Biochem - metabolism Flashcards
Metabolism that happens specifically in mitochondria
Fatty acid oxidation acetyl-Coa production TCA cycle oxidative phosphorylation ketogenesis
ATP production in malate-aspartate shuttle vs. G3P shuttle
Electrons moved to ETC b/c NADH can’t cross membrane
Malate-aspartate shuttle: utilizes malate, creates 32 ATP (heart, liver)
G3P shuttle: utilizes G3P, creates 30 ATP since electrons delivered directly to complex 2 (skeletal muscle)
Key enzymes in glycolysis
Hexokinase/glucokinase
PFK-1 (incr. by F26BP)
Pyruvate kinase
Regulation by F26BP
incr. F26BP = more glycolysis, less gluconeogenesis
less F26BP = less glycolysis
Two complexes in glycolysis and TCA cycle that are similar
Pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase
use same cofactors, similar substrates and actions
PDH complex deficiency
X-linked, causes pyruvate shunting to lactate and alanine starting in infancy
tx: incr. lysine/leucine intake! ketogenic nutrients/high fat content
Four possible endpoints for pyruvate
- ) alanine: ALT, B6
- ) oxaloacetate: pyruvate carboxylase, biotin
- ) acetyl-CoA: PDH, B1/2/3/5
- ) lactate: LDH, B3
ETC inhibitors
decr. proton gradient
cyanide, carbon monoxide, antimycin A, rotenone
Uncoupling agents
Disconnects ETC from O2 consumption
Generates free heat
2,4-dinitrophenol (weight loss), aspirin, thermogenin
Four main gluconeogenesis enzymes
Pyruvate carboxylase (makes oxaloacetate)
PEP carboxykinase (OAA to PEP)
Fructose-1,6-bisphosphatase
Glucose-6-phosphatase
Odd-chain fatty acids
produce 1 propionyl-CoA, which enters TCA, then gluconeogenesis, thus a source of glucose
Uses of NADPH
glutathione reduction in RBCs
fatty acid and cholesterol/steroid synthesis
Location of HMP shunt
RBCs (glutathione reduction
lactating mammary glands, liver, adrenal cortex (fatty acid/steroid synthesis)
G6P DH deficiency
decr. NADPH in RBCs
hemolysis precipitated by oxidizing agents or infections (from inflammatory response)
random: incr. malarial resistance
Fructokinase vs. aldolase B deficiency
Essential fructosuria - asx
Fructose intolerance - incr. F-1-P, decr. free PO4, decr. GNG. Sx present after sugar consumption (jaundice, cirrhosis, vomiting), incr. fructose in urine
Galactokinase vs. galactose-1-phosphate uridyltransferase deficiency
Galactokinase deficiency - mild condition, infantile cataracts
Classic galactosemia - failure to thrive, jaundice, hepatomegaly, ID, E. coli sepsis
Enzymes in sorbitol metabolism
Aldose reducatase: glucose to sorbitol
Sorbitol dehydrogenase: sorbitol to fructose
Aldose reductase only locations
Schwann cells, retina, kidneys, lens
Findings in lactase deficiency
Stool: decr. in pH
Breath: incr. H content
Urea cycle key steps
Carbamoyl phosphate: in mito, converts CO2 + NH3 to carbamoyl phosphate
OTC: combines CP with ornithine to make citrulline
Citrulline + aspartate/ATP = argininosuccinate
Loss of fumarate = arginine
Arginase makes ornithine again! This is loss of UREA
Components of urea
1 NH3
1 CO2
1 Aspartate
Path of ammonia from amino acids to excretion
Muscle: amino acids –> glutamate –> alanine
Cori or Cahill cycle: muscle to liver (requires alanine and lactate)
Liver: alanine –> glutamate –> urea
Urea cycle deficiencies
N-acetylglutamate synthase deficiency: leads to hyperammonemia (required cofactor for carbamoyl phosphate synthetase)
OTC deficiency: X-linked recessive, look for orotic aciduria w/o megaloblastic anemia
Defects in amino acid metabolism
Phenylketonuria Maple syrup urine disease Alkaptonuria Homocystinuria Cystinuria
Intellectual disability, seizures, fair skin, musty body odor
Phenylketonuria - decr. phenylalanine hydroxylase (decr. Phe to Tyr)
tx: tyrosine supplementation, avoid aspartame (Phe)
Severe CNS defects, death, urine smells like burnt sugar
Maple syrup urine disease - blocked degradation of branched amino acids (isoleucine, leucine, valine)
decr. alpha-ketoacid dehydrogenase
tx: thiamine supplementation and restrict isoleucine, leucine, valine in diet
Dark connective tissue, brown sclerae, urine turns black on expsoure to air
Alkaptonuria - def. of homogentisate oxidase in the degradative pathway of tyrosine to fumarate
Homogentisic acid accumulates in tissues
Osteoporosis, marfanoid habitus, kyphosis, lens subluxation
Homocystinuria
- cystathione synthase (B6 enzyme) deficiency (leads to decr. cysteine and incr. methionine)
- homocysteine methyltransferase (B12 enzyme) deficiency (leads to decr. methionine)
Recurrent hexagonal kidney stones, positive urinary cyanide-nitroprusside test
Cystinuria - defect in renal PCT/intestinal reabsorption of Cysteine, Ornitihine, Lysine, Arginine
tx: potassium citrate/acetazolomide, chelating agents
Homocyteine products
Homocysteine methyltransferase - converts to methionine using B12
Cystathione synthase - converts to cystathione using B6
Stimulators of glycogenolysis
Glucagon (incr. cAMP, PKA)
Epinephrine alpha and beta receptors (incr. cAMP, PKA)
Stimulators of glycogen synthesis
Insulin (tyrosine kinase receptor, phosphorylation of glycogen synthase)
Glycogen breakdown
Muscle - glycogen to G6P (uses phosphoglucomutase) to enter glycolysis
Liver - Glycogen phosphorylase, debranching enzymes cleaves off in orderly pattern
Glycogen storage diseases
Type I: Von gierke (glucose-6-phosphatase)
Type II: Pompe (acid maltase)
Type III: Cori (debranching)
Type IV: McArdle (skeletal muscle glycogen phosphorylase)
Severe fasting hypoglycemia, incr. glycogen in liver (hepatomegaly), incr. TGs, lactic acidemia
Von gierke - glucose-6-phosphatase
tx: frequent oral glucose/cornstarch, avoid fructose/galactose
Hypertrophic cardiomyopathy, cardiomegaly, exercise intolerance, early death
Pompe - acid maltase
Pompe trashes the pump
Fasting hypoglycemia with normal lactate levels
Cori - debranching enzyme
Gluconeogenesis intact
Painful muscle cramps, myoglobinuria, arrhythmia from electrolyte disturbances
McArdle (skeletal muscle phosphorylase)
Blood glucose levels are unaffected
McArdle = muscle
Tx: B6 supplementation
HSM, pancytopenia, aseptic necrosis of femur, bone crises, Gaucher cell (lipid-laden macs, tissue paper)
Gaucher disease - glucocerebridase
accum of glucocerebroside
Progressive neurogeneration, foam cells, cherry-red macula, HSM
Niemann-Pick disease - sphingomyelinase
accum of sphingomyelin
Progessive neurodegeneration, developmental delay, cherry-red macula, onion skin lysosomes, NO HSM
Tay-Sachs disease - hexosiaminidase A
NOTE: NO HEPATOMEGALY!
Optic atrophy, globoid cells, peripheral neuropathy
Krabbe disease - galactocerebridase
Hurler vs. Hunter syndrome
Mucopolysaccharides
Hurler - corneal clouding, airway obstruction
Hunter - no corneal clouding, aggressive behavior
Citrate shuttle
used in fatty acid synthesis to move citrate from mitochondria to the cytosol
sytrate = synthesis
Carnitine shuttle
used to move fatty acyl-CoA from the cytosol to the mitochondria
carnitine = fatty acyl carnage
Minor illness leading sudden death, liver dysfunction, present in infancy or early childhood with vomiting
MCAD deficiency
accumulation of 8 to 10 carbon fatty acyl carnitines in the blood
leads to hypoketotic hypoglycemia***
Causes of ketogenesis
prolonged starvation or diabetes - depletion of oxaloacetate for gluconeogenesis
alcoholism - excess NADH shunts oxaloacetate to malate
Fat sources for gluconeogenesis
Odd-chain FFAs
Adipose tissue glycerol
LPP that mediates remnant uptake (extra remnantsq
Apo-E
LPP that activates LCAT
Apo-A1
LPP that serve as lipoprotein lipase cofactor
Apo-C2
LPP that mediates chylomicron secretion
Apo-B48
LPP that binds LDL receptor
Apo-B100
Xanthomas, pancreatitis, HSM, creamy layer in supernatant
Type I hyperchylomicronemia
lipoprotein lipase deficiency
Accelerated atherosclerosis, tendon xanthoma, corneal arcus
Type II hypercholesterolemia
absent/defective LDL receptor
Hepatic overproduction of VLDL
Type IV hypertriglyceridemia
