Metabolism Flashcards
Primary lactose intolerance
Age-dependent decline after childhood (absence of lactase-persistent allele)
Common in people of Asian, African or NA descent
Intestinal biopsy reveals normal mucosa in pts with hereditary lactose intolerance
Secondary lactose intolerance
Loss of brush boarder enzyme due to gastroenteritis (e.g. Rotavirus), autoimmune disease, etc.
Congenital lactose intolerance
Rare, but due to a defective gene
Urea Cycle
Amino acid catabolism results in the formation of common metabolite (e.g. Pyre ate, actual-CoA) which serve as metabolic fuels
Excess nitrogen (NH3) generate by this process is converted to urea and excreted by kidneys
Ordinarily (Ornithine), Careless (Carbomoyl Phosphate) Crappers (Citruline) Are (Aspartate) Also (Arginosuccinate) Frivolous (Fumarate) About (Arginine) Urination (Urea)
Hyperammonemia
Can be acquired (e.g. Liver disease) or hereditary (urea cycle enzyme deficiencies)
Results in excess NH3 which depletes alpha-KG, leading to inhibition of the TCA cycle
Clinical findings: tremor (asterixis), slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision
Treatment of Hyperammonemia
Treatment to decrease ammonia levels:
lactose to acidity the GI tract and trap NH4+ for excretion
Rifaximin to decrease colonic ammoniagenic bacteria
Benzoate, phenyl acetate or phenyl iterate to bind NH4+ and lead to excretion
Glycogen: Skeletal muscle
Glycogen undergoes glyconeolysis to glucose 1-phosphate to glucose 6 phosphate, which is rapidly metabolized during exercise
Glycogen
Storage form of glucose
Branches have alpha (1-6) bonds
Linkages have alpha (1-4) bonds
Glycogen: hepatocytes
Stored and undergoes glyconeolysis to maintain blood sugar at appropriate levels
Glycogen phosphorylase liberates glucose 1-phosphate residues off branched glycogen until four glucose units remain on a branch
Then 4-alpha-glucanotransferase moves three molecules of glucose 1-phosphate from branch to the linkage
Then alpha-1,6-glycosidase cleaves off the last residue, liberating glucose
Fatty Acid Metabolism
Fatty acid synthesis requires transport of citrate from mitochondria to cytoskeleton
Predominantly occurs in liver, lactating mammary glands and adipose tissue
Long chain FA degradation requires carnitine-dependent transport into the mitochondrial matrix
Ketone bodies
Ketones: acetone, acetoacetate, beta-hydroxybutyrate
In the liver FAs and AAs are metabolized to acetoacetate and beta-HB to be used by muscle and brain
In prolonged starvation and DKA, oxaloacetate is depleted for glyconeogeneis
In alcoholism, excess NADH shuts oxaloacetate to maleate
Both processes cause a build up of acetyl-CoA, which shunts glucose and FFA toward the production of ketone bodies
Fed State
Glycolysis and aerobic respiration
Insulin stimulates storage of lipids, proteins and glycogen
Fasting
Hepatic glycogenolysis (major); hepatic glyconeogeneis, adipose release of FFA (minor) Glucagon and Epi stimulate use of fuel reserves
Starvation days 1-3
Blood glucose levels maintained by:
Hepatic glycogenolysis
Adipose release of FFA
Muscle & liver which shift fuel use from glucose to FFA
Hepatic glyconeogenesis from peripheral tissue lactate and alanine and from adipose tissue glycerol and propionyl-CoA
Glycogen reserves depleted after day 1
RBCs lack mitochondria and therefore cannot use ketones
Starvation after day 3
Adipose stores (ketone bodies become main source of energy for the brain).
After these are depleted, vital protein degradation accelerates, leading to organ failure and death
Amount of excess stores determines survival time
Apolipoprotein E
Mediates remnant uptake
Present in chylomicron, chylomicron remnant, VLDL, IDL and HDL
Apolipoprotein A-I
Activates LCAT
Present in: chylomicron and HDL
Apolipoprotein C-II
Lipoprotein lipase co-factor
Present in Chylomicron, HDL and VLDL
Apolipoprotein B-48
Mediates chylomicron secretion
Present in chylomicron so, chylomicron remnant
Apolipoprotein B-100
Binds LDL receptor
Present in VLDL, IDL and LDL
Lipoprotein functions
Lipoproteins are composed of varying proportions of cholesterol, TGs, and phospholipids
LDL and HDL carry the most cholesterol
LDL
transports cholesterol from liver to tissues
LDL is Lousy
Formed by hepatic lipase modification of IDL in the liver and peripheral tissue
Taken up by target cells via receptor mediated endocytic is
HDL
Transports cholesterol from the periphery to liver
HDL is Healthy
Mediates reverse cholesterol transport. Acts as repository for apolipoproteins C & E (which are needed for chylomicron and VLDL metabolism)
Secreted from both liver and intestine
alcohol increases synthesis
Chylomicron
Delivers dietary TGs to peripheral tissue
Delivers cholesterol to liver in the form of chylomicron remnants, which are mostly depleted of their TGs
Secreted by intestinal epithelial cells
VLDL
Delivers hepatic TGs to peripheral tissue
Secreted by liver
IDL
Formed in the degradation of VLDL
Delivers TG and cholesterol to the liver
Lactase decificiency
Insufficient lactase enzyme leading to dietary lactose intolerance
Lactase functions on the brush border to digest lactose into glucose and galactose
Stool demonstrates a decreased pH and breath shows increased H content with lactose hydrogen breath test
Findings: Bloating, cramps, flatulence, osmotic diarrhea
Treatment: avoid dairy products or add lactase pills to diet
Ethanol metabolism
Ethanol – alcohol dehydrogenase –acetaldehyde
Acetaldehyde – acetaldehyde dehydrogenase – acetate
Both steps require NAD+ to NADH (NAD+ is the limiting reagent)
Alcohol dehydrogenase
Zero order kinetics
Fomepizole
Inhibits alcohol dehydrogenase and is an antidote for methanol or ethylene glycol poisoning
Disulfiram
Inhibits acetaldehyde dehydrogenase
Acetaldehyde accumulates contributing to hangover symptoms
Ethanol metabolism Increase NADH/NAD+ ratio
Causes:
Pyruvate to lactate conversion (lactic acidosis)
Oxaloacetate to malate (prevents gluconeogenesis- fasting hypoglycemia)
Dihydroxyacetone phosphate to glycerol-3-phosphate (combines with FAs to make TGs - hepatosteatosis)
Disfavors TCA production of NADH - increased utilization of acetyl-CoA for ketogenesis (ketoacidosis) and lips genesis (hepatosteatosis)
Metabolism: Mitochondria
FA oxidation (beta-oxidation), acetyl-CoA production, TCA cycle, oxidative phosphorylation, ketogenesis
Metabolism: Cytoplasm
Glycolysis, HMP shunt, and synthesis of steroids (SER), proteins (ribosomes, RER), FAs, cholesterol and nucleotides
Metabolism: Both mitochondria and cytoplasm
Heme synthesis, urea cycle, gluconeogenesis
HUGs take two (i.e. Both)
Kinase
Catalyzes transfer of a phosphate group from a high energy molecule (usually ATP) to a substrate (eg phosphofructokinase)
Phosphorylase
Adds inorganic phosphate onto a substrate without using ATP (eg glycogen phosphorylase)
Phosphatase
Removes phosphate onto substrate (eg fructose 1,6 bisphosphatase)
Dehydrogenase
Catalyzes oxidation-reduction reactions (eg pyruvate dehydrogenase)
Hydroxylase
Adds hydroxyl group (OH) onto substrate (e.g. Tyrosine hydroxylase)
Carboxylase
Transfers CO2 groups with help of biotin (pyruvate carboxylase)
Mutase
Relocates a functional group within a molecule (eg vitamin B12 dependent methylmalonyl-CoA)
Rate Determining enzyme: glycolysis
Enzyme: phosphofructokinase-1 (PFK-1)
Regulators: AMP (+), fructose-2,6-bisphosphate (+), ATP (-), citrate (-)
Rate Determining enzyme: Gluconeogenesis
Enzyme: Fructose 1,6, bisphosphate
Regulators: AMP (-), fructose 2,6-bisphosphate (-)
Rate Determining enzyme: TCA cycle
Enzyme: Isocitrate dehydrogenase
Regulators: ADP (+), ATP (-), NADH (-)
Rate Determining enzyme: Glycogenesis
Enzyme: glycogen synthase
Regulators: glucose-6-phosphate (+), insulin (+), cortisol (+), Epi (-), glucagon (-)
Rate Determining enzyme: Glycogenolysis
Enzyme: glycogen phosphorylase
Regulators: Epi (+), glucagon (+), AMP (+), glucose-6-phosphate (-), insulin (-), ATP (-)
Rate Determining enzyme: HMP shunt
Enzyme: glucose-6-phosphate dehydrogenase
Regulators: NADP+ (+), NADPH (-)
Rate Determining enzyme: De novo pyrimidine synthesis
Enzyme: carbamoyl phosphate synthetase II
Regulators: ATP (+), PRPP (+), UTP (-)
Rate Determining enzyme: De novo purine synthesis
Enzyme: glutamine phosphoribosylpyrophosphate (PRPP) amindotransferase
Regulators: AMP (-), inosine monophosphate (IMP) (-), GMP (-)
Rate Determining enzyme: Urea cycle
Enzyme: carbamoyl phosphate synthetase I
Regulators: N-acetylglutamate (+)
Rate Determining enzyme: FA synthesis
Enzyme: acetyl-CoA carboxylase (ACG)
Regulators: insulin (+), citrate (+), glucagon (-), palmitoyl-CoA (-)
Rate Determining enzyme: FA oxidation
Enzyme: carnitine acyltransferase I
Regulators: Malonyl-CoA (-)
Rate Determining enzyme: Ketogenesis
Enzyme: HMG-CoA synthase
Rate Determining enzyme: Cholesterol synthesis
Enzyme: HMG-CoA reductase
Regulators: insulin (+), thyroxin (+), glucagon (-), cholesterol (-)
ATP production
Aerobic metabolism of glucose produces 32 net ATP via malate-aspartate shuttle (heart and liver)
30 net ATP via glycerol-3-phosphate shuttle (muscle)
Anaerobic glycolysis produces only 2 net ATP per glucose molecule
ATP hydrolysis can be coupled to energetically unfavorable reactions
Arsenic causes glycolysis to produce 0 ATP
Activated carriers
ATP: phosphoryl groups NADH, NADPH, FADH2: electrons CoA, lipoamide: Acyl groups Biotin: CO2 Tetrahydrofolates: 1-carbon units S-adenosylmethionine (SAM): CH3 groups TTP: aldehydes
Universal electron acceptors
Nicotinamides (NAD+ from VitB3, NADP+)
NAD+ is generally used in catabolic processes to carry reducing equivalents away as NADH
NADPH (product of HMP shunt) is used in anabolic processes (steroid and FA synthesis) as a supply of reducing equivalents
Uses of NADPH
Anabolic processes
Respiratory burst
Cytochrome P-450 system
Glutathione reductase
First committed step of glycolysis
Phosphorylation of glucose to yield glucose-6-phosphate
Reaction is either catalyzes by hexokinase or glucokinase, depending on the tissue
At low glucose concentrations hexokinase sequesters glucose in the tissue. At high glucose concentrations excess glucose is stored in the liver
Hexokinase
Location: most tissues, except liver and pancreatic beta cells Km: lower (increased affinity) Vmax: lower (decreased capacity) Induced by insulin: No Feedback inhibited by G6P: Yes Gene mutation associate with MODY: No
Glucokinase
Location: liver, beta cells of pancreas Km: higher (decreased affinity) Vmax: higher (increased capacity) Induced by insulin: yes Feedback inhibited by G6P: No Gene mutation associated with MODY: yes
Glycolysis regulation
Net glycolysis (cytoplasm) Glucose + 2Pi + 2ADP + 2NAD+ -- 2 pyruvate + 2ATP + 2NADH + 2H+ + 2H2O
Key enzymes in glycolysis that require ATP
Hexokinase/glucokinase (glucose to G6P)
Phosphofructokinase-1 (Fructose 6-phosphate to Fructose 1,6 BP)
Key enzymes in glycolysis that produce ATP
Phosphoglycerate kinase (1,3 BPG to 3 PG) Pyruvate kinase (phosphoenolpyruvate to pyruvate)
Sorbitol
An alternative method of trapping glucose in the cell s to convert it to its alcohol counterpart (sorbitol) via aldose reductase
Some tissues convert sorbitol into fructose using sorbitol dehydrogenase (liver, ovaries, seminal vesicles)
Tissue with an insufficient amount/activity (Schwann cells, retina, kidney, lens) of this enzyme are at risk for intracellular sorbitol accumulation, causing osmotic damage (eg cataracts, retinopathy and peripheral neuropathy seen with chronic hyperglycemia in diabetic pts)
Essential Amino Acids
Glucogenic: methionine (Met), valine (Val), histidine (His)
Glucogenic/ketogenic: isoleucine (Ile), phenylalanine (Phe), Threonine (Thr), tryptophan (Trp)
Ketogenic: Leucine (Leu), Lysine (Lys)
Acidic Amino Acids
Aspartic acid (Asp) and glutamic acid (Glu) Negatively charged at body pH
Basic Amino Acids
Arginine (Arg) - most basic, lysine (Lys), histidine (His)-no charge at body pH
Arg & His are required during periods of growth
Arg & Lys are increased in his tones, which bind negatively charged DNA
N-acetylglutamate synthase deficiency
Required cofactor for carbamoyl phosphate synthetase I. Absence of N-acetylglutamate = Hyperammonemia
Presents in neonates as poorly regulated respiration and body temp, poor feeding, developmental delay, intellectual disability (identical to presentation of carbamoyl phosphate synthetase I deficiency)
Ornithine transcarbamylase deficiency
Most common urea cycle disorder (X-linked recessive - all other urea cycle disorders are AR)
Interferes with the body’s ability to eliminate ammonia, often evident in first few days of life, but may present later. Excess carbamoyl phosphate is converted to orotic acid (part of the Pyrimidine synthesis pathway)
Findings: increased orotic acid in blood and urine, decreased BUN, symptoms of Hyperammonemia, no megaloblastic anemia (vs. orotic aciduria)
Amino Acid derivatives: Phenylalanine
Phenylalanine –> Tryosine –> Dopa –> Dopamine –> NE –> Epi
Phenylalanine –> Tyrosine –> Thyroxine
Phenylalanine –> Tyrosine –> Dopa –> Melanin
Amino Acid derivatives: Tryptophan
Tryptophan –> Niacin –> NAD+/NADP+
Tryptophan –> Serotonin –> Melatonin
Amino Acid derivatives: Histidine
Histidine –> Histamine
Amino Acid derivatives: Glycine
Glycine –> porphyrin –> heme
Amino Acid derivatives: Glutamate
Glutamate –> GABA
Glutamate –> Glutathione
Amino Acid derivatives: Arginine
Arginine –> Creatine
Arginine –> Urea
Arginine –> Nitric Oxide
Phenylkentonuria
AR
Due to decreased phenylalanine hydroxylase or decreased tetrahydrobiopterin cofactor (malignant PKU). Tyrosine becomes essential
Increased phenylalanine –> excess phenylketonuria in urine
Findings: intellectual disability, growth retardation, seizures, fair skin, eczema, musty body odor (disorder of AROMATIC amino acid metabolism - musty body ODOR)
Tx: decrease Phe and increase Tyr in diet, tetrahydrobiopterin supplementation
Maternal PKU
Lack of proper dietary therapy during pregnancy
Findings in infant: microcephaly, intellectual disability, growth retardation, congenital heart defects
Male Syrup Urine disease
Blocked degradation of branched amino acids (AR) - Isoleucine, Leucine, Valine due to decreased branched-chain alpha-ketoacid dehydrogenase (B1). Causes increase in alpha-ketoacids in blood
Causes severe CNS defects, intellectual disability and death; presents with vomiting, poor feeding, urine that smells sweet
Tx: restriction of Iso, Leu, Val in diet and thiamine supplementation
(I Love Vermont MAPLE SYRUP from maple trees with B1ranches)
Alkaptonuria
Congenital deficiency of homogentisate oxidase (AR) in the degradation pathway of tyrosine to Fumarate –> pigment-forming homogentistic acid accumulates in tissue
Findings: bluish-black CT and sclerae (ochronosis); urine turns black on prolonged exposure to air. May have debilitating arthralgias (homogentistic acid toxic to cartilage)
Homocystinuria: findings
All forms result in excess homocysteine
Findings: increased homocysteine in urine, intellectual disability, osteoporosis, marfanoid habitus, kyphosis, lens subluxation (downward and inward), thrombosis, atherosclerosis (stroke/MI)
Homocystinuria: Types
- Cystathionine synthase deficiency (tx: decrease Met, increase cysteine, increase B12 & folate in diet
- decreased affinity of cystathionine synthase for pyridoxal phosphate (tx: highly increase B6 and increase cysteine in diet)
- Methionine synthase (homocysteine methyltransferase) deficiency (tx: increase Met in diet)
Cystinuria
Hereditary defect (AR) of renal PCT and intestinal AA transporter that prevents reabsorption of Cystine, Ornithine, Lysine, Arginine (COLA)
Excess cystine in the urine can lead to recurrent precipitation of hexagonal cystine stones
Diagnosis: urinary cyanide-nitroprusside test positive
Tx: urinary alkali inaction (e.g. K citrate, acetazolamide) and chelating agents (penicillamine) to increase solubility of cystine stones; good hydration
Glycogen: skeletal muscle
Branches have alpha-1,6 bonds; linkages have alpha-1,4 bonds
Glycogen undergoes glycogenolysis –> glucose-1-phosphate –> glucose-6-phosphate
G6P is rapidly metabolized during exercise
Glycogen: Hepatocytes
Branches have alpha-1,6 bonds; linkages have alpha-1,4 bonds
Glycogen is stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels
Glycogen phosphorylase liberates glucose-1-phosphate residues off branched glycogen until 4 glucose remain on a branch –> 4-alpha-D-glucanotransferase (debranching enzyme) moves three molecules of glucose of G1P from branch to linkage –> alpha-1,6-glucosidase cleaves off the last residue, liberating glucose
Glycogen Storage diseases
Abnormal glycogen metabolism and an accumulation of glycogen within the cells
Periodic acid-Schiff stain identifies glycogen and is useful in identification
Very Poor Carbohydrate Metabolism
Types I, II, III, & V are AR
Von Gierke Disease (type I)
Severe fasting hypoglycemia
Very highly Increased Glycogen in liver, increased blood lactate, increased TGs and uric acid (Gout), hepatomegaly
Glucose-6-phosphatase deficiency - impaired gluconeogenesis and glycogenolysis
(Gs of Gierke - Glycogen & Gout due to Glucose-6-phosphatase)
Tx: frequent oral glucose/cornstarch, avoidance of fructose and galactose
Pompe Disease (type II)
Cardiomegaly, hypertrophic cardiomyopathy, exercise intolerance, systemic findings leading to early death
Lysosomal alpha-1,4-glucosidase with alpha-1,6-glucosidase activity (acid maltase) deficiency.
Pompe trashes the Pump (heart, liver, muscle)
Cori disease (type III)
Milder form of Von Gierke with normal blood lactate levels. Accumulation of limit dextrin-like structures in cytosol.
Deficient debranching enzyme (alpha-1,6-glucosidase)
Gluconeogenesis is intact
McArdle disease (type V)
Increased glycogen in muscle but muscle cannot break it down –> painful muscle cramps, myoglobinuria (red urine) with strenuous exercise, and arrhythmia from electrolyte abnormalities. Second wind phenomenon noted during exercise duet to increased muscular blood flow
Deficient skeletal muscle phosphorylase (Myophosphorylase)
Blood glucose levels typically unaffected
(*The Ms of McArdle’s - Muscle cramps, Myoglobiuria, Myophosphorylase)
Lysosomal Storage Disease: Fabry disease
Sphingolipidoses
Findings: (early): triad of episodic peripheral neuropathy, angiokeratomas, hypohidrosis (late): progressive renal failure, CVD
Deficiency: alpha-galactosidase A
Accumulated substrate: Ceramide Trihexoside
Inheritance: XR
Lysosomal Storage Disease: Gaucher disease
Sphinolipidoses
Findings: (most common) hepatospenomegaly, panctyopenia, osteoporosis, aseptic necrosis of femur, bone crisis, Guacher cells (lipid-laden MP resembling tissue paper)
Deficiency: glucocerebrosidase (beta-glucosidase); treat with recombinant glucocerebrosidase
Accumulated substrate: glucocerebrosidase
Inheritance: AR
Lysosomal Storage Disease: Niemann-Pick disease
Sphingolipidoses Findings: Progressive neurodegeneration, hepatospenomegaly, foam cells (lipid laden MPs), cherry red spot on macula Deficiency: sphingomyelinase Accumulated substrate: sphingomyelin Inheritance: AR
Lysosomal Storage Disease: Tay-Sachs disease
Sphingolipioses Findings: progressive neurodegeneration, developmental delay, cherry red spot on macula, lysosomes with onion skin, no hepatospenomegaly (vs. Neimann-Pick) Deficiency: hexoaminidase A accumulated substrate: GM2 ganglioside Inheritance: AR
Lysosomal Storage Disease: Krabbe disease
Sphingolipioses
Findings: peripheral neuropathy, developmental delay, optic atrophy, globoid cells
Deficiency: glactocerebrosidase
Accumulated substrate: galactocerebroside, psychosine
Inheritance: AR
Lysosomal Storage Disease: Metachromatic Leukodystrophy
Sphingolipioses
Findings: Central and peripheral demyelination with ataxia, dementia
Deficiency: arylsulfatase A
Accumulated substrate: cerebroside sulfate
Inheritance: AR
Lysosomal Storage Disease: Hurler syndrome
Mucopolysaccharidoses
Findings: developmental delay, gargoylism, airway obstruction, corneal clouding, hepatospenomegaly
Deficiency: alpha-L-iduronidase
Accumulated substrate: heparan sulfate, dermatan sulfate
Inheritance: AR
Lysosomal Storage Disease: Hunter syndrome
Mucopolysaccharidoses
Findings: mild hurler + aggressive behavior, no corneal clouding
Deficiency: iduronate sulfatase
Accumulated substrate: heparan sulfate, dermatan sulfate
Inheritance: XR
How to remember Lysosomal storage diseases
No man picks (Niemann-Pick) his nose with his sphinger (sphingomyelinase)
Tay-SaX lacks heXosaminidase
Hunters see clearly (no corneal clouding) and aggressively aim for the X (X-linked recessive)
Fatty Acid metabolism
FA synthesis requires transport of citrate from mitochondria to cytosol. Predominantly occurs in liver, lactating mammary glands, and adipose tissue
LCFA degradation requires carnitine-dependent transport into the mitochondrial matrix
SYtrate = SYnthesis
CARnintine = CARnage of fatty acids
Systemic primary carnitine deficiency
Inherited defect in transport of LCFAs into the mitochondria –> toxic accumulation
Causes weakness, hypotonia, hypoketotic hypoglycemia
Medium chain acyl-CoA dehydrogenase deficiency
AR disorder of FA oxidation
Decreased ability to break down FAs into acetyl-CoA –> accumulation of 8 to 10 carbon fatty acyl carnitines in the blood and hypoketotic hypoglycemia
May present in infancy or early childhood with vomiting, lethargy, seizures, coma and liver dysfunction.
Minor illness can lead to sudden death. Treat by avoiding fasting.
Ketone bodies
Acetone, acetoacetate, beta-hydroxybuterate
In the liver FAs and AAs are metabolized to acetoacetate and beta-hydroxybuterate (to be used by muscle and brain)
In prolonged starvation and diabetic ketoacidosis, oxaloacetate is depleted for gluconeogenesis. (Breath smells like acetone - fruity; can detect acetoacetate in the urine)
Ketone bodies: alcoholism
Excess NADH shunts oxaloacetate to malate. Both DKA and alcoholism cause a build up of acetyl-CoA, which shunts glucose and FFA toward the production of ketone bodies
Metabolic Fuel Use
1g of protein or carbohydrate = 4kcal
1g fat = 9 kcal
1g alcohol = 7kcal
Fed State
Glycolysis and aerobic respiration
Insulin stimulates storage of lipids, proteins and glycogen
Fasting (between meals)
Hepatic glycogenolysis (major), hepatic gluconeogenesis, adipose release of FFA (minor) Glucagon and Epi stimulate use of fuel reserves
Starvation (day 1-3)
Blood glucose levels maintained by
-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
Glycogen reserves are depleted after day one
RBCs lack mitochondria and therefore cannot use ketones
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
Amount of excess stores determines survival time
Cholesterol synthesis
Needed to maintain cell membrane integrity and to synthesize bile acid, steroids and VitD
Rate-limiting step catalyzes by HMG-CoA reductase (induced by insulin) which converts HMG-CoA to mevalonate
2/3 of plasma cholesterol esterified by lecithin-cholesterol acyltransferase (LCAT)
Statins - competitively and reversibly inhibit HMG-CoA reductase
Key Lipid enzymes & Transport: Pancreatic lipase
Degradation of dietary TGs in SI
Key Lipid enzymes & Transport: Lipoprotein Lipase (LPL)
Degradation of TGs circulating in chylomicrons and VLDLs found on vascular endothelial surface
Key Lipid enzymes & Transport: Hepatic TG Lipase (HL)
Degradation of TGs remaining in IDL
Key Lipid enzymes & Transport: Hormone-sensitive Lipase
Degradation of TGs stored in adipocytes
Key Lipid enzymes & Transport: LCAT
Catalyzes esterification of cholesterol
Key Lipid enzymes & Transport: Cholesterol ester transfer protein (CETP)
Mediates transfer of cholesterol esters to other lipoprotein particles
Familial dyslipidemias: Type I - Hyperchylomicronemia
Inheritance: AR
Pathogenesis: lipoprotein lipase or apolipoprotein CII deficiency
-increased blood levels of chylomicrons, TG & cholesterol
Clinical: pancreatitis, hepatospenomegaly, and eruption/pruritic xanthomas (no increased risk for atherosclerosis)
Creamy layer in supernatant
Familial dyslipidemias: Type IIa - familial hypercholesterolemia
Inheritance: AD
Pathogenesis: absent or defective LDL receptors
-increased levels of LDL or cholesterol
Heterozygotes have high cholesterol (300) and homozygotes levels of 700+
Accelerated atherosclerosis (may have MI before 20), tendon (Achilles) xanthomas, and corneal arcus
Familial dyslipidemias: Type IV - hypertriglyceridemia
Inheritance: AD
Pathogenesis: hepatic overproduction of VLDL
-increased levels of VLDL, TG
Clinical: hypertriglyceridemia (>1000) can cause acute pancreatitis
Sorbitol
An alternative method of trapping glucose in the cell s to convert it to its alcohol counterpart (sorbitol) via aldose reductase
Some tissues convert sorbitol into fructose using sorbitol dehydrogenase (liver, ovaries, seminal vesicles)
Tissue with an insufficient amount/activity (Schwann cells, retina, kidney, lens) of this enzyme are at risk for intracellular sorbitol accumulation, causing osmotic damage (eg cataracts, retinopathy and peripheral neuropathy seen with chronic hyperglycemia in diabetic pts)
Essential Amino Acids
Glucogenic: methionine (Met), valine (Val), histidine (His)
Glucogenic/ketogenic: isoleucine (Ile), phenylalanine (Phe), Threonine (Thr), tryptophan (Trp)
Ketogenic: Leucine (Leu), Lysine (Lys)
Acidic Amino Acids
Aspartic acid (Asp) and glutamic acid (Glu) Negatively charged at body pH
Basic Amino Acids
Arginine (Arg) - most basic, lysine (Lys), histidine (His)-no charge at body pH
Arg & His are required during periods of growth
Arg & Lys are increased in his tones, which bind negatively charged DNA
N-acetylglutamate synthase deficiency
Required cofactor for carbamoyl phosphate synthetase I. Absence of N-acetylglutamate = Hyperammonemia
Presents in neonates as poorly regulated respiration and body temp, poor feeding, developmental delay, intellectual disability (identical to presentation of carbamoyl phosphate synthetase I deficiency)
Ornithine transcarbamylase deficiency
Most common urea cycle disorder (X-linked recessive - all other urea cycle disorders are AR)
Interferes with the body’s ability to eliminate ammonia, often evident in first few days of life, but may present later. Excess carbamoyl phosphate is converted to orotic acid (part of the Pyrimidine synthesis pathway)
Findings: increased orotic acid in blood and urine, decreased BUN, symptoms of Hyperammonemia, no megaloblastic anemia (vs. orotic aciduria)
Amino Acid derivatives: Phenylalanine
Phenylalanine –> Tryosine –> Dopa –> Dopamine –> NE –> Epi
Phenylalanine –> Tyrosine –> Thyroxine
Phenylalanine –> Tyrosine –> Dopa –> Melanin
Amino Acid derivatives: Tryptophan
Tryptophan –> Niacin –> NAD+/NADP+
Tryptophan –> Serotonin –> Melatonin
Amino Acid derivatives: Histidine
Histidine –> Histamine
Amino Acid derivatives: Glycine
Glycine –> porphyrin –> heme
Amino Acid derivatives: Glutamate
Glutamate –> GABA
Glutamate –> Glutathione
Amino Acid derivatives: Arginine
Arginine –> Creatine
Arginine –> Urea
Arginine –> Nitric Oxide
Phenylkentonuria
AR
Due to decreased phenylalanine hydroxylase or decreased tetrahydrobiopterin cofactor (malignant PKU). Tyrosine becomes essential
Increased phenylalanine –> excess phenylketonuria in urine
Findings: intellectual disability, growth retardation, seizures, fair skin, eczema, musty body odor (disorder of AROMATIC amino acid metabolism - musty body ODOR)
Tx: decrease Phe and increase Tyr in diet, tetrahydrobiopterin supplementation
Maternal PKU
Lack of proper dietary therapy during pregnancy
Findings in infant: microcephaly, intellectual disability, growth retardation, congenital heart defects
Male Syrup Urine disease
Blocked degradation of branched amino acids (AR) - Isoleucine, Leucine, Valine due to decreased branched-chain alpha-ketoacid dehydrogenase (B1). Causes increase in alpha-ketoacids in blood
Causes severe CNS defects, intellectual disability and death; presents with vomiting, poor feeding, urine that smells sweet
Tx: restriction of Iso, Leu, Val in diet and thiamine supplementation
(I Love Vermont MAPLE SYRUP from maple trees with B1ranches)
Alkaptonuria
Congenital deficiency of homogentisate oxidase (AR) in the degradation pathway of tyrosine to Fumarate –> pigment-forming homogentistic acid accumulates in tissue
Findings: bluish-black CT and sclerae (ochronosis); urine turns black on prolonged exposure to air. May have debilitating arthralgias (homogentistic acid toxic to cartilage)
Homocystinuria: findings
All forms result in excess homocysteine
Findings: increased homocysteine in urine, intellectual disability, osteoporosis, marfanoid habitus, kyphosis, lens subluxation (downward and inward), thrombosis, atherosclerosis (stroke/MI)
Homocystinuria: Types
- Cystathionine synthase deficiency (tx: decrease Met, increase cysteine, increase B12 & folate in diet
- decreased affinity of cystathionine synthase for pyridoxal phosphate (tx: highly increase B6 and increase cysteine in diet)
- Methionine synthase (homocysteine methyltransferase) deficiency (tx: increase Met in diet)
Cystinuria
Hereditary defect (AR) of renal PCT and intestinal AA transporter that prevents reabsorption of Cystine, Ornithine, Lysine, Arginine (COLA)
Excess cystine in the urine can lead to recurrent precipitation of hexagonal cystine stones
Diagnosis: urinary cyanide-nitroprusside test positive
Tx: urinary alkali inaction (e.g. K citrate, acetazolamide) and chelating agents (penicillamine) to increase solubility of cystine stones; good hydration
Glycogen: skeletal muscle
Branches have alpha-1,6 bonds; linkages have alpha-1,4 bonds
Glycogen undergoes glycogenolysis –> glucose-1-phosphate –> glucose-6-phosphate
G6P is rapidly metabolized during exercise
Glycogen: Hepatocytes
Branches have alpha-1,6 bonds; linkages have alpha-1,4 bonds
Glycogen is stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels
Glycogen phosphorylase liberates glucose-1-phosphate residues off branched glycogen until 4 glucose remain on a branch –> 4-alpha-D-glucanotransferase (debranching enzyme) moves three molecules of glucose of G1P from branch to linkage –> alpha-1,6-glucosidase cleaves off the last residue, liberating glucose
Glycogen Storage diseases
Abnormal glycogen metabolism and an accumulation of glycogen within the cells
Periodic acid-Schiff stain identifies glycogen and is useful in identification
Very Poor Carbohydrate Metabolism
Types I, II, III, & V are AR
Von Gierke Disease (type I)
Severe fasting hypoglycemia
Very highly Increased Glycogen in liver, increased blood lactate, increased TGs and uric acid (Gout), hepatomegaly
Glucose-6-phosphatase deficiency - impaired gluconeogenesis and glycogenolysis
(Gs of Gierke - Glycogen & Gout due to Glucose-6-phosphatase)
Tx: frequent oral glucose/cornstarch, avoidance of fructose and galactose
Pompe Disease (type II)
Cardiomegaly, hypertrophic cardiomyopathy, exercise intolerance, systemic findings leading to early death
Lysosomal alpha-1,4-glucosidase with alpha-1,6-glucosidase activity (acid maltase) deficiency.
Pompe trashes the Pump (heart, liver, muscle)
Cori disease (type III)
Milder form of Von Gierke with normal blood lactate levels. Accumulation of limit dextrin-like structures in cytosol.
Deficient debranching enzyme (alpha-1,6-glucosidase)
Gluconeogenesis is intact
McArdle disease (type V)
Increased glycogen in muscle but muscle cannot break it down –> painful muscle cramps, myoglobinuria (red urine) with strenuous exercise, and arrhythmia from electrolyte abnormalities. Second wind phenomenon noted during exercise duet to increased muscular blood flow
Deficient skeletal muscle phosphorylase (Myophosphorylase)
Blood glucose levels typically unaffected
(*The Ms of McArdle’s - Muscle cramps, Myoglobiuria, Myophosphorylase)
Lysosomal Storage Disease: Fabry disease
Sphingolipidoses
Findings: (early): triad of episodic peripheral neuropathy, angiokeratomas, hypohidrosis (late): progressive renal failure, CVD
Deficiency: alpha-galactosidase A
Accumulated substrate: Ceramide Trihexoside
Inheritance: XR
Lysosomal Storage Disease: Gaucher disease
Sphinolipidoses
Findings: (most common) hepatospenomegaly, panctyopenia, osteoporosis, aseptic necrosis of femur, bone crisis, Guacher cells (lipid-laden MP resembling tissue paper)
Deficiency: glucocerebrosidase (beta-glucosidase); treat with recombinant glucocerebrosidase
Accumulated substrate: glucocerebrosidase
Inheritance: AR
Lysosomal Storage Disease: Niemann-Pick disease
Sphingolipidoses Findings: Progressive neurodegeneration, hepatospenomegaly, foam cells (lipid laden MPs), cherry red spot on macula Deficiency: sphingomyelinase Accumulated substrate: sphingomyelin Inheritance: AR
Lysosomal Storage Disease: Tay-Sachs disease
Sphingolipioses Findings: progressive neurodegeneration, developmental delay, cherry red spot on macula, lysosomes with onion skin, no hepatospenomegaly (vs. Neimann-Pick) Deficiency: hexoaminidase A accumulated substrate: GM2 ganglioside Inheritance: AR
Lysosomal Storage Disease: Krabbe disease
Sphingolipioses
Findings: peripheral neuropathy, developmental delay, optic atrophy, globoid cells
Deficiency: glactocerebrosidase
Accumulated substrate: galactocerebroside, psychosine
Inheritance: AR
Lysosomal Storage Disease: Metachromatic Leukodystrophy
Sphingolipioses
Findings: Central and peripheral demyelination with ataxia, dementia
Deficiency: arylsulfatase A
Accumulated substrate: cerebroside sulfate
Inheritance: AR
Lysosomal Storage Disease: Hurler syndrome
Mucopolysaccharidoses
Findings: developmental delay, gargoylism, airway obstruction, corneal clouding, hepatospenomegaly
Deficiency: alpha-L-iduronidase
Accumulated substrate: heparan sulfate, dermatan sulfate
Inheritance: AR
Lysosomal Storage Disease: Hunter syndrome
Mucopolysaccharidoses
Findings: mild hurler + aggressive behavior, no corneal clouding
Deficiency: iduronate sulfatase
Accumulated substrate: heparan sulfate, dermatan sulfate
Inheritance: XR
How to remember Lysosomal storage diseases
No man picks (Niemann-Pick) his nose with his sphinger (sphingomyelinase)
Tay-SaX lacks heXosaminidase
Hunters see clearly (no corneal clouding) and aggressively aim for the X (X-linked recessive)
Fatty Acid metabolism
FA synthesis requires transport of citrate from mitochondria to cytosol. Predominantly occurs in liver, lactating mammary glands, and adipose tissue
LCFA degradation requires carnitine-dependent transport into the mitochondrial matrix
SYtrate = SYnthesis
CARnintine = CARnage of fatty acids
Systemic primary carnitine deficiency
Inherited defect in transport of LCFAs into the mitochondria –> toxic accumulation
Causes weakness, hypotonia, hypoketotic hypoglycemia
Medium chain acyl-CoA dehydrogenase deficiency
AR disorder of FA oxidation
Decreased ability to break down FAs into acetyl-CoA –> accumulation of 8 to 10 carbon fatty acyl carnitines in the blood and hypoketotic hypoglycemia
May present in infancy or early childhood with vomiting, lethargy, seizures, coma and liver dysfunction.
Minor illness can lead to sudden death. Treat by avoiding fasting.
