH3 + NADH
A ketoglutarate -> glutamate NADP+ + NH3
How is excess nitrogen removal from peripheral tissues removed?
- Glutamine: via glutamate + ammonia (through Flutamide synthaetase)
- Alanine: via glucose -> pyruvate + glutamate -> alanine cycle
Glutaminase deaminates glutamine to produce ammonium ion which is excreted from the body. Where are the two tissues this enzyme could be located?
Kidneys and small intestines
Another name for urea cycle
Ornithine cycle or krebs-henseleit cycle
What are the donors of the urea molecule?
- NH3 from free ammonia
- NH3 from aspartate
- 1C and 1O from CO2
Reactions in the urea cycle
- Formation of carbamoyl phosphate (via carbamoyl phosphate synthetase I)
- Formation of citrulline (via Ornithine transcarbamoylase)
- Synthesis of arginosuccinate (arginosuccinate synthetase)
- Cleavage of arginosuccinate to form arginine (Arginosuccinase)
- Arginine cleavage to yield urea and Ornithine (arginase)
Rate limiting step of urea cycle
Carbamoyl phosphate synthetase I
Energy requirement of urea cycle
4 ATP
Co factors of urea cycle
N-acetylglutamate
Biotin
Hereditary hyperammonemia produces symptoms such as
Hyperammonemia, elevated blood glutamine, decreased BUN
Parents with lethargy, vomiting, hyperventilation, convulsions, cerebral edema, coma, and death
Treatment for hereditary hyperammonemia
Low protein diet
Administration of sodium benzoate or phenylpyruvate to capture and excrete excess nitrogen
Ketogenic carbon skeletons of AA
Leucine
Lysine
Yields acetoacetate or acetyl-coa/ acetoacetyl-coa
Ketogenic and glucogenic carbon skeletons of AA
WIFY Phenylalanine Isoleucine Tryptophan Tyrosine
Yields Ketogenic and glucose or glycogen by products
This amino acid acts as a raw material in the biosynthesis of Heme, purines, creatine
Glycine
This amino acid acts as a raw material in the biosynthesis of phospholipid, sphingolipid, purines, thymine
Serine
This amino acid acts as a raw material in the biosynthesis of GABA
Glutamate
This amino acid acts as a raw material in the biosynthesis of creatine, polyamines, nitric oxide
Arginine
This amino acid acts as a raw material in the biosynthesis of serotonin, NAD+, NADP+, melatonin
Tryptophan
This amino acid acts as a raw material in the biosynthesis of catecholamines, thyroid hormones, melanin
Tyrosine
3 hormones dependent on tyrosine
Thyroid hormones
Melanin
Catecholamines
Deficiency of homogenistic acid oxidase in the degrative pathway of tyrosine which results in urine turning to black on standing with dark connective tissues (ochronosis)
Alkaptonuria
Congenital deficiency due tyrosinase deficieny or defective tyrosine transporters which leads to an increased risk for skin cancer.
Albinism
Autosomal recessive disorder that may either be due to decreased methionine, increased cysteine, B6, and folate or decreased affinity for cystathione synthase. This results in mental retardation, osteoporosis, tall stature, lens subluxation, and atherosclerosis.
Homocystinuria
Common inherited defect of renal tubular amino acid transporter for its parent compound, Ornithine, Lysine, and arginine, in the PCT of the kidneys. It eventually precipitates and cause staghorn caliculi. What is its treatment?
Cystinuria is treated with acetazolamide to alkalinize the urine
The initial and last three steps of heme synthesis occurs in?
The mitochondria
Heme synthesis summary
- Formation of ALA (via ALA synthase and B6)
- Formation of porphobilinogen
- Formation of uroporphyrinogen
- Formation of heme
Lead inhibits what two steps in heme synthesis?
- Introduction of Fe 2+ into protoporphyrin IX via ferrochelatase
- Condensation of two ALA molecules by zinc containing ALA dehydratase
Where is B6 a cofactors of?
- Heme synthesis
- Synthesis of cystathionine from homocysteine
- Transamination between alanine and a-ketoglutarate
Most common porphyria
Porphyria cutanea tarda
Which part of heme synthesis do these symptoms appear?
- Photosensitivity
- Neuropsychiatric symptoms
- After ring formation
2. Before ring formation
Pyridoxine ficiency associated with isoniazid therapy results in this histopathologic finding
Sideroblastic anemia with ringed sideroblast
Poisoning due to this heavy metal leads to coar basophilic stippling of RBC, peripheral neuropathy, lines in gums, increas in urinary ALA and free erythrocytes porphorin
lead poisoning
Microcytic hypo chromic anemia is found in
IDA
Thalassemia
Lead poisoning
Megaloblastic anemia is found in
Folate or B12 deficiency
Pernicious anemia
Normoyctic normochromic anemia is found in
Anemia of chronic kidney disease
Blood loss
Increase in MCHC is found in
Hereditary spherocytosis
Summary of heme degradation
- Formation of bilirubin
- Uptake of bilirubin by the liver
- Formation of bilirubin diglucoronide
- Secretion of bilirubin into bile
- Formation of urobilins in the intestine
Colors of biliverdin, bilirubin, urobilinogen, stercolin, urobilin
Biliverdin: green Bilirubin: red orange Urobilinogen: colorless Stercolin: brown orange red Urobilin: yellow
Examples of unconjugated hyperbilirubinemia
Hemolytic anemia Physiologic jaundice Crigler-najjar syndrome types I and II Gilbert syndrome Toxic hyperbilirubinemia
What reaction measures total and direct bilirubin?
Van den bergs reaction
Examples of conjugated hyperbilirubinemia
Biliary tree obstruction
Dubin-Johnson syndrome
Rotor syndrome
What enzyme activates fatty acid for metabolism use?
Fatty-acyl-CoA synthetase
Cofactor required for fatty acid activation
Vitamin B5 or Panthotenic acid
Energy required to activate fatty acid
2 ATP
What is the product formed in fatty acid synthesis?
Palmitate (16:0)
Where does fatty acid synthesis occur?
Cytosol
Major: Liver and lactating mammary glands
Minor: adipose tissue
Substrates for fatty acid synthesis
1 acetyl CoA
7 malonyl CoA
NADPH
ATP
Rate limiting step in fatty acid synthesis
Acetyl CoA + ATP -> malonyl CoA
Enzyme: acetyl CoA carboxylase
Steps in fatty acid synthesis
- Synthesis of cytoplasmic acetyl CoA (transfer of mitochondrial acetyl CoA to cytoplasm via citrate shuttle)
- Acetyl CoA carboxylation to malonyl CoA (via acetyl CoA carboxylase with biotin) [+ insulin, citrate]
- Assembly of palmitate (via fatty acid synthase and Vit B5)
Steps in palmitate assembly
- Condensation
- Reduction
- Dehydration
- Reduction
What is the fate of Palmitate after its production?
- Further elongation in SER and mitochondria
2. Desaturated in the ER (but not past the 9th carbon)
Main storage form of fatty acids
Triacylglycerols
Where does TAG synthesis occur?
Liver and adipose tissue
Sources of glycerol-3-phosphate
- DHAP from glycolysis (liver and adipose)
2. Phosphorylation of free glycerol (liver)
What enzyme is responsible for the release of free fatty acids from TAGs?
Hormone sensitive lipases
In the bloodstream fatty acids are always bound to?
Albumin
Hormone sensitive lipases can only release what free fatty acids stored in TAG?
C1 & 3 thus resulting in
TAG -> 2 free FA and 2-mono acyl glycerol
Where does B-oxidation of fatty acids occur
Mitochondria of all cells, but the fatty acid activation raft occurs in the Cytosol
Exception: RBC, kidney medulla, neurons, testes
Rate limiting step in B-oxidation
Fatty acyl CoA + carnitine -> fatty acyl carnitine + CoA
Enzyme: carnitine acyl transferase I
Cutoff number of carbons that do not need a shuttle
Less than 12 carbons
Steps in the carnitine shuttle
- Fatty acyl synthase activates the fatty acid
- Carnitine acyl transferase 1 attaches to fatty acyl to carnitine in the outer mitochondrial membrane
- Fatty acyl-carnitine is shuttle through the inner membrane
- Carnitine acyl transferase-2 transfers fatty acyl group back to a CoA in the mitochondrial matrix
Steps in beta oxidation
- Oxidation
- Hydratiion
- Oxidation
- Thiolysis
Beta oxidation of fatty acids with an odd number of carbon atoms releases?
Propionyl CoA which is converted to methylmalonyl coa (requires B12) then to succinyl CoA
Which is responsible for the conversion of very long chain fatty acids?
Peroxisomes but if unsaturated it requires 3,2 enol-CoA isomerase
Energy yield in ATP of beta oxidation of palmitate
129 ATP
7 NADH= 21
7 FAD= 14
8 acetyl CoA= 96
Activation = -2
Intake of this compound depletes the body’s NAD+ supply leading to accumulation Of fat in the liver
Alcohol
Type of carnitine deficiency which leads to impaired FA oxidation and ketogenesis with hypoglycemia?
CPT-1 deficiency
Type of carnitine deficiency which affects skeletal muscle and when severe the liver
CPT-2 deficiency
It is a disorder school results in decreased fatty acid oxidation. Without the ATP to support gluconeogenesis, hypoglycemia becomes profound which may eventually leads to SIDS. It is prevented by frequent feeding with high carbohydrate and low fat diet.
Medium-chain fatty acyl-CoA dehydrogenase (MCAD) deficiency
Associated with eating unripe fruit of the akee tree which contains hypoglycin thus activating MC and SC acyl CoA dehydrogenase
Jamaican vomiting sickness
Rare neurological disorder which results to the accumulation of phytanic acid found in plant food stuff which blocks Boxidation
Refsum disease
Cerebrohepatorenal syndrome resulting from the absence of peroxisomes in all tissues, it is characterized by liver dysfunction, jaundice, MR, weakness, hypotonia, and craniofacial dimorphism
Zellweger syndrome
Defect in peroxismal activation of VLCFA thus leading to its accumulation. Ssx: apathy, behavral change, then visual loss spasticity, ataxia. All due to the fact since VLCFA are found in myelin tissue.
X-lied adrenoleukodystrophy
Where does ketogenesis occur?
Liver mitochondria
Products of ketogenesis
Acetoacetate and B-hydroxybutyrate (fuel)
Acetone (cannot be used as fuel)
Rate limiting step of ketogenesis
Acetoacetyl CoA + acetyl CoA –(HMG CoA synthase)–> HMG CoA
What are the initial products that lead to the formation of acetyl CoA in ketogenolysis?
B-hydroxybutyrate -> acetoacetate -> acetyl coa
What peripheral tissues can oxidize ketone bodes?
Those with mitochondria like the renal cortex, brain, and skeletal muscle
Why cant liver convert acetoacetate to acetyl CoA?
It lacks succinyl-CoA acetoacetyl-CoA reductase (thiophorase)
What is the Urine test for ketones? What ketone type does not it detect?
Nitroprusside test
Does not detect b-hydroxybutyrate
Which part of cholesterol can a fatty acid attach to form a cholesteryl ester?
Single hydroxyl group of carbon 3 of the alpha ring
Where does cholesterol synthesis occur?
All cells in the Cytosol and SER majority of which are found in the liver and intestines
Substrates of cholesterol synthesis
Acetyl CoA, NADPH, ATP
Rate limiting step in cholesterol synthesis
HMG CoA –(HMG CoA reductase)–> mevalonate
Steps in Cholestid synthesis
- Biosynthesis of mevalonate
- Formation of isoprenoid units
- Isoprene unit is formed from 6 isoprenoid units
- Formation of lanosterol
- Formation of cholesterol
How is the cholesterol ring eliminated?
Through conversion to bile salts then secretion to bile
Bile acid synthesis, found in the liver and Cytosol, rate limiting enzyme is?
Cholesterol-7-a-hydroxylase
What are the primary bile acids?
Cholic acid
Chenocholic acid
What are the two amino acids used in bile acid conjugation to form bile salts?
Taurine and glycine
What are the secondary bile acids?
Deoxycholic acid
Lithocholic acid
Where does steroid hormone synthesis occur?
SER of the adrenal glands, ovaries and testes, and placenta
What is blocked by the drug aminogluthetimide?
The conversion of cholesterol to pregnenolone by desmolase
The enzyme responsible for the breakdown of TAG to FA and:
A) 2-MAG from diet
B) FREE glycerol from chylomicrons and VLDL
C) 2-MAG from adipose
A) pancreatic lipase
B) Lipoprotein lipase
C) hormone sensitive lipase
Lipoprotein with the largest percentage of TG
Chylomicrons
Lipoprotein with the largest percentage of cholesteryl esters
LDL
Chylomicrons transport TG and cholesterol from where to where?
Intestines to tissues
VLDL transports TG from where to where?
Liver to tissues
What apoprotein activates lipoprotein lipase?
APO-CII
What apolipoprotein uptakes remnants by the liver?
APO E
Apolipoprotein B-48 is used by chylomicrons which are created by the?
Epithelial cells
What apolipoprotein is secreted by the liver for VDL?
B-100
How does IDL become LDL?
By picking up cholesterol from HD!
Which apoprotein delivers cholesterol into cells?
LDL
Which apolipoprotein is used by HDL to activate lecithin cholesterol acyl transferase or LCAT to produce cholesterol esters?
APO-A1
Difference between Type II familial hypercholesterolemia and type IV familial hypertriglyceredemia?
The former has high LDL leader to xanthomas and xanthelasmas with increased risk of atherosclerosis and CHD
The latter has increased VLDL production leading to a triad of
- DM type 2
- CAD
- Obesity
Phospholipid is composed of
DAG
Alcohol
Phosphodiester bond
Most abundant phospholipid which is important in nervous transmission
Phosphatidylcholine
Phospholipid playing a role in apoptosis
Phosphatidyl serine
Phospholipid that is a major component of surfactant?
Dipalmitoylphosphatidylcholine
Phospholipid reservoir for arachidonic acid in the membranes
Phosphatidylinositol
What phospholipid is essential in mitochondrial function which is also used as a non-troponemal test due to its ability to act as an antigen?
Cardiolipin
Composition of these glycolipids: Ceramide Cerebroside Globoside Ganglioside Sulfatide
Ceramide: sphingosine + FA
Ceramide + \_\_\_\_\_\_\_\_ Glucose or galactose = Cerebroside Oligosacchardide = Globoside N-acetylneuramic acid = Ganglioside Sulfated galactose = Sulfatide
Hexosaminidase a ficiency leading to Ssx like cherry red macula, MR, hypotonia
Tay-Sachs disease
A-galactosidase deficiency leading to 3Rs: recessive x-linked, rash, renal failure
Fabrys disease
B-glucosidase deficiency leading to hepatosplenomegaly and erosion of long bones
Gauchers dissease
Sphingomyelinase deficiency leading to hepatosplenomegaly
Nieman-pick disease
The set of all proteins expressed by an individual at a particular time
Proteome
Aims to identify the entire complement of proteins elaborated by a cell under diverse conditions
Proteomics
What amino acid is needed to form ALA in heme synthesis?
Glycine combined with succinyl CoA
Which amino acid carries nitrogen from the liver?
Alanine
Which amino acids are implicated in maple syrup disease
valine, lucine, isoleucine
What enzyme is responsible for the buildup of phenyl lactate, phenyl acetate, and phenylpyruvate?
Phenylalanine hydroxylase
What amino acid is the precursor for niacin, serotonin, and melatonin?
Serotonin
What is the amino acid precursor for homocysteine?
Methionine
What amino acid contributes to the fibrous structure of collagen and interrupts a-helices in globular proteins?
Proline
Increase of the combination of this Amino acid is responsible for the curly hair of people?
Cysteine + cysteine = cystine
Amino acids with sites for O-linked glycosylation in the Golgi apparatus?
Serine and threonine
Site for n-linked glycosylation in the ER
Asparagine
Amino acid deaminated by an enzyme which results in the formation of ammonia. This is the major carrier of nitrogen to the liver from peripheral tissues,
Glutaminase deaminates glutamine
Amino acid used in the determination for Folic acid deficiency. What is the test called?
Histidine used in the N-forminoglutamate excretion test
Increased amounts of FIGu in urine by Folic acid deficient individuals after histindine intake
Precursor amino acid for creatinine, urea, nitric oxide
Arginine
Essential amino acids that cannot be synthesized by the body and must come from the diet
PVT TIM HALL always ARGues and never TYRes
Phenylalanine, valine, tryptophan, threonine’ isoleucine, methionine, histidine, argenine, Leucine, Lysine
Heme is a complex of?
Protoporphorin IX and heme
What is the Bohr effect?
HBO2 + H+ HbH + O2
What is an oxidized for of HB (Fe 3+) that does not bind O2 readily which could lead to chocolate cyanosis ? It is treated with oral methylene blue or ascorbic acid up to IV methylene blue.
Methemoglobin
Hemoglobin bound to carbon monoxide instead of O2 leading to a cherry pink color.
Carboxyhemoglobin
HB bound to carbon dioxide is called
Carbaminohenoglobin
Classification of alpha and beta thalassemia
Alpha: silent carrier, a-thalassemia trait, Hb H disease, hydrops fetalis
Beta: B-thalassemia minor and major
Most frequently affected collagen in Ehler Danlos syndrome leading to hyper extensible skin, tendency to bleed, hyper mobile joints, and increased risk for berry aneurysms.
Collagen type 3
Collagen I mutation leading to bendable and easily fractured bones. Accompanied with blue sclerae, hearing loss, and dental imperfections.
Osteogenesis imperfecta
Vitamin C deficiency leading to decreased hydroxylation of collagen. This leads to sore spongy gums, loose teeth, poor wound healing, and petecchiae on skin and mucous membranes.
Scurvy
Type IV collagen defect leading to hematuria and ESRD
Alpert syndrome
Collagen defect leading to kinky hair due to a deficiency of copper required by lysyl oxidase to strengthen collagen fibers.
Menke syndrome
Skin breaking and blisters as a result for minor trauma. This disease is due to a defect in collage VII.
Epidermolysis bullosa
Like collagen elastin has pro line and Lysine but has little and no?
Hydroxyproline
Hydroxylysine
Protein degradation mechanisms of nitrogen
Energy dependent ubiquitin-proteosome mechanism
Non-energy dependent degradation enzyme
Phases in amino acid catabolism
First phase: removal of a-amino group forming ammonia and a corresponding ketoacid
Second phase: carbon skeletons of a-ketoacids are converted to common intermediates of energy producing metabolic pathwas
Two main steps in nitrogen removal from AA
- Transamination
2. Oxidative deamination
Where does transamination occur?
All cells of the body
All but two amino acids transfer their amino groups to a-ketoglutarate except?
Lysine and threonine
What is the coenzyme for the two aminotransferases?
Pyridoxal phosphate (vitamin B6)
Oxidative deamination occurs where and for which amino acid only?
Liver and kidney
Only glutamate
Glutamate is oxidized by glutamate dehydrogenases and deaminated to form ?
free ammonia which is used to make urea
What does the conversion of glutamate to a-ketoglutarate yield? What about vice versa?
Glutamate -> a ketoglutarate NH3 + NADH
A ketoglutarate -> glutamate NADP+ + NH3
How is excess nitrogen removal from peripheral tissues removed?
- Glutamine: via glutamate + ammonia (through Flutamide synthaetase)
- Alanine: via glucose -> pyruvate + glutamate -> alanine cycle
Glutaminase deaminates glutamine to produce ammonium ion which is excreted from the body. Where are the two tissues this enzyme could be located?
Kidneys and small intestines
Another name for urea cycle
Ornithine cycle or krebs-henseleit cycle
What are the donors of the urea molecule?
- NH3 from free ammonia
- NH3 from aspartate
- 1C and 1O from CO2
Reactions in the urea cycle
- Formation of carbamoyl phosphate (via carbamoyl phosphate synthetase I)
- Formation of citrulline (via Ornithine transcarbamoylase)
- Synthesis of arginosuccinate (arginosuccinate synthetase)
- Cleavage of arginosuccinate to form arginine (Arginosuccinase)
- Arginine cleavage to yield urea and Ornithine (arginase)
Rate limiting step of urea cycle
Carbamoyl phosphate synthetase I
Energy requirement of urea cycle
4 ATP
Co factors of urea cycle
N-acetylglutamate
Biotin
Hereditary hyperammonemia produces symptoms such as
Hyperammonemia, elevated blood glutamine, decreased BUN
Parents with lethargy, vomiting, hyperventilation, convulsions, cerebral edema, coma, and death
Treatment for hereditary hyperammonemia
Low protein diet
Administration of sodium benzoate or phenylpyruvate to capture and excrete excess nitrogen
Ketogenic carbon skeletons of AA
Leucine
Lysine
Yields acetoacetate or acetyl-coa/ acetoacetyl-coa
Ketogenic and glucogenic carbon skeletons of AA
WIFY Phenylalanine Isoleucine Tryptophan Tyrosine
Yields Ketogenic and glucose or glycogen by products
This amino acid acts as a raw material in the biosynthesis of Heme, purines, creatine
Glycine
This amino acid acts as a raw material in the biosynthesis of phospholipid, sphingolipid, purines, thymine
Serine
This amino acid acts as a raw material in the biosynthesis of GABA
Glutamate
This amino acid acts as a raw material in the biosynthesis of creatine, polyamines, nitric oxide
Arginine
This amino acid acts as a raw material in the biosynthesis of serotonin, NAD+, NADP+, melatonin
Tryptophan
This amino acid acts as a raw material in the biosynthesis of catecholamines, thyroid hormones, melanin
Tyrosine
3 hormones dependent on tyrosine
Thyroid hormones
Melanin
Catecholamines
Deficiency of homogenistic acid oxidase in the degrative pathway of tyrosine which results in urine turning to black on standing with dark connective tissues (ochronosis)
Alkaptonuria
Congenital deficiency due tyrosinase deficieny or defective tyrosine transporters which leads to an increased risk for skin cancer.
Albinism
Autosomal recessive disorder that may either be due to decreased methionine, increased cysteine, B6, and folate or decreased affinity for cystathione synthase. This results in mental retardation, osteoporosis, tall stature, lens subluxation, and atherosclerosis.
Homocystinuria
Common inherited defect of renal tubular amino acid transporter for its parent compound, Ornithine, Lysine, and arginine, in the PCT of the kidneys. It eventually precipitates and cause staghorn caliculi. What is its treatment?
Cystinuria is treated with acetazolamide to alkalinize the urine
The initial and last three steps of heme synthesis occurs in?
The mitochondria
Heme synthesis summary
- Formation of ALA (via ALA synthase and B6)
- Formation of porphobilinogen
- Formation of uroporphyrinogen
- Formation of heme
Lead inhibits what two steps in heme synthesis?
- Introduction of Fe 2+ into protoporphyrin IX via ferrochelatase
- Condensation of two ALA molecules by zinc containing ALA dehydratase
Where is B6 a cofactors of?
- Heme synthesis
- Synthesis of cystathionine from homocysteine
- Transamination between alanine and a-ketoglutarate
Most common porphyria
Porphyria cutanea tarda
Which part of heme synthesis do these symptoms appear?
- Photosensitivity
- Neuropsychiatric symptoms
- After ring formation
2. Before ring formation
Pyridoxine ficiency associated with isoniazid therapy results in this histopathologic finding
Sideroblastic anemia with ringed sideroblast
Poisoning due to this heavy metal leads to coar basophilic stippling of RBC, peripheral neuropathy, lines in gums, increas in urinary ALA and free erythrocytes porphorin
lead poisoning
Microcytic hypo chromic anemia is found in
IDA
Thalassemia
Lead poisoning
Megaloblastic anemia is found in
Folate or B12 deficiency
Pernicious anemia
Normoyctic normochromic anemia is found in
Anemia of chronic kidney disease
Blood loss
Increase in MCHC is found in
Hereditary spherocytosis
Summary of heme degradation
- Formation of bilirubin
- Uptake of bilirubin by the liver
- Formation of bilirubin diglucoronide
- Secretion of bilirubin into bile
- Formation of urobilins in the intestine
Colors of biliverdin, bilirubin, urobilinogen, stercolin, urobilin
Biliverdin: green Bilirubin: red orange Urobilinogen: colorless Stercolin: brown orange red Urobilin: yellow
Examples of unconjugated hyperbilirubinemia
Hemolytic anemia Physiologic jaundice Crigler-najjar syndrome types I and II Gilbert syndrome Toxic hyperbilirubinemia
Examples of conjugated hyperbilirubinemia
Biliary tree obstruction
Dubin-Johnson syndrome
Rotor syndrome
What reaction measures total and direct bilirubin?
Van den bergs reaction
What enzyme activates fatty acid for metabolism use?
Fatty-acyl-CoA synthetase
Cofactor required for fatty acid activation
Vitamin B5 or Panthotenic acid
Energy required to activate fatty acid
2 ATP
What is the product formed in fatty acid synthesis?
Palmitate (16:0)
Where does fatty acid synthesis occur?
Cytosol
Major: Liver and lactating mammary glands
Minor: adipose tissue
Substrates for fatty acid synthesis
1 acetyl CoA
7 malonyl CoA
NADPH
ATP
Rate limiting step in fatty acid synthesis
Acetyl CoA + ATP -> malonyl CoA
Enzyme: acetyl CoA carboxylase
Steps in fatty acid synthesis
- Synthesis of cytoplasmic acetyl CoA (transfer of mitochondrial acetyl CoA to cytoplasm via citrate shuttle)
- Acetyl CoA carboxylation to malonyl CoA (via acetyl CoA carboxylase with biotin) [+ insulin, citrate]
- Assembly of palmitate (via fatty acid synthase and Vit B5)
Steps in palmitate assembly
- Condensation
- Reduction
- Dehydration
- Reduction
What is the fate of Palmitate after its production?
- Further elongation in SER and mitochondria
2. Desaturated in the ER (but not past the 9th carbon)
Main storage form of fatty acids
Triacylglycerols
Where does TAG synthesis occur?
Liver and adipose tissue
Sources of glycerol-3-phosphate
- DHAP from glycolysis (liver and adipose)
2. Phosphorylation of free glycerol (liver)
What enzyme is responsible for the release of free fatty acids from TAGs?
Hormone sensitive lipases
In the bloodstream fatty acids are always bound to?
Albumin
Hormone sensitive lipases can only release what free fatty acids stored in TAG?
C1 & 3 thus resulting in
TAG -> 2 free FA and 2-mono acyl glycerol
Where does B-oxidation of fatty acids occur
Mitochondria of all cells, but the fatty acid activation raft occurs in the Cytosol
Exception: RBC, kidney medulla, neurons, testes
Rate limiting step in B-oxidation
Fatty acyl CoA + carnitine -> fatty acyl carnitine + CoA
Enzyme: carnitine acyl transferase I
Cutoff number of carbons that do not need a shuttle
Less than 12 carbons
Steps in the carnitine shuttle
- Fatty acyl synthase activates the fatty acid
- Carnitine acyl transferase 1 attaches to fatty acyl to carnitine in the outer mitochondrial membrane
- Fatty acyl-carnitine is shuttle through the inner membrane
- Carnitine acyl transferase-2 transfers fatty acyl group back to a CoA in the mitochondrial matrix
Steps in beta oxidation
- Oxidation
- Hydratiion
- Oxidation
- Thiolysis
Beta oxidation of fatty acids with an odd number of carbon atoms releases?
Propionyl CoA which is converted to methylmalonyl coa (requires B12) then to succinyl CoA
Which is responsible for the conversion of very long chain fatty acids?
Peroxisomes but if unsaturated it requires 3,2 enol-CoA isomerase
Energy yield in ATP of beta oxidation of palmitate
129 ATP
7 NADH= 21
7 FAD= 14
8 acetyl CoA= 96
Activation = -2
Intake of this compound depletes the body’s NAD+ supply leading to accumulation Of fat in the liver
Alcohol
Type of carnitine deficiency which leads to impaired FA oxidation and ketogenesis with hypoglycemia?
CPT-1 deficiency
Type of carnitine deficiency which affects skeletal muscle and when severe the liver
CPT-2 deficiency
It is a disorder school results in decreased fatty acid oxidation. Without the ATP to support gluconeogenesis, hypoglycemia becomes profound which may eventually leads to SIDS. It is prevented by frequent feeding with high carbohydrate and low fat diet.
Medium-chain fatty acyl-CoA dehydrogenase (MCAD) deficiency
Associated with eating unripe fruit of the akee tree which contains hypoglycin thus activating MC and SC acyl CoA dehydrogenase
Jamaican vomiting sickness
Rare neurological disorder which results to the accumulation of phytanic acid found in plant food stuff which blocks Boxidation
Refsum disease
Cerebrohepatorenal syndrome resulting from the absence of peroxisomes in all tissues, it is characterized by liver dysfunction, jaundice, MR, weakness, hypotonia, and craniofacial dimorphism
Zellweger syndrome
Defect in peroxismal activation of VLCFA thus leading to its accumulation. Ssx: apathy, behavral change, then visual loss spasticity, ataxia. All due to the fact since VLCFA are found in myelin tissue.
X-lied adrenoleukodystrophy
Where does ketogenesis occur?
Liver mitochondria
Products of ketogenesis
Acetoacetate and B-hydroxybutyrate (fuel)
Acetone (cannot be used as fuel)
Rate limiting step of ketogenesis
Acetoacetyl CoA + acetyl CoA –(HMG CoA synthase)–> HMG CoA
What are the initial products that lead to the formation of acetyl CoA in ketogenolysis?
B-hydroxybutyrate -> acetoacetate -> acetyl coa
What peripheral tissues can oxidize ketone bodes?
Those with mitochondria like the renal cortex, brain, and skeletal muscle
Why cant liver convert acetoacetate to acetyl CoA?
It lacks succinyl-CoA acetoacetyl-CoA reductase (thiophorase)
What is the Urine test for ketones? What ketone type does not it detect?
Nitroprusside test
Does not detect b-hydroxybutyrate
Which part of cholesterol can a fatty acid attach to form a cholesteryl ester?
Single hydroxyl group of carbon 3 of the alpha ring
Where does cholesterol synthesis occur?
All cells in the Cytosol and SER majority of which are found in the liver and intestines
Substrates of cholesterol synthesis
Acetyl CoA, NADPH, ATP
Rate limiting step in cholesterol synthesis
HMG CoA –(HMG CoA reductase)–> mevalonate
Steps in Cholestid synthesis
- Biosynthesis of mevalonate
- Formation of isoprenoid units
- Isoprene unit is formed from 6 isoprenoid units
- Formation of lanosterol
- Formation of cholesterol
How is the cholesterol ring eliminated?
Through conversion to bile salts then secretion to bile
Bile acid synthesis, found in the liver and Cytosol, rate limiting enzyme is?
Cholesterol-7-a-hydroxylase
What are the primary bile acids?
Cholic acid
Chenocholic acid
What are the two amino acids used in bile acid conjugation to form bile salts?
Taurine and glycine
What are the secondary bile acids?
Deoxycholic acid
Lithocholic acid
Where does steroid hormone synthesis occur?
SER of the adrenal glands, ovaries and testes, and placenta
What is blocked by the drug aminogluthetimide?
The conversion of cholesterol to pregnenolone by desmolase
The enzyme responsible for the breakdown of TAG to FA and:
A) 2-MAG from diet
B) FREE glycerol from chylomicrons and VLDL
C) 2-MAG from adipose
A) pancreatic lipase
B) Lipoprotein lipase
C) hormone sensitive lipase
Lipoprotein with the largest percentage of TG
Chylomicrons
Lipoprotein with the largest percentage of cholesteryl esters
LDL
Chylomicrons transport TG and cholesterol from where to where?
Intestines to tissues
VLDL transports TG from where to where?
Liver to tissues
What apoprotein activates lipoprotein lipase?
APO-CII
What apolipoprotein uptakes remnants by the liver?
APO E
Apolipoprotein B-48 is used by chylomicrons which are created by the?
Epithelial cells
What apolipoprotein is secreted by the liver for VDL?
B-100
How does IDL become LDL?
By picking up cholesterol from HD!
Which apoprotein delivers cholesterol into cells?
LDL
Which apolipoprotein is used by HDL to activate lecithin cholesterol acyl transferase or LCAT to produce cholesterol esters?
APO-A1
Difference between Type II familial hypercholesterolemia and type IV familial hypertriglyceredemia?
The former has high LDL leader to xanthomas and xanthelasmas with increased risk of atherosclerosis and CHD
The latter has increased VLDL production leading to a triad of
- DM type 2
- CAD
- Obesity
Phospholipid is composed of
DAG
Alcohol
Phosphodiester bond
Most abundant phospholipid which is important in nervous transmission
Phosphatidylcholine
Phospholipid playing a role in apoptosis
Phosphatidyl serine
Phospholipid that is a major component of surfactant?
Dipalmitoylphosphatidylcholine
Phospholipid reservoir for arachidonic acid in the membranes
Phosphatidylinositol
What phospholipid is essential in mitochondrial function which is also used as a non-troponemal test due to its ability to act as an antigen?
Cardiolipin
Composition of these glycolipids: Ceramide Cerebroside Globoside Ganglioside Sulfatide
Ceramide: sphingosine + FA
Ceramide + \_\_\_\_\_\_\_\_ Glucose or galactose = Cerebroside Oligosacchardide = Globoside N-acetylneuramic acid = Ganglioside Sulfated galactose = Sulfatide
Hexosaminidase a ficiency leading to Ssx like cherry red macula, MR, hypotonia
Tay-Sachs disease
A-galactosidase deficiency leading to 3Rs: recessive x-linked, rash, renal failure
Fabrys disease
B-glucosidase deficiency leading to hepatosplenomegaly and erosion of long bones
Gauchers dissease
Sphingomyelinase deficiency leading to hepatosplenomegaly
Nieman-pick disease
The set of all proteins expressed by an individual at a particular time
Proteome
Aims to identify the entire complement of proteins elaborated by a cell under diverse conditions
Proteomics
What amino acid is needed to form ALA in heme synthesis?
Glycine combined with succinyl CoA
Which amino acid carries nitrogen from the liver?
Alanine
Which amino acids are implicated in maple syrup disease
valine, lucine, isoleucine
What enzyme is responsible for the buildup of phenyl lactate, phenyl acetate, and phenylpyruvate?
Phenylalanine hydroxylase
What amino acid is the precursor for niacin, serotonin, and melatonin?
Serotonin
What is the amino acid precursor for homocysteine?
Methionine
What amino acid contributes to the fibrous structure of collagen and interrupts a-helices in globular proteins?
Proline
Increase of the combination of this Amino acid is responsible for the curly hair of people?
Cysteine + cysteine = cystine
Amino acids with sites for O-linked glycosylation in the Golgi apparatus?
Serine and threonine
Site for n-linked glycosylation in the ER
Asparagine
Amino acid deaminated by an enzyme which results in the formation of ammonia. This is the major carrier of nitrogen to the liver from peripheral tissues,
Glutaminase deaminates glutamine
Amino acid used in the determination for Folic acid deficiency. What is the test called?
Histidine used in the N-forminoglutamate excretion test
Increased amounts of FIGu in urine by Folic acid deficient individuals after histindine intake
Precursor amino acid for creatinine, urea, nitric oxide
Arginine
Essential amino acids that cannot be synthesized by the body and must come from the diet
PVT TIM HALL always ARGues and never TYRes
Phenylalanine, valine, tryptophan, threonine’ isoleucine, methionine, histidine, argenine, Leucine, Lysine
Heme is a complex of?
Protoporphorin IX and heme
What is the Bohr effect?
HBO2 + H+ HbH + O2
What is an oxidized for of HB (Fe 3+) that does not bind O2 readily which could lead to chocolate cyanosis ? It is treated with oral methylene blue or ascorbic acid up to IV methylene blue.
Methemoglobin
Hemoglobin bound to carbon monoxide instead of O2 leading to a cherry pink color.
Carboxyhemoglobin
HB bound to carbon dioxide is called
Carbaminohenoglobin
Classification of alpha and beta thalassemia
Alpha: silent carrier, a-thalassemia trait, Hb H disease, hydrops fetalis
Beta: B-thalassemia minor and major
Most frequently affected collagen in Ehler Danlos syndrome leading to hyper extensible skin, tendency to bleed, hyper mobile joints, and increased risk for berry aneurysms.
Collagen type 3
Collagen I mutation leading to bendable and easily fractured bones. Accompanied with blue sclerae, hearing loss, and dental imperfections.
Osteogenesis imperfecta
Vitamin C deficiency leading to decreased hydroxylation of collagen. This leads to sore spongy gums, loose teeth, poor wound healing, and petecchiae on skin and mucous membranes.
Scurvy
Type IV collagen defect leading to hematuria and ESRD
Alpert syndrome
Collagen defect leading to kinky hair due to a deficiency of copper required by lysyl oxidase to strengthen collagen fibers.
Menke syndrome
Skin breaking and blisters as a result for minor trauma. This disease is due to a defect in collage VII.
Epidermolysis bullosa
Like collagen elastin has pro line and Lysine but has little and no?
Hydroxyproline
Hydroxylysine
Protein degradation mechanisms of nitrogen
Energy dependent ubiquitin-proteosome mechanism
Non-energy dependent degradation enzyme
Phases in amino acid catabolism
First phase: removal of a-amino group forming ammonia and a corresponding ketoacid
Second phase: carbon skeletons of a-ketoacids are converted to common intermediates of energy producing metabolic pathwas
Two main steps in nitrogen removal from AA
- Transamination
2. Oxidative deamination
Where does transamination occur?
All cells of the body
All but two amino acids transfer their amino groups to a-ketoglutarate except?
Lysine and threonine
What is the coenzyme for the two aminotransferases?
Pyridoxal phosphate (vitamin B6)
Oxidative deamination occurs where and for which amino acid only?
Liver and kidney
Only glutamate
Glutamate is oxidized by glutamate dehydrogenases and deaminated to form ?
free ammonia which is used to make urea
What does the conversion of glutamate to a-ketoglutarate yield? What about vice versa?
Glutamate -> a ketoglutarate NH3 + NADH
A ketoglutarate -> glutamate NADP+ + NH3
How is excess nitrogen removal from peripheral tissues removed?
- Glutamine: via glutamate + ammonia (through Flutamide synthaetase)
- Alanine: via glucose -> pyruvate + glutamate -> alanine cycle
Glutaminase deaminates glutamine to produce ammonium ion which is excreted from the body. Where are the two tissues this enzyme could be located?
Kidneys and small intestines
Another name for urea cycle
Ornithine cycle or krebs-henseleit cycle
What are the donors of the urea molecule?
- NH3 from free ammonia
- NH3 from aspartate
- 1C and 1O from CO2
Reactions in the urea cycle
- Formation of carbamoyl phosphate (via carbamoyl phosphate synthetase I)
- Formation of citrulline (via Ornithine transcarbamoylase)
- Synthesis of arginosuccinate (arginosuccinate synthetase)
- Cleavage of arginosuccinate to form arginine (Arginosuccinase)
- Arginine cleavage to yield urea and Ornithine (arginase)
Rate limiting step of urea cycle
Carbamoyl phosphate synthetase I
Energy requirement of urea cycle
4 ATP
Co factors of urea cycle
N-acetylglutamate
Biotin
Hereditary hyperammonemia produces symptoms such as
Hyperammonemia, elevated blood glutamine, decreased BUN
Parents with lethargy, vomiting, hyperventilation, convulsions, cerebral edema, coma, and death
Treatment for hereditary hyperammonemia
Low protein diet
Administration of sodium benzoate or phenylpyruvate to capture and excrete excess nitrogen
Ketogenic carbon skeletons of AA
Leucine
Lysine
Yields acetoacetate or acetyl-coa/ acetoacetyl-coa
Ketogenic and glucogenic carbon skeletons of AA
WIFY Phenylalanine Isoleucine Tryptophan Tyrosine
Yields Ketogenic and glucose or glycogen by products
This amino acid acts as a raw material in the biosynthesis of Heme, purines, creatine
Glycine
This amino acid acts as a raw material in the biosynthesis of phospholipid, sphingolipid, purines, thymine
Serine
This amino acid acts as a raw material in the biosynthesis of GABA
Glutamate
This amino acid acts as a raw material in the biosynthesis of creatine, polyamines, nitric oxide
Arginine
This amino acid acts as a raw material in the biosynthesis of serotonin, NAD+, NADP+, melatonin
Tryptophan
This amino acid acts as a raw material in the biosynthesis of catecholamines, thyroid hormones, melanin
Tyrosine
3 hormones dependent on tyrosine
Thyroid hormones
Melanin
Catecholamines
Deficiency of homogenistic acid oxidase in the degrative pathway of tyrosine which results in urine turning to black on standing with dark connective tissues (ochronosis)
Alkaptonuria
Congenital deficiency due tyrosinase deficieny or defective tyrosine transporters which leads to an increased risk for skin cancer.
Albinism
Autosomal recessive disorder that may either be due to decreased methionine, increased cysteine, B6, and folate or decreased affinity for cystathione synthase. This results in mental retardation, osteoporosis, tall stature, lens subluxation, and atherosclerosis.
Homocystinuria
Common inherited defect of renal tubular amino acid transporter for its parent compound, Ornithine, Lysine, and arginine, in the PCT of the kidneys. It eventually precipitates and cause staghorn caliculi. What is its treatment?
Cystinuria is treated with acetazolamide to alkalinize the urine
The initial and last three steps of heme synthesis occurs in?
The mitochondria
Heme synthesis summary
- Formation of ALA (via ALA synthase and B6)
- Formation of porphobilinogen
- Formation of uroporphyrinogen
- Formation of heme
Lead inhibits what two steps in heme synthesis?
- Introduction of Fe 2+ into protoporphyrin IX via ferrochelatase
- Condensation of two ALA molecules by zinc containing ALA dehydratase
Where is B6 a cofactors of?
- Heme synthesis
- Synthesis of cystathionine from homocysteine
- Transamination between alanine and a-ketoglutarate
Most common porphyria
Porphyria cutanea tarda
Which part of heme synthesis do these symptoms appear?
- Photosensitivity
- Neuropsychiatric symptoms
- After ring formation
2. Before ring formation
Pyridoxine ficiency associated with isoniazid therapy results in this histopathologic finding
Sideroblastic anemia with ringed sideroblast
Poisoning due to this heavy metal leads to coar basophilic stippling of RBC, peripheral neuropathy, lines in gums, increas in urinary ALA and free erythrocytes porphorin
lead poisoning
Microcytic hypo chromic anemia is found in
IDA
Thalassemia
Lead poisoning
Megaloblastic anemia is found in
Folate or B12 deficiency
Pernicious anemia
Normoyctic normochromic anemia is found in
Anemia of chronic kidney disease
Blood loss
Increase in MCHC is found in
Hereditary spherocytosis
Summary of heme degradation
- Formation of bilirubin
- Uptake of bilirubin by the liver
- Formation of bilirubin diglucoronide
- Secretion of bilirubin into bile
- Formation of urobilins in the intestine
Colors of biliverdin, bilirubin, urobilinogen, stercolin, urobilin
Biliverdin: green Bilirubin: red orange Urobilinogen: colorless Stercolin: brown orange red Urobilin: yellow
Examples of unconjugated hyperbilirubinemia
Hemolytic anemia Physiologic jaundice Crigler-najjar syndrome types I and II Gilbert syndrome Toxic hyperbilirubinemia
Examples of conjugated hyperbilirubinemia
Biliary tree obstruction
Dubin-Johnson syndrome
Rotor syndrome
What reaction measures total and direct bilirubin?
Van den bergs reaction
What enzyme activates fatty acid for metabolism use?
Fatty-acyl-CoA synthetase
Cofactor required for fatty acid activation
Vitamin B5 or Panthotenic acid
Energy required to activate fatty acid
2 ATP
What is the product formed in fatty acid synthesis?
Palmitate (16:0)
Where does fatty acid synthesis occur?
Cytosol
Major: Liver and lactating mammary glands
Minor: adipose tissue
Substrates for fatty acid synthesis
1 acetyl CoA
7 malonyl CoA
NADPH
ATP
Rate limiting step in fatty acid synthesis
Acetyl CoA + ATP -> malonyl CoA
Enzyme: acetyl CoA carboxylase
Steps in fatty acid synthesis
- Synthesis of cytoplasmic acetyl CoA (transfer of mitochondrial acetyl CoA to cytoplasm via citrate shuttle)
- Acetyl CoA carboxylation to malonyl CoA (via acetyl CoA carboxylase with biotin) [+ insulin, citrate]
- Assembly of palmitate (via fatty acid synthase and Vit B5)
Steps in palmitate assembly
- Condensation
- Reduction
- Dehydration
- Reduction
What is the fate of Palmitate after its production?
- Further elongation in SER and mitochondria
2. Desaturated in the ER (but not past the 9th carbon)
Main storage form of fatty acids
Triacylglycerols
Where does TAG synthesis occur?
Liver and adipose tissue
Sources of glycerol-3-phosphate
- DHAP from glycolysis (liver and adipose)
2. Phosphorylation of free glycerol (liver)
What enzyme is responsible for the release of free fatty acids from TAGs?
Hormone sensitive lipases
In the bloodstream fatty acids are always bound to?
Albumin
Hormone sensitive lipases can only release what free fatty acids stored in TAG?
C1 & 3 thus resulting in
TAG -> 2 free FA and 2-mono acyl glycerol
Where does B-oxidation of fatty acids occur
Mitochondria of all cells, but the fatty acid activation raft occurs in the Cytosol
Exception: RBC, kidney medulla, neurons, testes
Rate limiting step in B-oxidation
Fatty acyl CoA + carnitine -> fatty acyl carnitine + CoA
Enzyme: carnitine acyl transferase I
Cutoff number of carbons that do not need a shuttle
Less than 12 carbons
Steps in the carnitine shuttle
- Fatty acyl synthase activates the fatty acid
- Carnitine acyl transferase 1 attaches to fatty acyl to carnitine in the outer mitochondrial membrane
- Fatty acyl-carnitine is shuttle through the inner membrane
- Carnitine acyl transferase-2 transfers fatty acyl group back to a CoA in the mitochondrial matrix
Steps in beta oxidation
- Oxidation
- Hydratiion
- Oxidation
- Thiolysis
Beta oxidation of fatty acids with an odd number of carbon atoms releases?
Propionyl CoA which is converted to methylmalonyl coa (requires B12) then to succinyl CoA
Which is responsible for the conversion of very long chain fatty acids?
Peroxisomes but if unsaturated it requires 3,2 enol-CoA isomerase
Energy yield in ATP of beta oxidation of palmitate
129 ATP
7 NADH= 21
7 FAD= 14
8 acetyl CoA= 96
Activation = -2
Intake of this compound depletes the body’s NAD+ supply leading to accumulation Of fat in the liver
Alcohol
Type of carnitine deficiency which leads to impaired FA oxidation and ketogenesis with hypoglycemia?
CPT-1 deficiency
Type of carnitine deficiency which affects skeletal muscle and when severe the liver
CPT-2 deficiency
It is a disorder school results in decreased fatty acid oxidation. Without the ATP to support gluconeogenesis, hypoglycemia becomes profound which may eventually leads to SIDS. It is prevented by frequent feeding with high carbohydrate and low fat diet.
Medium-chain fatty acyl-CoA dehydrogenase (MCAD) deficiency
Associated with eating unripe fruit of the akee tree which contains hypoglycin thus activating MC and SC acyl CoA dehydrogenase
Jamaican vomiting sickness
Rare neurological disorder which results to the accumulation of phytanic acid found in plant food stuff which blocks Boxidation
Refsum disease
Cerebrohepatorenal syndrome resulting from the absence of peroxisomes in all tissues, it is characterized by liver dysfunction, jaundice, MR, weakness, hypotonia, and craniofacial dimorphism
Zellweger syndrome
Defect in peroxismal activation of VLCFA thus leading to its accumulation. Ssx: apathy, behavral change, then visual loss spasticity, ataxia. All due to the fact since VLCFA are found in myelin tissue.
X-lied adrenoleukodystrophy
Where does ketogenesis occur?
Liver mitochondria
Products of ketogenesis
Acetoacetate and B-hydroxybutyrate (fuel)
Acetone (cannot be used as fuel)
Rate limiting step of ketogenesis
Acetoacetyl CoA + acetyl CoA –(HMG CoA synthase)–> HMG CoA
What are the initial products that lead to the formation of acetyl CoA in ketogenolysis?
B-hydroxybutyrate -> acetoacetate -> acetyl coa
What peripheral tissues can oxidize ketone bodes?
Those with mitochondria like the renal cortex, brain, and skeletal muscle
Why cant liver convert acetoacetate to acetyl CoA?
It lacks succinyl-CoA acetoacetyl-CoA reductase (thiophorase)
What is the Urine test for ketones? What ketone type does not it detect?
Nitroprusside test
Does not detect b-hydroxybutyrate
Which part of cholesterol can a fatty acid attach to form a cholesteryl ester?
Single hydroxyl group of carbon 3 of the alpha ring
Where does cholesterol synthesis occur?
All cells in the Cytosol and SER majority of which are found in the liver and intestines
Substrates of cholesterol synthesis
Acetyl CoA, NADPH, ATP
Rate limiting step in cholesterol synthesis
HMG CoA –(HMG CoA reductase)–> mevalonate
Steps in Cholestid synthesis
- Biosynthesis of mevalonate
- Formation of isoprenoid units
- Isoprene unit is formed from 6 isoprenoid units
- Formation of lanosterol
- Formation of cholesterol
How is the cholesterol ring eliminated?
Through conversion to bile salts then secretion to bile
Bile acid synthesis, found in the liver and Cytosol, rate limiting enzyme is?
Cholesterol-7-a-hydroxylase
What are the primary bile acids?
Cholic acid
Chenocholic acid
What are the two amino acids used in bile acid conjugation to form bile salts?
Taurine and glycine
What are the secondary bile acids?
Deoxycholic acid
Lithocholic acid
Where does steroid hormone synthesis occur?
SER of the adrenal glands, ovaries and testes, and placenta
What is blocked by the drug aminogluthetimide?
The conversion of cholesterol to pregnenolone by desmolase
The enzyme responsible for the breakdown of TAG to FA and:
A) 2-MAG from diet
B) FREE glycerol from chylomicrons and VLDL
C) 2-MAG from adipose
A) pancreatic lipase
B) Lipoprotein lipase
C) hormone sensitive lipase
Lipoprotein with the largest percentage of TG
Chylomicrons
Lipoprotein with the largest percentage of cholesteryl esters
LDL
Chylomicrons transport TG and cholesterol from where to where?
Intestines to tissues
VLDL transports TG from where to where?
Liver to tissues
What apoprotein activates lipoprotein lipase?
APO-CII
What apolipoprotein uptakes remnants by the liver?
APO E
Apolipoprotein B-48 is used by chylomicrons which are created by the?
Epithelial cells
What apolipoprotein is secreted by the liver for VDL?
B-100
How does IDL become LDL?
By picking up cholesterol from HD!
Which apoprotein delivers cholesterol into cells?
LDL
Which apolipoprotein is used by HDL to activate lecithin cholesterol acyl transferase or LCAT to produce cholesterol esters?
APO-A1
Difference between Type II familial hypercholesterolemia and type IV familial hypertriglyceredemia?
The former has high LDL leader to xanthomas and xanthelasmas with increased risk of atherosclerosis and CHD
The latter has increased VLDL production leading to a triad of
- DM type 2
- CAD
- Obesity
Phospholipid is composed of
DAG
Alcohol
Phosphodiester bond
Most abundant phospholipid which is important in nervous transmission
Phosphatidylcholine
Phospholipid playing a role in apoptosis
Phosphatidyl serine
Phospholipid that is a major component of surfactant?
Dipalmitoylphosphatidylcholine
Phospholipid reservoir for arachidonic acid in the membranes
Phosphatidylinositol
What phospholipid is essential in mitochondrial function which is also used as a non-troponemal test due to its ability to act as an antigen?
Cardiolipin
Composition of these glycolipids: Ceramide Cerebroside Globoside Ganglioside Sulfatide
Ceramide: sphingosine + FA
Ceramide + \_\_\_\_\_\_\_\_ Glucose or galactose = Cerebroside Oligosacchardide = Globoside N-acetylneuramic acid = Ganglioside Sulfated galactose = Sulfatide
Hexosaminidase a ficiency leading to Ssx like cherry red macula, MR, hypotonia
Tay-Sachs disease
A-galactosidase deficiency leading to 3Rs: recessive x-linked, rash, renal failure
Fabrys disease
B-glucosidase deficiency leading to hepatosplenomegaly and erosion of long bones
Gauchers dissease
Sphingomyelinase deficiency leading to hepatosplenomegaly
Nieman-pick disease
The set of all proteins expressed by an individual at a particular time
Proteome
Aims to identify the entire complement of proteins elaborated by a cell under diverse conditions
Proteomics
What amino acid is needed to form ALA in heme synthesis?
Glycine combined with succinyl CoA
Which amino acid carries nitrogen from the liver?
Alanine
Which amino acids are implicated in maple syrup disease
valine, lucine, isoleucine
What enzyme is responsible for the buildup of phenyl lactate, phenyl acetate, and phenylpyruvate?
Phenylalanine hydroxylase
What amino acid is the precursor for niacin, serotonin, and melatonin?
Serotonin
What is the amino acid precursor for homocysteine?
Methionine
What amino acid contributes to the fibrous structure of collagen and interrupts a-helices in globular proteins?
Proline
Increase of the combination of this Amino acid is responsible for the curly hair of people?
Cysteine + cysteine = cystine
Amino acids with sites for O-linked glycosylation in the Golgi apparatus?
Serine and threonine
Site for n-linked glycosylation in the ER
Asparagine
Amino acid deaminated by an enzyme which results in the formation of ammonia. This is the major carrier of nitrogen to the liver from peripheral tissues,
Glutaminase deaminates glutamine
Amino acid used in the determination for Folic acid deficiency. What is the test called?
Histidine used in the N-forminoglutamate excretion test
Increased amounts of FIGu in urine by Folic acid deficient individuals after histindine intake
Precursor amino acid for creatinine, urea, nitric oxide
Arginine
Essential amino acids that cannot be synthesized by the body and must come from the diet
PVT TIM HALL always ARGues and never TYRes
Phenylalanine, valine, tryptophan, threonine’ isoleucine, methionine, histidine, argenine, Leucine, Lysine
Heme is a complex of?
Protoporphorin IX and heme
What is the Bohr effect?
HBO2 + H+ HbH + O2
What is an oxidized for of HB (Fe 3+) that does not bind O2 readily which could lead to chocolate cyanosis ? It is treated with oral methylene blue or ascorbic acid up to IV methylene blue.
Methemoglobin
Hemoglobin bound to carbon monoxide instead of O2 leading to a cherry pink color.
Carboxyhemoglobin
HB bound to carbon dioxide is called
Carbaminohenoglobin
Classification of alpha and beta thalassemia
Alpha: silent carrier, a-thalassemia trait, Hb H disease, hydrops fetalis
Beta: B-thalassemia minor and major
Most frequently affected collagen in Ehler Danlos syndrome leading to hyper extensible skin, tendency to bleed, hyper mobile joints, and increased risk for berry aneurysms.
Collagen type 3
Collagen I mutation leading to bendable and easily fractured bones. Accompanied with blue sclerae, hearing loss, and dental imperfections.
Osteogenesis imperfecta
Vitamin C deficiency leading to decreased hydroxylation of collagen. This leads to sore spongy gums, loose teeth, poor wound healing, and petecchiae on skin and mucous membranes.
Scurvy
Type IV collagen defect leading to hematuria and ESRD
Alpert syndrome
Collagen defect leading to kinky hair due to a deficiency of copper required by lysyl oxidase to strengthen collagen fibers.
Menke syndrome
Skin breaking and blisters as a result for minor trauma. This disease is due to a defect in collage VII.
Epidermolysis bullosa
Like collagen elastin has pro line and Lysine but has little and no?
Hydroxyproline
Hydroxylysine
Protein degradation mechanisms of nitrogen
Energy dependent ubiquitin-proteosome mechanism
Non-energy dependent degradation enzyme
Phases in amino acid catabolism
First phase: removal of a-amino group forming ammonia and a corresponding ketoacid
Second phase: carbon skeletons of a-ketoacids are converted to common intermediates of energy producing metabolic pathwas
Two main steps in nitrogen removal from AA
- Transamination
2. Oxidative deamination
Where does transamination occur?
All cells of the body
All but two amino acids transfer their amino groups to a-ketoglutarate except?
Lysine and threonine
What is the coenzyme for the two aminotransferases?
Pyridoxal phosphate (vitamin B6)
Oxidative deamination occurs where and for which amino acid only?
Liver and kidney
Only glutamate
Glutamate is oxidized by glutamate dehydrogenases and deaminated to form ?
free ammonia which is used to make urea
What does the conversion of glutamate to a-ketoglutarate yield? What about vice versa?
Glutamate -> a ketoglutarate NH3 + NADH
A ketoglutarate -> glutamate NADP+ + NH3
How is excess nitrogen removal from peripheral tissues removed?
- Glutamine: via glutamate + ammonia (through Flutamide synthaetase)
- Alanine: via glucose -> pyruvate + glutamate -> alanine cycle
Glutaminase deaminates glutamine to produce ammonium ion which is excreted from the body. Where are the two tissues this enzyme could be located?
Kidneys and small intestines
Another name for urea cycle
Ornithine cycle or krebs-henseleit cycle
What are the donors of the urea molecule?
- NH3 from free ammonia
- NH3 from aspartate
- 1C and 1O from CO2
Reactions in the urea cycle
- Formation of carbamoyl phosphate (via carbamoyl phosphate synthetase I)
- Formation of citrulline (via Ornithine transcarbamoylase)
- Synthesis of arginosuccinate (arginosuccinate synthetase)
- Cleavage of arginosuccinate to form arginine (Arginosuccinase)
- Arginine cleavage to yield urea and Ornithine (arginase)
Rate limiting step of urea cycle
Carbamoyl phosphate synthetase I
Energy requirement of urea cycle
4 ATP
Co factors of urea cycle
N-acetylglutamate
Biotin
Hereditary hyperammonemia produces symptoms such as
Hyperammonemia, elevated blood glutamine, decreased BUN
Parents with lethargy, vomiting, hyperventilation, convulsions, cerebral edema, coma, and death
Treatment for hereditary hyperammonemia
Low protein diet
Administration of sodium benzoate or phenylpyruvate to capture and excrete excess nitrogen
Ketogenic carbon skeletons of AA
Leucine
Lysine
Yields acetoacetate or acetyl-coa/ acetoacetyl-coa
Ketogenic and glucogenic carbon skeletons of AA
WIFY Phenylalanine Isoleucine Tryptophan Tyrosine
Yields Ketogenic and glucose or glycogen by products
This amino acid acts as a raw material in the biosynthesis of Heme, purines, creatine
Glycine
This amino acid acts as a raw material in the biosynthesis of phospholipid, sphingolipid, purines, thymine
Serine
This amino acid acts as a raw material in the biosynthesis of GABA
Glutamate
This amino acid acts as a raw material in the biosynthesis of creatine, polyamines, nitric oxide
Arginine
This amino acid acts as a raw material in the biosynthesis of serotonin, NAD+, NADP+, melatonin
Tryptophan
This amino acid acts as a raw material in the biosynthesis of catecholamines, thyroid hormones, melanin
Tyrosine
3 hormones dependent on tyrosine
Thyroid hormones
Melanin
Catecholamines
Deficiency of homogenistic acid oxidase in the degrative pathway of tyrosine which results in urine turning to black on standing with dark connective tissues (ochronosis)
Alkaptonuria
Congenital deficiency due tyrosinase deficieny or defective tyrosine transporters which leads to an increased risk for skin cancer.
Albinism
Autosomal recessive disorder that may either be due to decreased methionine, increased cysteine, B6, and folate or decreased affinity for cystathione synthase. This results in mental retardation, osteoporosis, tall stature, lens subluxation, and atherosclerosis.
Homocystinuria
Common inherited defect of renal tubular amino acid transporter for its parent compound, Ornithine, Lysine, and arginine, in the PCT of the kidneys. It eventually precipitates and cause staghorn caliculi. What is its treatment?
Cystinuria is treated with acetazolamide to alkalinize the urine
The initial and last three steps of heme synthesis occurs in?
The mitochondria
Heme synthesis summary
- Formation of ALA (via ALA synthase and B6)
- Formation of porphobilinogen
- Formation of uroporphyrinogen
- Formation of heme
Lead inhibits what two steps in heme synthesis?
- Introduction of Fe 2+ into protoporphyrin IX via ferrochelatase
- Condensation of two ALA molecules by zinc containing ALA dehydratase
Where is B6 a cofactors of?
- Heme synthesis
- Synthesis of cystathionine from homocysteine
- Transamination between alanine and a-ketoglutarate
Most common porphyria
Porphyria cutanea tarda
Which part of heme synthesis do these symptoms appear?
- Photosensitivity
- Neuropsychiatric symptoms
- After ring formation
2. Before ring formation
Pyridoxine ficiency associated with isoniazid therapy results in this histopathologic finding
Sideroblastic anemia with ringed sideroblast
Poisoning due to this heavy metal leads to coar basophilic stippling of RBC, peripheral neuropathy, lines in gums, increas in urinary ALA and free erythrocytes porphorin
lead poisoning
Microcytic hypo chromic anemia is found in
IDA
Thalassemia
Lead poisoning
Megaloblastic anemia is found in
Folate or B12 deficiency
Pernicious anemia
Normoyctic normochromic anemia is found in
Anemia of chronic kidney disease
Blood loss
Increase in MCHC is found in
Hereditary spherocytosis
What reaction measures total and direct bilirubin?
Van den bergs reaction
Examples of conjugated hyperbilirubinemia
Biliary tree obstruction
Dubin-Johnson syndrome
Rotor syndrome
Examples of unconjugated hyperbilirubinemia
Hemolytic anemia Physiologic jaundice Crigler-najjar syndrome types I and II Gilbert syndrome Toxic hyperbilirubinemia
Colors of biliverdin, bilirubin, urobilinogen, stercolin, urobilin
Biliverdin: green Bilirubin: red orange Urobilinogen: colorless Stercolin: brown orange red Urobilin: yellow
Summary of heme degradation
- Formation of bilirubin
- Uptake of bilirubin by the liver
- Formation of bilirubin diglucoronide
- Secretion of bilirubin into bile
- Formation of urobilins in the intestine
What enzyme activates fatty acid for metabolism use?
Fatty-acyl-CoA synthetase
Cofactor required for fatty acid activation
Vitamin B5 or Panthotenic acid
Energy required to activate fatty acid
2 ATP
What is the product formed in fatty acid synthesis?
Palmitate (16:0)
Where does fatty acid synthesis occur?
Cytosol
Major: Liver and lactating mammary glands
Minor: adipose tissue
Substrates for fatty acid synthesis
1 acetyl CoA
7 malonyl CoA
NADPH
ATP
Rate limiting step in fatty acid synthesis
Acetyl CoA + ATP -> malonyl CoA
Enzyme: acetyl CoA carboxylase
Steps in fatty acid synthesis
- Synthesis of cytoplasmic acetyl CoA (transfer of mitochondrial acetyl CoA to cytoplasm via citrate shuttle)
- Acetyl CoA carboxylation to malonyl CoA (via acetyl CoA carboxylase with biotin) [+ insulin, citrate]
- Assembly of palmitate (via fatty acid synthase and Vit B5)
Steps in palmitate assembly
- Condensation
- Reduction
- Dehydration
- Reduction
What is the fate of Palmitate after its production?
- Further elongation in SER and mitochondria
2. Desaturated in the ER (but not past the 9th carbon)
Main storage form of fatty acids
Triacylglycerols
Where does TAG synthesis occur?
Liver and adipose tissue
Sources of glycerol-3-phosphate
- DHAP from glycolysis (liver and adipose)
2. Phosphorylation of free glycerol (liver)
What enzyme is responsible for the release of free fatty acids from TAGs?
Hormone sensitive lipases
In the bloodstream fatty acids are always bound to?
Albumin
Hormone sensitive lipases can only release what free fatty acids stored in TAG?
C1 & 3 thus resulting in
TAG -> 2 free FA and 2-mono acyl glycerol
Where does B-oxidation of fatty acids occur
Mitochondria of all cells, but the fatty acid activation raft occurs in the Cytosol
Exception: RBC, kidney medulla, neurons, testes
Rate limiting step in B-oxidation
Fatty acyl CoA + carnitine -> fatty acyl carnitine + CoA
Enzyme: carnitine acyl transferase I
Cutoff number of carbons that do not need a shuttle
Less than 12 carbons
Steps in the carnitine shuttle
- Fatty acyl synthase activates the fatty acid
- Carnitine acyl transferase 1 attaches to fatty acyl to carnitine in the outer mitochondrial membrane
- Fatty acyl-carnitine is shuttle through the inner membrane
- Carnitine acyl transferase-2 transfers fatty acyl group back to a CoA in the mitochondrial matrix
Steps in beta oxidation
- Oxidation
- Hydratiion
- Oxidation
- Thiolysis
Beta oxidation of fatty acids with an odd number of carbon atoms releases?
Propionyl CoA which is converted to methylmalonyl coa (requires B12) then to succinyl CoA
Which is responsible for the conversion of very long chain fatty acids?
Peroxisomes but if unsaturated it requires 3,2 enol-CoA isomerase
Energy yield in ATP of beta oxidation of palmitate
129 ATP
7 NADH= 21
7 FAD= 14
8 acetyl CoA= 96
Activation = -2
Intake of this compound depletes the body’s NAD+ supply leading to accumulation Of fat in the liver
Alcohol
Type of carnitine deficiency which leads to impaired FA oxidation and ketogenesis with hypoglycemia?
CPT-1 deficiency
Type of carnitine deficiency which affects skeletal muscle and when severe the liver
CPT-2 deficiency
It is a disorder school results in decreased fatty acid oxidation. Without the ATP to support gluconeogenesis, hypoglycemia becomes profound which may eventually leads to SIDS. It is prevented by frequent feeding with high carbohydrate and low fat diet.
Medium-chain fatty acyl-CoA dehydrogenase (MCAD) deficiency
Associated with eating unripe fruit of the akee tree which contains hypoglycin thus activating MC and SC acyl CoA dehydrogenase
Jamaican vomiting sickness
Rare neurological disorder which results to the accumulation of phytanic acid found in plant food stuff which blocks Boxidation
Refsum disease
Cerebrohepatorenal syndrome resulting from the absence of peroxisomes in all tissues, it is characterized by liver dysfunction, jaundice, MR, weakness, hypotonia, and craniofacial dimorphism
Zellweger syndrome
Defect in peroxismal activation of VLCFA thus leading to its accumulation. Ssx: apathy, behavral change, then visual loss spasticity, ataxia. All due to the fact since VLCFA are found in myelin tissue.
X-lied adrenoleukodystrophy
Where does ketogenesis occur?
Liver mitochondria
Products of ketogenesis
Acetoacetate and B-hydroxybutyrate (fuel)
Acetone (cannot be used as fuel)
Rate limiting step of ketogenesis
Acetoacetyl CoA + acetyl CoA –(HMG CoA synthase)–> HMG CoA
What are the initial products that lead to the formation of acetyl CoA in ketogenolysis?
B-hydroxybutyrate -> acetoacetate -> acetyl coa
What peripheral tissues can oxidize ketone bodes?
Those with mitochondria like the renal cortex, brain, and skeletal muscle
Why cant liver convert acetoacetate to acetyl CoA?
It lacks succinyl-CoA acetoacetyl-CoA reductase (thiophorase)
What is the Urine test for ketones? What ketone type does not it detect?
Nitroprusside test
Does not detect b-hydroxybutyrate
Which part of cholesterol can a fatty acid attach to form a cholesteryl ester?
Single hydroxyl group of carbon 3 of the alpha ring
Where does cholesterol synthesis occur?
All cells in the Cytosol and SER majority of which are found in the liver and intestines
Substrates of cholesterol synthesis
Acetyl CoA, NADPH, ATP
Rate limiting step in cholesterol synthesis
HMG CoA –(HMG CoA reductase)–> mevalonate
Steps in Cholestid synthesis
- Biosynthesis of mevalonate
- Formation of isoprenoid units
- Isoprene unit is formed from 6 isoprenoid units
- Formation of lanosterol
- Formation of cholesterol
How is the cholesterol ring eliminated?
Through conversion to bile salts then secretion to bile
Bile acid synthesis, found in the liver and Cytosol, rate limiting enzyme is?
Cholesterol-7-a-hydroxylase
What are the primary bile acids?
Cholic acid
Chenocholic acid
What are the two amino acids used in bile acid conjugation to form bile salts?
Taurine and glycine
What are the secondary bile acids?
Deoxycholic acid
Lithocholic acid
Where does steroid hormone synthesis occur?
SER of the adrenal glands, ovaries and testes, and placenta
What is blocked by the drug aminogluthetimide?
The conversion of cholesterol to pregnenolone by desmolase
The enzyme responsible for the breakdown of TAG to FA and:
A) 2-MAG from diet
B) FREE glycerol from chylomicrons and VLDL
C) 2-MAG from adipose
A) pancreatic lipase
B) Lipoprotein lipase
C) hormone sensitive lipase
Lipoprotein with the largest percentage of TG
Chylomicrons
Lipoprotein with the largest percentage of cholesteryl esters
LDL
Chylomicrons transport TG and cholesterol from where to where?
Intestines to tissues
VLDL transports TG from where to where?
Liver to tissues
What apoprotein activates lipoprotein lipase?
APO-CII
What apolipoprotein uptakes remnants by the liver?
APO E
Apolipoprotein B-48 is used by chylomicrons which are created by the?
Epithelial cells
What apolipoprotein is secreted by the liver for VDL?
B-100
How does IDL become LDL?
By picking up cholesterol from HD!
Which apoprotein delivers cholesterol into cells?
LDL
Which apolipoprotein is used by HDL to activate lecithin cholesterol acyl transferase or LCAT to produce cholesterol esters?
APO-A1
Difference between Type II familial hypercholesterolemia and type IV familial hypertriglyceredemia?
The former has high LDL leader to xanthomas and xanthelasmas with increased risk of atherosclerosis and CHD
The latter has increased VLDL production leading to a triad of
- DM type 2
- CAD
- Obesity
Phospholipid is composed of
DAG
Alcohol
Phosphodiester bond
Most abundant phospholipid which is important in nervous transmission
Phosphatidylcholine
Phospholipid playing a role in apoptosis
Phosphatidyl serine
Phospholipid that is a major component of surfactant?
Dipalmitoylphosphatidylcholine
Phospholipid reservoir for arachidonic acid in the membranes
Phosphatidylinositol
What phospholipid is essential in mitochondrial function which is also used as a non-troponemal test due to its ability to act as an antigen?
Cardiolipin
Composition of these glycolipids: Ceramide Cerebroside Globoside Ganglioside Sulfatide
Ceramide: sphingosine + FA
Ceramide + \_\_\_\_\_\_\_\_ Glucose or galactose = Cerebroside Oligosacchardide = Globoside N-acetylneuramic acid = Ganglioside Sulfated galactose = Sulfatide
Hexosaminidase a ficiency leading to Ssx like cherry red macula, MR, hypotonia
Tay-Sachs disease
A-galactosidase deficiency leading to 3Rs: recessive x-linked, rash, renal failure
Fabrys disease
B-glucosidase deficiency leading to hepatosplenomegaly and erosion of long bones
Gauchers dissease
Sphingomyelinase deficiency leading to hepatosplenomegaly
Nieman-pick disease
The set of all proteins expressed by an individual at a particular time
Proteome
Aims to identify the entire complement of proteins elaborated by a cell under diverse conditions
Proteomics
What amino acid is needed to form ALA in heme synthesis?
Glycine combined with succinyl CoA
Which amino acid carries nitrogen from the liver?
Alanine
Which amino acids are implicated in maple syrup disease
valine, lucine, isoleucine
What enzyme is responsible for the buildup of phenyl lactate, phenyl acetate, and phenylpyruvate?
Phenylalanine hydroxylase
What amino acid is the precursor for niacin, serotonin, and melatonin?
Serotonin
What is the amino acid precursor for homocysteine?
Methionine
What amino acid contributes to the fibrous structure of collagen and interrupts a-helices in globular proteins?
Proline
Increase of the combination of this Amino acid is responsible for the curly hair of people?
Cysteine + cysteine = cystine
Amino acids with sites for O-linked glycosylation in the Golgi apparatus?
Serine and threonine
Site for n-linked glycosylation in the ER
Asparagine
Amino acid deaminated by an enzyme which results in the formation of ammonia. This is the major carrier of nitrogen to the liver from peripheral tissues,
Glutaminase deaminates glutamine
Amino acid used in the determination for Folic acid deficiency. What is the test called?
Histidine used in the N-forminoglutamate excretion test
Increased amounts of FIGu in urine by Folic acid deficient individuals after histindine intake
Precursor amino acid for creatinine, urea, nitric oxide
Arginine
Essential amino acids that cannot be synthesized by the body and must come from the diet
PVT TIM HALL always ARGues and never TYRes
Phenylalanine, valine, tryptophan, threonine’ isoleucine, methionine, histidine, argenine, Leucine, Lysine
Heme is a complex of?
Protoporphorin IX and heme
What is the Bohr effect?
HBO2 + H+ HbH + O2
What is an oxidized for of HB (Fe 3+) that does not bind O2 readily which could lead to chocolate cyanosis ? It is treated with oral methylene blue or ascorbic acid up to IV methylene blue.
Methemoglobin
Hemoglobin bound to carbon monoxide instead of O2 leading to a cherry pink color.
Carboxyhemoglobin
HB bound to carbon dioxide is called
Carbaminohenoglobin
Classification of alpha and beta thalassemia
Alpha: silent carrier, a-thalassemia trait, Hb H disease, hydrops fetalis
Beta: B-thalassemia minor and major
Most frequently affected collagen in Ehler Danlos syndrome leading to hyper extensible skin, tendency to bleed, hyper mobile joints, and increased risk for berry aneurysms.
Collagen type 3
Collagen I mutation leading to bendable and easily fractured bones. Accompanied with blue sclerae, hearing loss, and dental imperfections.
Osteogenesis imperfecta
Vitamin C deficiency leading to decreased hydroxylation of collagen. This leads to sore spongy gums, loose teeth, poor wound healing, and petecchiae on skin and mucous membranes.
Scurvy
Type IV collagen defect leading to hematuria and ESRD
Alpert syndrome
Collagen defect leading to kinky hair due to a deficiency of copper required by lysyl oxidase to strengthen collagen fibers.
Menke syndrome
Skin breaking and blisters as a result for minor trauma. This disease is due to a defect in collage VII.
Epidermolysis bullosa
Like collagen elastin has pro line and Lysine but has little and no?
Hydroxyproline
Hydroxylysine
Protein degradation mechanisms of nitrogen
Energy dependent ubiquitin-proteosome mechanism
Non-energy dependent degradation enzyme
Phases in amino acid catabolism
First phase: removal of a-amino group forming ammonia and a corresponding ketoacid
Second phase: carbon skeletons of a-ketoacids are converted to common intermediates of energy producing metabolic pathwas
Two main steps in nitrogen removal from AA
- Transamination
2. Oxidative deamination
Where does transamination occur?
All cells of the body
All but two amino acids transfer their amino groups to a-ketoglutarate except?
Lysine and threonine
What is the coenzyme for the two aminotransferases?
Pyridoxal phosphate (vitamin B6)
Oxidative deamination occurs where and for which amino acid only?
Liver and kidney
Only glutamate
Glutamate is oxidized by glutamate dehydrogenases and deaminated to form ?
free ammonia which is used to make urea
What does the conversion of glutamate to a-ketoglutarate yield? What about vice versa?
Glutamate -> a ketoglutarate NH3 + NADH
A ketoglutarate -> glutamate NADP+ + NH3
How is excess nitrogen removal from peripheral tissues removed?
- Glutamine: via glutamate + ammonia (through Flutamide synthaetase)
- Alanine: via glucose -> pyruvate + glutamate -> alanine cycle
Glutaminase deaminates glutamine to produce ammonium ion which is excreted from the body. Where are the two tissues this enzyme could be located?
Kidneys and small intestines
Another name for urea cycle
Ornithine cycle or krebs-henseleit cycle
What are the donors of the urea molecule?
- NH3 from free ammonia
- NH3 from aspartate
- 1C and 1O from CO2
Reactions in the urea cycle
- Formation of carbamoyl phosphate (via carbamoyl phosphate synthetase I)
- Formation of citrulline (via Ornithine transcarbamoylase)
- Synthesis of arginosuccinate (arginosuccinate synthetase)
- Cleavage of arginosuccinate to form arginine (Arginosuccinase)
- Arginine cleavage to yield urea and Ornithine (arginase)
Rate limiting step of urea cycle
Carbamoyl phosphate synthetase I
Energy requirement of urea cycle
4 ATP
Co factors of urea cycle
N-acetylglutamate
Biotin
Hereditary hyperammonemia produces symptoms such as
Hyperammonemia, elevated blood glutamine, decreased BUN
Parents with lethargy, vomiting, hyperventilation, convulsions, cerebral edema, coma, and death
Treatment for hereditary hyperammonemia
Low protein diet
Administration of sodium benzoate or phenylpyruvate to capture and excrete excess nitrogen
Ketogenic carbon skeletons of AA
Leucine
Lysine
Yields acetoacetate or acetyl-coa/ acetoacetyl-coa
