Step 1 - Biochem 4

denniskwinn's version from 2015-04-25 15:56


Question Answer
Gluconeogenesis irreversible enzymesPyruvate carboxylase, PEP carboxylase, Fructose 1,6, bisphosphatase, Glucose6phosphatase - Pathway Produces Fresh Glucose
Pyruvate carboxylaseirreversible enzyme - in mitochondria converts pyruvate to oxaloacetate (requires biotin, ATP, Activated by acetyl-CoA)
PEP carboxykinaseirreversible enzyme - in cytosol converts oxaloacetate to phosphoenolpyruvate (requires GTP)
Fructose 1,6 bisphosphataseirreversible enzyme - in cytosol - converts F16BP to F6P
Glucose 6 phosphataseirreversible enzyme - in ER - G6P to glucose
GluconeogenesisOccurs primarily in livcr. Enzymcs also found in kidney, intestinal epithelium. Deficiency of the key gluconeogenic enzymes cause hypoglycemia. - Odd chain fatty acids yield 1 propionyl-CoA during metabolism, which can enter the TCA cycle (as succinyl coa), undergo gluconeogenesis and server as a glucose source. Even chain FA cannot produce new glucose, since they yield only acetyl coA equivalents
HMP shunt purposeprovide source of NADPH from G6P - also yields ribose for nucleotide synthesis and glycolytic intermediates - 2 distinct phases - No ATP used or produced - sites: lactating mammary glands, liver, adrenal cortex (sites of fatty acid or steroid synthesis), RBCs
HMP shunt irreversible (oxidative) reactionsG6P → 2 NADPH, Ribulose 5P, CO2 - rate limiting enzyme = Glucose-6-P dehydrogenase
HMP shunt reversible (nonoxidative) reactionsRibulose 5P→Ribose 6P, G3P, F6P - enzymes = transketolases (required B1)
Respiratory burstactivation of mcmbrane- bound NADPH oxidase (e.g. In neutrophils, macrophages). Plays an important role in the immune response→results in the rapid release of reactive oxygen intermediates (ROIs)
Glucose 6 phosphate dehydrogenase deficiencycannot produced NADPH - leads to hemolytic anemia - X linked recessive, Heinz bodies, Bite cells
Metabolic vitaminsThiamine (B1), Riboflavin (B2), Niacin (B3), Pantothenic acid (B5), Pyridoxine (B6), Biotin (B7)
B complex deficiencies result indermatitis, glossitis, diarrhea
Fructose intoleranceHcreditary deficiency of aldolase B. Autosomal recessive. Fructose-1-phosphate accumulates, causing a ↓ in available phosphate, which results in inhibition of glycogenolysis and gluconeogenesis. 2. Symptoms: hypoglycemia, jaundice, cirrhosis, vomiting Treatment: ↓ intake of both fructose and sucrose (glucose+fructose)
Essential fructosuria1. Involves a defect in fructokinase. Autosomal recessive. A benign, asymptomatic condition, since fructose does not enter cells. Sx: fructose in blood and urine. Disorders of fructose metabolism cause milder symptoms that analogous disorders of galactose metabolism
Draw fructose metabolismpage 103
Classic galactosemiaAbsence of Galactose 1 phosphate uridyltransferase. Autosomal recessive. Damage is caused by accumulation of toxic substances (including galactitol, which accumulates in the lens of the eye) Symptoms: failure to thrive, jaundice, hepatomegaly, infantile cataracts, mental retardation. . Treatment: exclude galactose and lactose (galactose+glucose) from diet
Galactose deficiencyHereditary deficiency of galactokinase, galactitol accumulates if galactose is present in diet. Relatively mild condition. Autosomal recessive. Symptoms: galactose appears in blood and urine, infantile cataracts. May initially present as failure to track objects or to develop a social smile.
Draw galactose metabolismpage 103
Sorbitolglucose converted to alcohol, keeps it in cell (via aldose reductase w/NADPH) - can be converted to fructose in cell via sorbitol dehydrogenase (in liver, ovaries and seminal vesicles) - - prolonged hyperglycemic state leads to sorbitol accumulation causing water to enter cell→osmotic damage (cataracts, retinopathy, peripheral neuropathy) - - also happens to fructose and galactose with high blood levels
Lactase deficiencyAge-dependent and/or hereditary lactose intolerance (African Americans, Asians) due to loss of brush-border enzyme. May also follow gastroenteritis. . Symptoms: bloating, cramps, osmotic diarrhea. Treatment: avoid dairy products or add lactase pills to diet.
Glucogenic essential amino acidsMet, Val, Arg, His
Glucogenic/ketogenic essential amino acidsIle, Phe, Thr, Trp
Ketogenic essential amino acidsLeu, Lys
Acidic amino acidsAsp and Glu (negatively charged at body pH)
Basic amino acidsArg, Lys, His, - Arg is most basic, His has no charge at body pH
Draw urea cycle picture105
Urea cycle stepsOrdinarily, Careless Crappers Are Also Frivolous About Urination - Ornithine+ Carbamoyl phosphate→Citruline→Aspartate→Arginosuccinate→Fumarate→Arginine→Urea
Urea cycleamino acid metabolism leads to excess nitrogen -
Urea formationCO2+NH4→Carbamoyl phosphate (via carbamoyl phosphate synthetase I and 2ATP)
Ammonium transportAmino acids in muscle break down to ammonia - which is combined w/alpha-ketoglutarate to make glutamate then moved from glutamate to combine with pyruvate making alanine and alpha-ketoglutarate. Alanine gets transported to liver to get ammonia to liver for urea cycle.
Ammonia intoxicationtremor, slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision


Question Answer
HyperammonemiaCan be acquired (e.g., liver disease) or hereditary (e.g., urea cycle enzyme deficiencies). . Results in excess NH/, which depletes a-ketoglutarate, leading to inhibition of TCA cycle. Treatment: limit protein in diet. Benzoate or phenylbutyrate (both of which bind amino acid and lead to excretion) may be given to ↓ ammonia levels.
Ornithine transcarbamoylase (OTC) deficiencyMost common urea cycle disorder - X-linked recessive (vs. Urea cycle enzyme deficiencies which are autosomal dominant) - Interferes with the body's ability to eliminate ammonia. Often evident in the first few days of life, but may present with late onset. Excess carbamoyl phosphate is converted to orotic acid (part of the pyrimidine synthesis pathway). Findings: orotic acid in blood and urine, ↓ BUN, symptoms or hyperammonemia
Phenylalanine derivativesTyrosine, thyroxine, Dopa, Melanin, dopamine, NE, Epi
Tryptophan derivatives(need B6)Niacin (NAD+,NADP+), (needs BH4)Serotonin, Melatonin
Histidine derivatives(needs B6) Histamine
Glycine derivatives(needs B6) Porphyrin to Heme
Arginine derivativesCreatinine, Urea, Nitric Oxide
Glutamate derivatives(needs B6) GABA (glutamate decarboxylase - requires B6), Glutathione
Phenylalanine to Tyrosine (Phenylalanine hydroxylase)
Tyrosine to Dopa (Tyrosine hydroxylase)
Dopa to dopamine (Dopa decarboxylase, needs b6, inhibited by carbidopa)
Dopamine to Norepinephrine(dopamine beta hydroxylase, requires vitamin C)
Norepinepherine to EpinepherinePNMT (requires SAM)
Dopamine breakdown products (via MAO and COMT)HVA
Norepinepherine breakdown products (via MAO and COMT)VMA
Epinepherine breakdown products (via MAO and COMT)Metanepherine
PKU cause↓ phenylalanine hydroxylase or ↓ tetrahydrobiopterin cofactor. Tyrosine becomes essential.
PKU findings↑ phenylalanine leads to excess phenylketones in urine(phenylacetate, phenyllactate, and phenylpyruvate.) mental retardation, growth retardation, seizures, fair skin, eczema, musty body odor (aromatic amino acid metabolism disorder)
PKU treatmentdecrease phenylalanine (contained in aspartame/nutrasweet) and increase tyrosine in diet
Maternal PKUlack of proper dietary therapy during pregnancy. Findings in infant: microcephaly, mental rctardation, growth retardation, congellital heart defects.
Alkaptonuria (ochronosis)Congenital deficiency of homogentisic acid oxidase in the degradative pathway of tyrosine, Autosomal recessive - benign disease - Findings: dark connective tissuc, pigmcntcd sclera, urine turns black on standing - may have debilitating arthralgias
AlbinismCongenital deficiency of either of the following. I. Tyrosinase (inability to synthesize melanin From tyrosine-autosomal recessive. . 2. Defective tyrosine transporters (↓ amounts of tyrosinc and thus melanin) - Can result from a lack of migration of neural crest cells. - increased risk of skin cancer, variable inheritance due to locus heterogeneity
HomocystinuriaExcess homocysteine, cytstein becomes essential. Findings: ↑↑ homocysteine in urine, mental retardation, osteoperosis, tall stature, kyphosis, lens subluxation (downward and inward) and atherosclerosis (stroke and MI) 3 forms (all autosomal recessive): 1. Cystathionine synthase deficiency (treat w/↓Met, ↑Cys,↑B12 and folate in diet) 2. ↓Affinity of cystathionine synthase for pyridoxal phosphate (treat w/ ↑↑vitamin B6) 3. Homocyteine methyltransferase deficiency
Draw homocysteine108
CystinuriaHereditary defect of renal tubular amino acid transporter for cysteine, ornithine, lysine, arginine in the PCT of the kidneys. Excess cystinc in urine can lead to the precipitation of cystine kidney stones (cystine staghorn calculi), Autosomal recessive, Treat with acetazolamide to alkalanize the urine. Cystine is made of 2 cysteines connected by disulfide bond
MSUDBlocked degradation of branched amino acids (Ile. Leu, Val) due to ↓ alpha ketoacid dehydrogenase -Causes ↑ a-ketoacids In the blood, especially Leu - severe CNS defects, MR, and death -
Hartnup diseaseAutosomal recessive disorder characterized by defective neutral amino acid transporter on renal and intestinal epithelial cells - causes tryptophan excretion in urine and ↓ absorption from the gut - leads to pellagra
Glycogen regulation by insulinGlucagon and Epinepherine turn on cAMP to protein kinase A which phosphorylates glycogen phosphorylase kinase which activates glycogen phosphorylase. Insulin activated receptor tyrosine kinase activating protein phosphatase taking phosphate off of glycogen phosphorylase
Glycogen bondingbranches have alpha 1,6, linkages have alpha 1,4
Skeletal muscle and glycogenGlycogen undergoes glycogenolysis to form glucose which is metabolized during exercise
Glycogen and hepatocytesGlycogen is stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels
Glycogen synthesisG6P to G1P to UDP gluc to glycogen chain
Draw glycogen synth picture109, 110


Question Answer
Glycogen storage disease12 types, all resulting in abnormal glycogen metabolism and an accumulation of glycogen within cells. - Very Poor Carbhydrate Metabolism
Von Gierke’s disease (type I) findingsSevere fasting hypoglycemia, ↑↑ glycogen in liver, ↑ blood lactate, hepatomegaly
Von Gierke’s disease (type I) deficient enzymeGlucose-6-phosphatase
Pompe’s disease (type II) findingsCardiomegaly and systemic findings leading to early death - P trashes Pump (heart, liver and muscle)
Pompe’s disease (type II) deficient enzymeLysosomal alpha 1,4 -glucosidase (acid maltase) -
Cori’s disease (type III) findingsMilder form of type I with normal blood lactate levels - gluconeogenesis is intact
Cori’s disease (type III) deficient enzymedebranching enzyme (alpha 1,6 glucosidase)
McArdle’s disease (type V) findings↑ glycogen in muscle, but cannot break it down, leading to painful muscle cramps, myoglobinuria with strenous exercise
McArdle’s disease (type V) deficient enzymeskeletal muscle glycogen phosphorylase

lysosomal storage diseases

Question Answer
Lysosomal storage diseasesmultiple kinds - results in accumulation of abnormal metabolic products - sphingolipidoses, polysaccharideoses - X linked recessive
Fabry’s disease findingssphingolipidosis - peripheral neuropathy of hands/feet, angiokeratomas, CV/renal disease
Fabry’s disease deficient enzymealpha galactosidase A
Fabry’s disease accumulated substrateCeramide trihexidose
Gaucher’s disease findings(most common) Autosomal recessive - sphingolipodosis - Hepatosplenomegaly, aseptic necrosis of femur, bone crises, Gaucher's cells (macrophages that look like crumpled tissue paper)
Gaucher’s disease deficient enzymeBeta-glucocerebrosidase
Gaucher’s disease accumulated substrateGlucocerebroside
Niemann-Pick disease findingsAutosomal recessive - Progressive neurodegeneration, hepatosplenomegaly, cherry-red spot on macula, foam cells
Niemann-Pick disease deficient enzymesphingomyelinase
Niemann-Pick disease accumulated substratesphingomyelin
Tay-sachs disease findingsAutosomal recessive - progressive neurodegeneration, developmental delay, cherry red spot on macula, lysosomes with onion skin, no hepatosplenomegaly (vs Niemann pick)
Tay-sachs disease deficient enzymeHexosaminidase A
Tay-sachs disease accumulated substrateGM2 ganglioside
Krabbe’s disease findingsAutosomal recessive, peripheral neuropathy, developmental delay, optic atrophy, globoid cells
Krabbe’s disease deficient enzymeGalactocerebrosidase
Krabbe’s disease accumulated substrateGalactocerebroside
Metachromatic leukodystrophy findingsAutosomal recessive - Central and peripheral demyelination with ataxia, dementia
Metachromatic leukodystrophy deficient enzymeArylsulfatase A
Metachromatic leukodystrophy accumulated substrate Cerebroside sulfate
Hurler’s syndrome findings Autosomal recessive Developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly
Hurler’s syndrome deficient enzymealpha-L-iduronidase
Hurler’s syndrome accumulated substrateHeparan sulfate, dermatan sulfate
Hunter’s syndrome findingsX linked recessive - Mild Hurlers (developmental delay, gargoylism, airway obstruction, hepatosplenomegaly) No corneal clouding, add aggressive behavior
Hunter’s syndrome deficient enzymeIduronate sulfatase
Hunter’s syndrome accumulated substrateHeparan sulfate, dermatan sulfate
Draw lysosomal storage drawing111


Question Answer
Draw fa synthesis112
Carnitine deficiencyinability to transport LCFAs into the mitochondria resulting in toxic accumulation - causes weakness, hypotonia and hypoketonic hypoglycemia
Acyl-Coa dehydrogenase deficiency↑ dicarboxylic acids, ↓ glucose and ketones
Ketone bodiesIn the liver, fatty acids and amino acids are metabolized to acetoacetate and Beta-hydroxybutyrate (to be in muscle and brain). 2. In prolonged starvation and diabetic ketoacidosis, oxaloacetate is depleted for gluconeogenesis. In alcoholism, excess NADH shunts oxaloacetate to malate, both processes stall TCA cycle which shunts glucose and FFA toward the production of ketone bodies - made from HMG-CoA - metabolized by the brain to 2 molecules of acetyl-CoA - excreted in urine