Biochemistry- Metabolism Flashcards
Metabolism sites
Mitochondria
Fatty acid oxidation (β-oxidation), acetyl- CoA production, TCA cycle, oxidative phosphorylation, ketogenesis.
Metabolism sites
Cytoplasm Glycolysis
HMP shunt, and synthesis of steroids (SER), proteins (ribosomes, RER), fatty acids, cholesterol, and nucleotides.
Metabolism sites
Both
Heme synthesis, Urea cycle, Gluconeogenesis. HUGs take two (ie, both).
Enzyme terminology
Kinase Phosphorylase Phosphatase Dehydrogenase Hydroxylase Carboxylase Carboxylase Synthase/synthetase
Rate-determining enzymes of metabolic processes Glycolysis Gluconeogenesis TCA cycle Glycogenesis Glycogenolysis HMP shunt
Phosphofructokinase-1 (PFK-1) Fructose-1,6-bisphosphatase Isocitrate dehydrogenase Glycogen synthase Glycogen phosphorylase Glucose-6-phosphate dehydrogenase (G6PD)
Rate-determining enzymes of metabolic processes De novo pyrimidine synthesis De novo purine synthesis Urea cycle Fatty acid synthesis Fatty acid oxidation Ketogenesis Cholesterol synthesis
- Carbamoyl phosphate synthetase II
- Glutamine-phosphoribosylpyrophosphate (PRPP) amidotransferase
- Carbamoyl phosphate synthetase I
- Acetyl-CoA carboxylase (ACC)
- Carnitine acyltransferase I
- HMG-CoA synthase
- HMG-CoA reductase
Arsenic causes glycolysis to…
produce zero net ATP.
Arsenic poisoning clinical findings: vomiting, rice-water stools, garlic breath, QT prolongation.
Activated carriers: ATP NADH, NADPH, FADH2 CoA, lipoamide Biotin Tetrahydrofolates S-adenosylmethionine (SAM) TPP
Phosphoryl groups Electrons Acyl groups CO2 1-carbon units CH3 groups Aldehydes
NADPH is used in:
Anabolic processes
Respiratory burst
Cytochrome P-450 system
Glutathione reductase
NAD+ is generally used in…
NADPH is used in…
Catabolic processes to carry reducing equivalents away as NADH.
Anabolic processes (steroid and fatty acid synthesis) as a supply of reducing equivalents.
Hexokinase : Location Km Vmax Induced by insulin Feedback-inhibited by glucose-6-phosphate
Most tissues, except liver and pancreatic β cells. Lower (higher affinity) Lower (lower capacity) No Yes
Glucokinase: Location Km Vmax Induced by insulin Feedback-inhibited by glucose-6-phosphate
Liver, β cells of pancreas. Higher (lower affinity) Higher (higher capacity) Yes No
Glycolysis regulation, key enzymes
Hexokinase/glucokinase
Phosphofructokinase-1
Phosphoglycerate kinase
Pyruvate kinase
Regulation by fructose-2,6- bisphosphate
FBPase-2 (fructose bisphosphatase-2) and PFK-2 (phosphofructokinase-2) are the same bifunctional
enzyme whose function is reversed by phosphorylation by protein kinase A.
Fasting state: FBPase-2
Fed state: PFK-2
Pyruvate dehydrogenase complex
The Lovely Co-enzymes For Nerds:
- Thiamine pyrophosphate (B1)
- Lipoic acid (inhibited by arsenic)
- CoA (B5, pantothenic acid)
- FAD (B2, riboflavin)
- NAD+ (B3, niacin)
Pyruvate dehydrogenase complex deficiency
Findings
TREATMENT
pyruvate that gets shunted to lactate (via LDH) and alanine (via ALT). X-linked.
Neurologic defects, lactic acidosis, higher serum
alanine starting in infancy.
Lysine and Leucine—the onLy pureLy ketogenic
amino acids.
Functions of different pyruvate metabolic
pathways (and their associated cofactors):
Alanine aminotransferase (B6) Pyruvate carboxylase (biotin) Pyruvate dehydrogenase (B1, B2, B3, B5, lipoic acid) Lactic acid dehydrogenase (B3)
TCA cycle (Krebs cycle)
Citrate Is Krebs’ Starting Substrate For Making
Oxaloacetate:
Citrato, Isocitrato, alfaKetoglutarato, Succinil coa, Succinato, malato, Fumarato, Oxalato.
Electron transport chain and oxidative phosphorylation
NADH electrons from glycolysis enter mitochondria via the malate-aspartate or glycerol-3-phosphate shuttle.
FADH2 electrons are transferred to complex II (succinato deshidrogenasa)
Electron transport inhibitors
RotenONE: complex ONE inhibitor.
“An-3-mycin” (antimycin) A: complex 3 inhibitor.
CO/CN: complex 4 inhibitors (4 letters).
ATP synthase inhibitors
Oligomycin
Uncoupling agents: ATP synthesis stops, but electron transport continues. Produces heat.
2,4-Dinitrophenol (used illicitly for weight
loss), aspirin, thermogenin.
Gluconeogenesis, irreversible enzymes
Pathway Produces Fresh Glucose.
Piruvato carboxilasa
Phosphoenolpiruvato carboxicinasa
Fructosa 1-6 bifosfatasa
Glucosa 6 fosfatasa
HMP shunt (pentose phosphate pathway)
FUNTCTION
REACTIONS
Provides a source of NADPH.
Yields ribose for nucleotide synthesis and glycolytic intermediates.
Oxidative (irreversible): Glucose-6-P dehydrogenase
NonOxidative (reversible): Phosphopentose isomerase,
transketolases (B1).
Glucose-6-phosphate dehydrogenase deficiency
X-linked recessive disorder; most common human enzyme deficiency.
Heinz bodies—denatured Hemoglobin precipitates within RBCs. Bite cells—result from the phagocytic removal of Heinz bodies by splenic macrophages.
Essential fructosuria
Defect in fructokinase. Autosomal recessive. A benign, asymptomatic condition.
Symptoms: fructose appears in blood and urine.
Fructose intolerance
Hereditary deficiency of aldolase B. Autosomal recessive. Fructose-1-phosphate accumulates, results in inhibition of glycogenolysis and gluconeogenesis.
Symptoms following consumption of fruit, juice, or honey: hypoglycemia, jaundice, cirrhosis, vomiting.
Galactokinase deficiency
deficiency of galactokinase. Galactitol accumulates. mild condition. Autosomal recessive
Galactosemia and galactosuria; infantile cataracts.
Classic galactosemia
Absence of galactose-1-phosphate uridyltransferase. Autosomal recessive.
Begins feeding and include failure to thrive, jaundice, hepatomegaly, infantile cataracts, intellectual disability. Can predispose to E coli sepsis in neonates.
Fructose is to Aldolase B as Galactose is to
UridylTransferase (FAB GUT).
Fructose intolerance
Classic galactosemia
Sorbitol synthesis and enzyme location
Aldose reductase and Sorbitol dehydrogenase.
Lens has primarily aldose reductase. Retina, Kidneys, and Schwann cells have only aldose reductase (LuRKS).
Amino acids
Essential
Glucogenic: methionine (Met), histidine (His),
valine (Val). “I met his valentine, she is so sweet (glucogenic)”.
Glucogenic/ketogenic: isoleucine (Ile), phenylalanine (Phe), threonine (Thr), tryptophan (Trp).
Ketogenic: leucine (Leu), lysine (Lys)
Basic
His lys (lies) are basic:
Histidine (His), lysine (Lys), arginine (Arg).
Arg is most basic
Acidic
Aspartic acid (Asp) and glutamic acid (Glu).
Urea cycle
Excess nitrogen generated by Amino acid catabolism is converted to urea and excreted by the kidneys.
Ordinarily, Careless Crappers Are Also
Frivolous About Urination:
Ornitina Carbamoil fosfato Citrulina Aspartato Argininosuccinato Fumarato Arginina Urea
Hyperammonemia
Can be acquired (eg, liver disease) or hereditary
(eg, urea cycle enzyme deficiencies).
tremor (asterixis), slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision.
May be given to reduce ammonia levels:
- Lactulose to acidify the GI tract and trap
NH4 + for excretion. - Antibiotics (eg, rifaximin) to reduce colonic
ammoniagenic bacteria. - Benzoate, phenylacetate, or phenylbutyrate react with glycine or glutamine, forming products that are renally excreted.
Ornithine transcarbamylase deficiency
X-linked recessive. Interferes with the body’s ability to eliminate ammonia. Often evident in the first few days of life.
Higher orotic acid in blood and urine, Decreased BUN, symptoms of hyperammonemia.
Amino acid derivatives:
Phenylalanine
BH4… Tyrosine + BH4… Dopa + B6… Dopamine + Vitaminca C… Norepinefrina + SMA… Epinefrina
Amino acid derivatives:
Tryptophan
B2 + B6… Niacin
BH4 + B6… Serotonina… Melatonina
Amino acid derivatives:
Histidine
Glycine
B6… Histamine
B6… porfirina
Amino acid derivatives:
Glutamate
B6… GABA
Glutation
Amino acid derivatives:
Arginine
Creatinina
Urea
BH4… Oxido nítrico
Albinism mutation
Mutación en la tirosinasa
DOPA + Tirosinasa = Melanina
Carbidopa
inhibits DOPA decarboxylase
Phenylketonuria (PKU)
Phenylalanine hydroxylase or tetrahydrobiopterin (BH4)
Autosomal recessive
Findings: intellectual disability, growth retardation, seizures, fair skin, eczema, musty body odor.
Maternal PKU
lack of proper dietary therapy during pregnancy.
Findings in infant: microcephaly, intellectual disability, growth retardation, congenital heart defects.
Maple syrup urine
disease
Autosomal recessive
Blocked degradation of branched amino acids (Isoleucine, Leucine, Valine) due to branched-chain α-ketoacid dehydrogenase (B1).
Causes severe CNS defects, intellectual disability, and death.
Alkaptonuria
Autosomal recessive. Deficiency of homogentisate oxidase in the degradative pathway of tyrosine to fumarate.
Findings: bluish-black connective tissue, ear cartilage, and sclerae (ochronosis); urine turns black on prolonged exposure to air. May have debilitating arthralgias (homogentisic acid toxic to cartilage).
Homocystinuria
Types
(all autosomal recessive):
Cystathionine synthase deficiency
Reduced affinity of cystathionine synthase for
pyridoxal phosphate.
Methionine synthase deficiency
Homocystinuria findings
HOMOCYstinuria:
- Homocysteine in urine
- Osteoporosis
- Marfanoid habitus
- Ocular changes
- Cardiovascular effects
- kYphosis
- intellectual disability.
Cystinuria
Defect of renal PCT and intestinal amino acid transporter that prevents reabsorption of Cystine, Ornithine, Lysine, and Arginine (COLA).
Autosomal recessive. Common (1:7000).
Urinary cyanide-nitroprusside test is diagnostic.
Glycogen storage diseases
Periodic acid–Schiff stain identifies glycogen and is useful in identifying these diseases.
“Very Poor Carbohydrate Metabolism”.
Types I, II, III, and V are autosomal recessive.
Von Gierke
Pompe
Cori
McArdle
Von Gierke disease
type I
Glucose-6-phosphatase deficiency
Severe fasting hypoglycemia, aumented Glycogen in liver, higher blood lactate, higher triglycerides, higher uric acid (Gout), and hepatomegaly.
Pompe disease (type II)
PomPe trashes the PumP (1,4) (heart, liver, and muscle).
Lysosomal acid α-1,4- glucosidase (acid maltase)
Cardiomegaly, hypertrophic cardiomyopathy, hypotonia,
exercise intolerance, and systemic findings lead to early
death.
Cori disease (type III)
Debranching enzyme (α-1,6-glucosidase)
Milder form of von Gierke (type I) with normal blood
lactate levels.
McArdle disease (type V)
Skeletal muscle glycogen phosphorylase (Myophosphorylase).
Higher Glycogen in muscle, but muscle cannot break it down, painful Muscle cramps, Myoglobinuria (red urine)
with strenuous exercise, and arrhythmia from electrolyte
abnormalities.
Lysosomal storage diseases
Tay-Sachs disease
HeXosaminidase A (“TAy-SaX”). AR. GM2 ganglioside accumulates.
Neurodegeneration, developmental delay, “cherry-red”
spot on macula, lysosomes with onion skin, no hepatosplenomegaly (vs Niemann-Pick).
Lysosomal storage diseases
Fabry disease
α-galactosidase A. XR.
Ceramide trihexoside accumulates.
Early: Triad of episodic peripheral neuropathy, angiokeratomas, hypohidrosis.
Lysosomal storage diseases
Metachromatic leukodystrophy
Arylsulfatase A. AR.
Cerebroside sulfate accumulates.
Central and peripheral demyelination with ataxia, dementia.
Lysosomal storage diseases
Krabbe disease
Galactocerebrosidase.AR.
Galactocerebroside, psychosine accumulates.
Peripheral neuropathy, destruction of oligodendrocytes, developmental delay, optic atrophy, globoid cells.
Lysosomal storage diseases
Gaucher disease
Most common. Glucocerebrosidase (β-glucosidase); AR.
Glucocerebroside accumulates.
Hepatosplenomegaly, pancytopenia, osteoporosis, avascular necrosis of femur, bone crises, Gaucher cells.
Lysosomal storage diseases
Niemann-Pick disease
Sphingomyelinase. AR.
Sphingomyelin accumulates.
Progressive neurodegenera tion, hepatosplenomegaly, foam cells (lipid-laden macrophages), “cherry-red” spot on macula.
Mucopolysaccharidoses
Hurler syndrome
α-l-iduronidase. AR.
Heparan sulfate, dermatan sulfate accumulates.
Developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly.
Mucopolysaccharidoses
Hunter syndrome
Iduronate sulfatase. XR.
Heparan sulfate, dermatan sulfate accumulates.
Mild Hurler + aggressive behavior, no corneal clouding.
Higher incidence of Tay-Sachs, Niemann-Pick, and
some forms of Gaucher disease in…
Ashkenazi
Jews.
Fatty acid synthesis requires…
“SYtrate” = SYnthesis.
Transport of citrate from mitochondria to cytosol.
Long-chain fatty acid (LCFA) degradation requires…
CARnitine = CARnage of fatty acids.
carnitine-dependent transport into the mitochondrial matrix.
Systemic 1° carnitine deficiency
inherited defect in transport of LCFAs into the
mitochondria and toxic accumulation.
Causes weakness, hypotonia, and hypoketotic hypoglycemia.
Medium-chain acyl-CoA dehydrogenase
deficiency
lower ability to break down fatty acids into acetyl-CoA accumulation of fatty acyl carnitines in the blood with hypoketotic hypoglycemia.
Causes vomiting, lethargy, seizures, coma, liver dysfunction. Can lead to sudden death in infants or children.
Treat by avoiding fasting.
Ketogenesis
In prolonged starvation and diabetic ketoacidosis, oxaloacetate is depleted for gluconeogenesis.
In alcoholism, excess NADH shunts oxaloacetate to malate.
Both processes cause a buildup of acetyl-CoA, which shunts glucose and FFA toward the production of ketone bodies.
Ketone bodies:
acetone, acetoacetate, β-hydroxybutyrate.
Urine test for ketones can detect acetoacetate, but not β-hydroxybutyrate.
Fed state (after a meal).
Glycolysis and aerobic respiration.
Fasting (between meals)
Hepatic glycogenolysis (major); hepatic gluconeogenesis, adipose release of FFA (minor).
Starvation days 1–3
Hepatic glycogenolysis
Adipose release of FFA
Muscle and liver, which shift fuel use from glucose to FFA.
Hepatic gluconeogenesis from peripheral tissue lactate and alanine, and from adipose tissue glycerol and propionyl-CoA (from odd-chain FFA—the only
triacylglycerol components that contribute to gluconeogenesis)
Starvation after day 3
Adipose stores (ketone bodies become the main source of energy for the brain).
After these are depleted, vital protein degradation accelerates, leading to organ failure and death.
*Glycogen reserves depleted after day 1.
kcal
1g carb =
1g alcohol =
1g fatty acid =
4 kcal
7 kcal
9 kcal
Lipoprotein lipase (LPL)
Degradation of TGs circulating in chylomicrons and VLDLs. Found on vascular endothelial surface.
Hepatic TG lipase (HL)
degradation of TGs remaining in IDL.
Hormone-sensitive lipase
degradation of TGs stored in adipocytes.
LCAT
catalyzes esterification of 2⁄3 of plasma cholesterol.
Cholesterol ester transfer protein (CETP)
mediates transfer of cholesterol esters to other
lipoprotein particles.
Apolipoprotein E
Mediates remnant uptake (Everything Except LDL).
Apolipoprotein A-I
Activates LCAT
Apolipoprotein C-II
Lipoprotein lipase Cofactor that Catalyzes Cleavage
Apolipoprotein B-48
Mediates chylomicron secretion into lymphatics
Apolipoprotein B-100
Binds LDL receptor
LDL
HDL
VLDL
IDL
transports cholesterol from liver to tissues.
transports cholesterol from periphery to
liver.
Delivers hepatic TGs to peripheral tissue.
Formed in the degradation of VLDL. Delivers TGs and cholesterol to liver.
Abetalipoproteinemia
Autosomal recessive. Chylomicrons, VLDL, LDL absent. Deficiency in ApoB48, ApoB100.
Severe fat malabsorption, steatorrhea, failure to thrive.
Late manifestations include retinitis pigmentosa, spinocerebellar degeneration due to vitamin E
deficiency, progressive ataxia, acanthocytosis.
Familial dyslipidemias
I—Hyperchylomicronemia
AR. Lipoprotein lipase or apolipoprotein C-II deficiency.
Higher Chylomicrons, TG, cholesterol.
Pancreatitis, hepatosplenomegaly, and eruptive/pruritic xanthomas (no risk for atherosclerosis).
Creamy layer in supernatant.
Familial dyslipidemias
II—Familial hypercholesterolemia
AD. Absent or defective LDL receptors.
IIa: higher LDL, cholesterol
IIb:higher LDL, cholesterol, VLDL
Heterozygotes (1:500) have cholesterol ≈ 300mg/dL;
homozygotes (very rare) have cholesterol ≈ 700+ mg/dL.
Accelerated atherosclerosis (may have MI before age 20), tendon (Achilles) xanthomas, and corneal arcus.
Familial dyslipidemias
III—Dysbetalipoproteinemia
AR. Defective ApoE.
higher Chylomicrons, VLDL.
Premature atherosclerosis, tuberoeruptive xanthomas,
xanthoma striatum palmare.
Familial dyslipidemias
IV—Hypertriglyceridemia
AD. Hepatic overproduction of VLDL.
Higher VLDL, TG.
Hypertriglyceridemia (> 1000 mg/dL) can cause acute pancreatitis.
