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Biochemistry - Metabolism 2

matic2's version from 2012-06-10 19:40

Urea Cycle

Question Answer
Urea cycleAA catabolism forms common metabolites (pyruvate/Acetyl CoA) to serve as fuel, excess NH4+ from this process-->urea and excreted by kidneys- Ordinarily (ornithine) Careless (carbamoyl phosphate) Crappers (citrulline) Are (aspartate) Also (Arginosuccinate) Frivolous (fumarate) About (arginine) Urination (urea)
Urea structure and originNH2 (from ammonium), C=O (from CO2), NH2 (from aspartate)
Hyperammonemiaacquired (liver disease) or hereditary (urea cycle enzyme deficiencies), excess NH4+ depletes alpha-ketoglutarate which inhibits TCA cycle, tx is to limit protein in diet or meds
Hyperammonemia sxstremor, slurred speech, somnolence, vomiting, cerebral edema, blurred vision
What drugs reduce ammonia levelsphenylbutyrate and benzoate (tx Hyperammonemia) - binds A.A. for excretion
Ornithine transcarbamoylase deficiencymost common urea cycle disorder- XR (most others are auto recessive), converts carboymyl phosphate to citrulline usually, can’t eliminate ammonia very well- often evident in first few days of life but can have later onset- excess carbamoyl phosphate-->orotic acid (part of pyrimidine synthesis pathway), sxs of hyperammonemia
OTC deficiency sxsorotic acid in urine/blood, decreased BUN, sxs of Hyperammonemia (tremor, slurred speech, blurred vision, somnolence, vomiting, cerebral edema)

Amino Acids & their Derivatives

Question Answer
Phenylalanine is precursor to?phe (phenylalanine hydroxylase)-->tyrosine (tyr hydroxylase)-->thyroxine + DOPA-->melanin + DA-->NE (via PNMT that needs SAM)-->epi
Tryptophan is precursor totryp-->niacin + serotonin-->melatonin
Histidine is precursor tohistamine (requires B6)
Glycine is precursor toporphyrin-->heme (requires B6)
Arginine is precursor tocreatine, urea, NO
Glutamate is precursor toeither glutathione or GABA (requires B6 for glutamate decarboxylase)
Phenylketonuriadecreased phe hydroxylase or THB cofactor so no tyrosine made, increased phenylalanine-->excess phenylketones in urine
Findings: mental/growth retardation, fair skin, eczema, musty body odor (aromatic AA metabolism disorder)
Tx PKUdecreased phenylalanine in diet (which is in aspartame) and increase tyrosine in diet (disorder is screened for 2-3 days after birth- maternal enzyme functions right after birth)
Maternal PKUlack of proper diet therapy in pregnancy, can see mental/growth retardation, microcephaly, CHD in infant
Alkaptonuriacongenital defect of homogentisic acid oxidase in degradation of tyrosine-->fumarate
benign but will see dark CT, pigmented sclera, urine turns black on standing, may have debilitating arthralgias
Albinismcongenital def. of either tyrosinase (can’t make melanin from tyrosine) or defective tyrosine transporters (decreased amounts of tyrosine and melanin)- both have variable inheritance due to locus heterogeneity
Lack of melanin?increased risk of skin cancer- from inability to make melanin from tyrosine (defective tyrosine transporters or no tyrosinase)
Homocystinuria pathophysiology3 forms- AR - **all result in excess homocysteine so cysteine is essential**
1. cystathionine synthase deficiency (tx decreased Met/increased Cys and B12/folate in diet)
2. decreased affinity of cystathionine synthase for pyridoxal phosphate (tx with more B6 in diet)
3. homocysteine methyltransferase deficiency
Homocystinuria clinical findingstoo much homocysteine (found in urine), mental retardation, osteoporosis, tall stature, kyphosis, lens subluxation (in and down), atherosclerosis
Cystinuriaexcess cystine in urine as a result of defective renal tubular AA transporter (cystine, ornithine, lysine, arginine) in PCT of kidneys-->cystine stones can precipitate- these are acidic so alkalinize urine with acetazolamide to treat
Cystine made of2 cysteines with disulfide bond
Maple syrup urine diseaseblocked degradation of branched amino acids (Ile, Leu, Val) due to decreased alpha-ketoacid dehydrog.-->increased alpha ketoacids in the blood which can cause severe CNS defects, retardation, and death **I Love Vermont maple syrup from maple trees w/Branches**
Hartnup diseaseAR, defective neutral AA transporter on renal/intestinal epithelial cells, get tryptophan excretion in urine and decreased absorption from gut-->leads to pellagra b/c leads to B3 def.**
Pellagrafrom a niacin or tryptophan deficiency- 4 Ds-->diarrhea, dermatitis, dementia, death

Glycogen & Lysosomes

Question Answer
Glycogen phosphorylaseactivated when phosphorylated by PKA (via glucagon and epi), inactivated by insulin, converts glycogen to limit dextran (4 glucose residues in branched config) during breakdown
Insulin and glycogen phosphorylaseinsulin activates a protein phosphatase which dephosphorylates glycogen phosphorylase to make it INACTIVE (no glycogen breakdown occurs)
Glycogen branches vs linkages and respective bondslinks have alpha 1-4, branches have alpha 1-6
Enzyme to convert G1P-->UDP-glucose?UDP glucose pyrophosphorylase
Enzyme to convert UDP glucose to storage glycogen?glycogen synthase (activated by insulin and glucose, inhibited by glucagon & epi)
Glycogen synthase makes which linkages?1,4 linkage
Branching enzyme makes1,6 link
Debranching enzymetakes limit dextrin to glucose
Lysosomal alpha-1,4 glucosidasebreaks down some glycogen (in addition to glycogen phosphorylase)
Glycogen storage diseases12 types and all have disordered glycogen metabolism-->buildup of glycogen in cells
Von Gierke’s Diseasetype 1 glycogen storage disorder, deficient glucose-6-phosphatase (no G6P-->glucose), will get severe fasting hypoglycemia, increased glycogen in liver, increased blood lactate, hepatomegaly
Pompe’s diseasetype 2 glycogen storage disorder- no lysosomal alpha-1,4,glucosidase , will get cardiomegaly and systemic findings leading to early death “pompe’s trashes the Pump”
Cori’s diseasetype 3 glycogen storage disorder – no debranching enzyme (alpha 1-6 glucosidase), gluconeogenesis is fine, milder form of type 1 von gierke’s disease w/nL blood lactate, get fasting hypoglycemia/increased glycogen in liver
McArdle’s diseasetype 4 glycogen storage disorder- no skeletal m. glycogen phosphorylase so you get increased glycogen in MUSCLE but can’t break it down-->painful m. cramps, myoglobinuria with strenuous exercise due to cell death + lysis of myocyte
Lysosomal Storage Diseasesresults in accumulation of abnormal metabolic products
Fabry’s diseaselyso storage disorder- deficient alpha-galactosidase A so get accumulated ceramide trihexooside, x-linked recessive , will get peripheral neuropathy hands/feet, angiokeratomas, cardio/renal disease
Gaucher’s diseaselyso storage disorder auto recessive, no glucocerebrosidase so buildup of glucocerbroside, will see hepatosplenomegaly, aseptic necrosis of femur, bone crises, gaucher’s cells (macros like crumpled tissue paper)
Niemann-Pick diseaselyso storage disorder, auto recessive, no sphingomyelinase so buildup sphingomyelin, get progressive neurodegeneration, hepatosplenomegaly, cherry red spot on macula, foam cells
Tay sachslyso storage disorder, auto recessive, deficient hexosaminidase A so buildup GM2 ganglioside, will see progressive neurodegeneration, developmental delay, cherry red spot, lysos w/onion skin, no hepatosplenomegaly
Krabbe’s diseaselyso storage disorder, no galactocerebrosidase so buildup of this, will see peripheral neuropathy, developmental delay, optic atrophy, globoid cells
Metachromatic leukodystrophylyso storage disorder, deficient arylsulfatase A so buildup cerebroside sulfate, will see central/peripheral demyelination with ataxia/dementia
Hurler’s syndromemucopolysaccaridoses- no alpha-L-iduronidase so buildup heparan and dermatan sulfate- get developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly
Hunter’s syndromemucopolysaccharidoses-X-linked recessive, no iduronate sulfatase so buildup heparan/dermatan sulfate, have mild hurler’s syndrome + aggressive behavior, no corneal clouding - Hunter’s see clearly and aim for the X (x-linked)
Disease that are increased risk in Ashkenazi JewsTay Sach's, Niemann-Pick, Gaucher's - all AR

Fatty Acid Metabolism

Question Answer
Fatty acid synthesisstart with citrate-->citrate shuttle to take it from mito matrix-->cytoplasm, ATP citrate lysase -->acetyl CoA-->malonyl CoA-->palmitate (16C FA)
Malonyl CoAinhibits carnitine shuttle (FA breakdown) so that FA can be synthesized only
Fatty acid breakdownFatty Acid + CoA-->Acyl CoA via FA CoA synthetase-->thru carnitine shuttle then beta oxidized in mito matrix to ketone bodies and to TCA cycle
Carnitine deficiencycan’t transport long chain FAs into mitochondria so get toxic accumulation-->weaken, hypotonia, hypoketonic hypoglycemia
Acyl CoA dehydrogenase deficiencyincreased dicarboxylic acids, decreased ketones and glucose
Ketone bodiesacetoacetate and beta-hydroxybutyrate from FAs and AAs, in states like diabetic ketoacidosis/alcoholics/starvation then OAA is depleted for gluconeo- glucose and FFA shunted toward ketone body synthesis via HMG coA, metabolized by brain to 2 acetyl CoA and excreted in urine
Urine testing for ketonesno detection of beta-hydroxybutyrate (breath smells like acetone- fruity)
Beta-hydroxybutyrateketone body that predominates in pathologic conditions (diabetes/alcoholism) during ketoacidosis

Cholesterol & Lipids

Question Answer
Rate limiting step in Cholesterol synthesiscatalyzed by HMG Coa reductase (HMG CoA-->mevalonic acid)
Statinsinhibit HMG-CoA reductase
Essential FAslinoleic and linolenic acids (arachidonic acid if linoleic acid is absent)- eicosanoids are dependent on essential FAs
Pancreatic lipasedegrades dietary TG in small intestine
Lipoprotein lipasedegrades circulating TG in chylomicron and VLDL
Hepatic TG lipasedegradation of remaining TG in IDL
Hormone sensitive lipasedegradation of TG stored in adipocytes
LCATcatalyzes esterification of cholesterol (2/3 of all cholesterol made is esterified), activated by apolipo A1
CETPmediates transfer of cholesterol esters to other lipoprotein particles
Apolipo. A1activates LCAT, in HDL
Apolipo. B100binds to LDL receptors and mediates VLDL secretion, only in VLDL, IDL, LDL
Apolipo. CIICofactor for lipoprotein lipase, found in chylomicrons, VLDL, HDL (shuttles it around)
Apolipo. B48mediates chylomicron secretion, only in chylomicrons
Apolipo. Emediates Extra (remnant) uptake- only in chylomicron, VLDL, IDL, HDL (shuttles it around)
The only triacylglycerol components used for gluconeogenesisglycerol and propionyl Coa from odd chain FA metabolism
LDL functiontransfers cholesterol from liver to tissues, formed by lipoprotein lipase modification of VLDL in peripheral tissue, taken up by target cells via receptor-mediated endocytosis
HDL functiontransfers cholesterol from periphery to liver (reverse transport)- acts as a reserve for apoC and apoE (needed for chylomicron/VLDL metabolism), secreted from both liver/intestine
Chylomicron functiondelivers dietary TGs to peripheral tissues, also carries chylomicron remnants to liver which are mostly depleted of their TGs, secreted by intestinal epithelial cells (apolipoproteins B48, C-II, and E)
VLDL functiondelivers hepatic TGs to peripheral tissue, secreted by liver, apolipoproteins b100, C-II, E
IDLformed in degradation of VLDL, delivers TGs and cholesterol to liver where they’re degraded to LDL
Type 1 hyperchylomicronemiahave increased chylomicrons and elevated blood TG/cholesterol , due to a lipoprotein lipase deficiency or altered apolipo. CII, causes pancreatitis, hepatosplenomegaly, and xanthomas- NO INCREASED RISK for atherosclerosis
Type 2a familial hypercholesterolemiahigh LDL and increased blood cholesterol, auto dom, absent or decreased LDL receptors, causes ACCELERATED atherosclerosis, tendon (Achilles) xanthomas, and corneal arcus
Xanthomayellow cholesterol-rich deposit cutaneous/other body part- cutaneous manifestations of lipidosis (as in Type 1 or 2 dyslipidemias)
Type 4 hypertriglyceridemiaincreased VLDL and high blood TG- due to hepatic overproduction of VLDL, causes pancreatitis
Abeta-lipoproteinemiaauto recessive- inability to make lipoproteins from deficits in apoB-100/48, sxs in first few mo of life; findings: intestinal bx shows accumulation w/in enterocytes b/c chylomicrons can’t be exported
failure to thrive
acanthocytosis = thorny RBCs
ataxia = can't make myelin
night blindness = can't make vit A