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100 Cards in this Set
- Front
- Back
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glucose transporters on most tissues, basal glucose uptake
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GLUT 1 and GLUT 3
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glucose transporters on liver, pancreatic B cells
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GLUT 2
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glucose transporters on skeletal muscle and adipose tissue, insulin-dependent
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GLUT 4
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RDS glycolysis
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PFK-1
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glucose -> glucose 6 P
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hexokinase or glucokinase
hexokinase - all tissues, small Km glucokinase - only liver, pancreatic beta cell, large Km |
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activates PFK-1
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fructose 2,6 bis-P, product of PFK-2 on fructose 6P
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PEP -> pyruvate
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pyruvate kinase
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second most common genetic deficiency causing hemolytic anemia: 2 distinguishing features?
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pyruvate kinase deficiency -no Heinz bodies -increased 2,3 DPG (lower than normal oxygen affinity)
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pyruvate + NADH -> lactate + NAD
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lactate dehydrogenase: important in anaerobic glycolysis to reoxidize NADH
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pyruvate + CoA + NAD -> acetyl CoA + CO2+ NADH
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pyruvate dehydrogenase. requires cofactors (thiamine, lipoic acid, CoA, FAD, NAD)
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cause of neonatal type I diabetes
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glucokinase deficiency in newborn. pancreatic B cells cannot detect glucose and do not secrete insulin
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glycolysis intermediate used in trigylceride synthesis
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DHAP -> glycerol 3P -> triglyceride backbone
stimulated by high NADH in chronic alcoholism, leads to fatty liver |
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galactosemia (mild)
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galactokinase deficiency. sx: cataracts early in life, galactitol trapped in lens causes swelling and cataracts
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galactosemia (severe)
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galactose 1P uridyltransferase deficiency. more severe because galactose 1P accumulates in liver, brain, etc. sx: cataracts early in life, vomiting, diarrhea following lactose ingestion, lethargy, mental retardation, liver damage, hyperbilirubinemia
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fructosuria
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fructokinase deficiency, benign
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fructose intolerance
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aldolase B deficiency, autosomal recessive. sx: lethargy, vomiting, liver damage, hyperbilirubinemia, hypoglycemia, hyperuricemia, kidney disease
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RDS TCA cycle
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isocitrate dehydrogenase. activated by ADP, inhibited by NADH, ATP. no hormonal control
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location: glycolysis
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cytoplasm
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location: TCA cycle
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mitochondria
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purpose: TCA cycle
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oxidize acetyl CoA -> CO2. no net production of TCA intermediates!
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thiamine, lipoic acid are cofactors for these enzymes (3)
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-pyruvate dehydrogenase (glycolysis), a-ketoglutarate dehydrogenase (TCA), transketolase (HMP shunt)
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TCA intermediates involved in other pathways: gluconeogenesis, fatty acid synthesis, heme synthesis
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TCA intermediates involved in other pathways: malate, citrate, succinyl CoA
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location: electron transport chain
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inner mitochondrial membrane. protons pumped into intermembrane space
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mechanism: cyanide
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CN inhibits electron transport chain. antidote: nitrates to convert hemoglobin to methemoglobin, metHb binds CN avidly
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inhibitors of the electron transport chain
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cyanide, CO, uncouplers
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RDS HMP shunt
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glucose 6 phosphate dehydrogenase (G6PD)
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location: HMP shunt
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cytoplasm
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purpose of HMP shunt
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produce NADPH from abundant glucose 6 P, produce ribulose 5P for nucleotide synthesis
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oxidative, irreversible step in HMP shunt
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glucose 6P -> NADPH and ribulose. enzyme: glucose 6P dehydrogenase
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nonoxidative, reversible step in HMP shunt
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ribulose 5P -> ribulose 6P. enzyme: transketolases
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purpose of NADPH
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NADPH oxidase cofactor: PMN bacteria killing, regenerates reduced glutathione: protects against ROS damage
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G6PD deficiency
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glucose 6P dehydrogenase is RDS enzyme in HMP shunt. acute, episodic hemolytic anemia with oxidative stress (overwhelming infxn, fava beans). x-linked recessive, heterozygote females have malaria advantage"
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key enzymes in glycogen synthesis
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glycogen synthase (RDS) (a 1,4 bonds), branching enzyme (a 1,6 bonds)"
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key enzymes in glycogenolysis
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"glycogen phosphorylase (RDS) (a 1,4 bonds), debranching enzyme (a 1,6 bonds)"
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von Gierke's disease
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"type I glycogen storage disease, glucose 6 phosphatase deficiency. sx: severe fasting hypoglycemia, high glycogen accumulation in liver leads to hepatomegaly, high blood lactate, hyperuricemia, hyperlipidemia"
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Pompe's disease
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"type II glycogen storage disease, more similar to lysosomal storage diseases: inclusion bodies in lysosomes. lysosomal a 1,4 glucosidase deficiency. sx: glycogen accumulation leads to hepatomegaly, cardiomegaly and muscle weakness. early death without tx. tx: enzyme replacement"
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Cori's disease
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"type III glycogen storage disease, debranching enzyme deficency. sx: milder form of type I - mild hypoglycemia and mild hepatomegaly, normal blood lactate"
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McArdle's disease
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"type V glycogen storage disease, muscle glycogen phophorylase deficiency. sx: cramps & weakness with exercise. tx: sucrose load before excercise"
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purpose of Cori cycle
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"lactate becomes glucose in liver. cost of 4 ATP per cycle"
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RDS gluconeogenesis
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"fructose 1,6 bisphosphatase: fructose 1,6 bis-P -> fructose 6P. activated by ATP, inhibited by AMP, fructose 2,6 bis-P"
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pyruvate -> oxaloacetate
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pyruvate carboxylase, requires biotin
mitochondrial enzyme |
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oxaloacetate -> PEP
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PEP carboxykinase, requires GTP
cytoplasmic enzyme, PEPCK expression regulated by cortisol and glucagon |
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how does acetyl CoA regulate the fate of pyruvate?
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high acetyl CoA stimulates pyruvate carboxylase (gluconeogenesis) and inhibits pyruvate dehydrogenase. high acetyl CoA occurs during fasting (due to fatty acid oxidation).
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how does alcoholism predispose to hypoglycemia?
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"NAD is converted to NADH in alcohol metabolism by alcohol dehydrogenase. high NADH diverts gluconeogenic substrates (pyruvate -> lactate, etc)
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mechanism: arsenic
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inhibits lipoic acid, which is a cofactor for pyruvate dehydrogenase and a-ketogluterate dehydrogenase
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location: fatty acid synthesis
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cytosol
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RDS fatty acid synthesis
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acetyl CoA carboxylase: acetyl CoA -> malonyl CoA (eventually forms palmitate)
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what is the citrate shuttle?
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carries acetyl CoA out of the mitochondria to cytoplasm where FA synthesis takes place
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sources of glycerol 3P for triglyceride synthesis
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DHAP from glycolysis, phosphorylation of free glycerol (liver only)
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chylomicron
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"triglyceride rich lipoprotein, secreted by intestinal epithelium, delivers dietary TG to periphery, Apo B-48, C and E"
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VLDL
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"triglyceride rich lipoprotein, secreted by liver
delivers TG from liver to periphery, Apo B-100, C and E |
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IDL
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aka VLDL remnant, acquire cholesterol from HDL and become LDL"
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LDL
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bad (Lousy) cholesterol, delivers cholesterol from liver to periphery, Apo B-100
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HDL
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good (Healthy) cholesterol, reverse cholesterol transport: delivers cholesterol from periphery to liver, secreted by liver and intestine, donates Apo C and E to chylomicrons and VLDL, Apo B-48
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on chylomicrons, required for secretion from intestinal epithelium
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Apo B-48 => what you ATE
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Apo B-100
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1. on VLDL and LDL, required for secretion from liver, 2. binds LDL receptor
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Apo C and E
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required for remnant uptake by liver, donated to chylomicrons and VLDL by HDL
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hyperchylomicronemia
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"type I familial dyslipidemia, lipoprotein lipase deficiency, high TG in the form of chylomicrons. sx: pancreatitis, hepatosplenomegaly, eruptive xanthomas, *no* increased risk of atheroscelrosis
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familial hypercholesterolemia
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type IIa familial dyslipidemia, LD receptor deficiency, autosomal dominant, high cholesterol in the form of LDL. sx: accelerated atherosclerosis, tendon xanthomas, corneal arcus
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hypertriglyceridemia
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"type IV familial dyslipidemia, high TG in the form of VLDL, hepatic overproduction of VLDL, sx: pancreatitis"
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abetalipoproteinemia
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"apo B-100 and B-48 deficiency, autosomal recessive. sx in the first few months of life: failure to thrive, steatorrhea, acanthocytosis, ataxia, night blindness"
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RDS cholesterol synthesis
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"HMG CoA reductase: HMG CoA -> mevalonate, inhibited by statins"
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lipoprotein lipase vs hormone sensitive lipase
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"LPL acts on chylomicrons and VLDL to release FA in adipose tissue. stimulated by insulin (fed state). HSL acts on adipose tissue to release FA for B oxidation. inhibited by insulin, stimulated by epi and cortisol (fasting state). "
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Lecithin cholesterol acyltransferase (LCAT)
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enables reverse trasnport of cholesterol from periphery to liver: forms cholesterol esters, which are soluble in HDL core
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cholesterol ester transfer protein (CETP)
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mediates transfer of cholesterol pesters from HDL to IDL (forming LDL).
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essential fatty acids
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"linolenic acid, linoleic acid"
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how do statins cause rhabdomyolysis?
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"one of the cholesterol synthesis intermediates can be used to synthesize coenzyme Q for the ETC. less CoQ -> impaired mito function and ATP synthesis -> muscle cell damage"
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Tay Sachs disease
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"lysosomal storage disease, AR. deficient enzyme: hexosaminidase A. accumulated substrate: ganglioside GM2 sx: death by 2yo, progressive neurodegeneration, cherry-red spot on macula, *NO* hepatosplenomegaly
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Gaucher's disease
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"lysosomal storage disease, AR, deficient enzyme: B-glucocerebrosidase, accumulated substrate: glucoserebroside. sx: *crumpled paper* macrophages, avascular necrosis of femur, hepatosplenomegaly"
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Niemann-Pick disease
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"lysosomal storage disease, AR. deficient enzyme: sphingomyelinase, accumulated substrate: sphingomyelin. sx: progressive neurodegeneration, hepatosplenomegaly, cherry-red spot on macula, foamy macrophages"
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RDS urea cycle
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"carbamoyl phosphate synthetase I: NH4+ + CO2 -> caramoyl phosphate, cost: 2ATP"
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purpose of urea cycle
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convert excess nitrogen (NH4+) to urea for excretion by kidneys
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location: urea cycle
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mitochondria and cytoplasm of liver
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lab values that suggest urea cycle defect
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"high ammonium, high glutamine, low urea (low BUN)"
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most common urea cycle disorder
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ornithine transcarbamoylase deficiency
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carbamoyl phosphate synthetase deficiency vs. ornithine transcarbamoylase deficiency
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uracil and orotic acid elevated in ornithine transcarbamoylase deficiency. OTC deficiency is x-linked recessive, CPS deficiency is AR. both are mitochondrial enzymes in urea cycle, cause high ammonium, high glutamine, low urea. sx: cerebral edema, lethargy, seizures, coma, death in neonate 24 hours after birth
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ketogenic amino acids
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leucine, lysine. can make ketone bodies in severe fasting
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ketogenic & glucogenic AA
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"isoleucine, threonine, tyrosine, tryptophan, phenylalanine. feed gluconeogenesis in severe fasting"
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phenylketonuria
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"phenylalanie hydrozylase deficiency, autosomal recessive. sx: MR, growth retardation, seizures, *musty* body odor. tx: limit dietary phenylalanine, tyrosine becomes essential, monitor in pregnancy *Nutrasweet (aspartame) contains phenylalanine
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Alkaptonuria
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"homogentisic acid oxidase deficiency, autosomal recessive. sx: ochronosis, arthritis. tx: *symptomatic* only, benign disease"
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Homocystinuria *increased risk of?*
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"cystathionine synthase deficiency or homocysteine methyltransferease deficiency, autosomal recessive. sx: mental retardation, osteoporosis, tall stature (Marfanoid), kyphosis, lens subluxation, atherosclerosis (*stroke and MI*). tx: for cystathionine synthase deficiency, use homocysteine methyltransferease to degrade homocysteine to methionine: decrease methionine and increase cysteine + B12 intake *cysteine becomes essential"
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"Cystinuria *tx*"
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"renal proximal tubular AA transporter defect. cystine = 2 cysteines linked by disulfide bond. sx: cystine kidney stones. tx: *acetazolamide* to alkalinize the urine"
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Maple syrup urine disease
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"branched chain ketoacid dehydrogenase deficiency. sx: days old infant becomes lethargic, CNS defects/MR/death if untreated. tx: limit dietary isoleucine, leucine, valine (I Love Vermont)"
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Hartnup disease
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"renal neutral AA transporter defect, *tryptophan* excretion in urine. sx: pellagra (niacin is derived from tryptophan)"
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RDS heme synthesis
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delta-aminolevulinate synthetase:
glycine + succinyl CoA -> delta-aminolevulinic acid. requires *vitamin B6* inhibited by heme |
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Acute intermittent porphyria
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"urobilinogen-1 synthase deficiency (heme synthesis). autosomal dominant but late onset and variable expression. SX: pain in abdomen, polyneuropathy, psych*, pink urine, precipitated by drugs (*barbituates*, OCP, sulfa drugs)"
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Other porphyrias
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"defect in other heme synthesis enzymes. cutaneous: photosensitivity, blistering"
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Lead poisoning
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"inhibits heme synthesis: ALA dehydrase, ferrochelatase. sx: microcytosis, basophilic stipling, ringed sideroblasts, lead lines in gums and epiphyses"
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Heme metabolism pathway: heme ->
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"biliverdin, bilirubin, conjugated bilirubin (in liver), urobilinogen (in intestine, by bacteria), stercobilin (feces) or urobilin (urine)"
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Crigler-Najjar syndrome
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UDP glucuronyl transferase deficiency
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Gilbert syndrome
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UDP glucuronyl transferase deficiency
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amination of uracil =
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cytosine
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methylation of uracil =
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thymine
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important purine and pyrimidine precursors
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"purine: IMP, pyrimidine: orotic acid, UMP"
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RDS de novo purine synthesis
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glutamine PRPP amidotransferase
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RDS de novo pyrimidine synthesis
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carbamoyl phosphate synthetase II:
glutamine + CO2 -> carbamoyl phosphate. *note: carbamoyl phosphate also a urea cycle intermediate |
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Adenosine deaminase deficiency
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"purine salvage deficiency, major cause of SCID. high levels of dATP inhibit synthesis of other DNA precursors -> B and T cell dysfunction"
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Lesch-Nyhan syndrome
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"absent HGPRT, defective purine salvage, X-linked recessive, sx: unrecovered purines are degraded to uric acid -> hyperuricemia, gout, *self-mutilation*, aggression "
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orotic aciduria
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"defect in de novo pyrimidine synthesis: cannot convert orotic acid to UMP, autosomal recessive, sx: days old infant with orotic acid in urine (but not hyperammonemia as in OTC deficiency - urea cycle defect), megaloblastic anemia that does not resolve with B12 or folate, failure to thrive. tx: oral uridine (salvaged to UMP)"
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"antineoplastic drugs that inhibit enzymes in pyrimidine de novo synthesis (3)
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"hydroxyurea - ribonucleotide reductase, 5-fluorouracil - thymidylate synthase, methotrexate - dihydrofolate reductase"
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