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Edward Goljan, M.D. 2002 4 Superficial cerebral veins: drain into supertor sagittal sinus Site adontoblasts develop from: odontoblasts develop into dentin, + odontoblasts arc on inner aspect of the developing tooth, # outer portion develops enamel from ameloblasts HIGH YIELD NOTES BIOCHEMISTRY ° = Hyperlipoproteinemias: » sype Land V have chylomicrons associated with them, « type Tl increase in LDL. » type II is remnant disease (dysbetalipoproteinemia). » increase ie VLDL in type TV and pe V ® PCR mechanism: uses DNA polymerase 1o break down DNA into fragments = Locations of biochemical processes in cell: # cytosol~ + glycolysis. » pentose phosphate shu Fa sunthess, + glycogen synthesis. « mitochondtial matrix~ ¥ Broxidation of FAs, = TCA exe voner mitochondrial membrane— Oxidative phosphorylation. * both eytosel and mitockondria~ = juconeogenesis, # urea cycle, * heme synthesis ‘earotransmitter from an essential amino acid: serotonin coming from tryptophan Brain energy during starvation: « ketone bodies, © uses glucose during fed and fasting suate Gluconeogenie enzymes: * pyruvate carboxylase, * phosphoenolpymuvate carboxkinese, # across 16-bisphosphatase (rate limbng}, ¢ glucose 6-phosphatase (defiesent wn von Grerkes ycogenosis) 2 RBC ribosomes: « lost after RBC leaves bone marrow, » persistence in peripheral blood produces basophihe sippting.« coarse basophilic sipping sign of Pb poisoning (nboruclease denatured by Pb} = BeThatassemia mechanisms: © most often a splicing defect for mild forms. « severe hal s duc to stop codon preventing (2-chain transcription s+ Man with 2900 calorie diet with 30% of it representing fat. how mapy grams is far ccal'g, © 2900 x 0.30 = $70 calories is fat, © 870 + 9=~97 grams = Veccand Ket © glucokinase— high Km (low affinity for glucose) and high Win ¢only reacts wih stloce), « hexokinase low Km (high affinity for glucose. good for fasting state) and low Von (reacts with all hexose sugars) » Faseatial fatty acids (FAS): © linoleic acid + C18:206. + produces arachidonic acid, * no: cardioprotective, © com oil/safflower oil, # a-linoleaic— + C18:303. * cardioprotective ‘ower rralveersées snkibit platelet aggregation, produce ant-inflammatory prostaglandins, less damage (0 revocardial tissue in infarctions. * found in fish oils. canola off (best ol) «Teall disease. inability 10 phosphorylate the mannose residues of potential iysosomel enzymes Tosated in Golgi apparatus. hence they cannot be taken up by the tysosomes to degrade complex substrates = Number of glucoses necessary to build palmitic acid a 16 earbon compound: 4 slucoses. <2: glucose run produces 2 acetyl CoA, the latter containing 2 earbons each fat bas 9 + inuatin lack in DKA: decreased glycolysis, glveogenesis, fatty acid synthesis. storage of fat m adipose parison Chart of the Well Fed State, Fasting State, and Starved State: TWellfeastate | Fasibgstare [starved sate Glycogenesis Tincreased. [None [None Glycogenolysis {Decreased none im /increased: early sapply | None: elycogen used ue he liver.some inj of glucose derived from | | muscle Liver not museleJ ms » ~ a. al = Note: This material is copy ighted. All rights reserved. Edward Goljan, M.D. 2002 Well fed state [Fasting state * Starved state ‘Giuconeogenesis Tone Increased: primary Decreased: just eno source of glucose after | supply RBCs | elycogenolysis Triacyigiveerol syathesiy | Increased | None ‘None in liver/adipose ! “Lipolysis | None. Increased Tnereased Fate of glyeeral | Synthesize more Substrate for Substrate for | tiacylelycerot in tiver | gluconeogenesis gluconeogenesis Broxidation of fatty acids | None Tnereased Markedly increased Musele catabolism None: increased protein synthesis and uptake of amino acids | Tnereased: supply amino acids for luconeogenesis [primary fuel for muscle Decreased: conserve muscle for important body | functions Urea synthesisiexeretion Remains constant: handles NH," load from protein degradation in gut by bacteria Tnereased: deamination of amino acids used for gluconeogenesis Imereases ures synthesis, "Decreased: less muscle breakdown of proteim with ess amino acids to degrade I | Markediy increased: by” Ketone body synthesis | None Tncreased | | product of aceiyi CoA from increased [- | oxidation of fatty acids Muscle usé of glucose for | Paimary fuel Decreased ‘None: mainly uses fatty fuel acids Muscle use of fatty acids | None Increased: primary fuel | Markedly increased for fuel primary fe] Muscle use of ketones None ‘Some: alternative fuel | None. allows the brain to for fuel i Brain use of glucose for fuel | Brain use of ketones for fuel i RBC use af glucose for fuel i = Acquired and Genetic Hyperipoprotel Lipid Disorders Typel + Familia! lipoprotein Inpase deficieney + Apo Cl deficiency Pathogenesis: cannot | hydrolyze chylomierons Remains constant None Remains constant ly nei Clinical Comments Rare childhood disease. Remains constant None Remains constant use ketones for fue! Desreascd: allows RBCS | to primarily use glucose for fuel Increased: primary Wee Remains constant | Laboratory Findings # Increased chylomicrons and TG with anormal cholesterol and LDL. + stan- ding chylomicron test supranate but noNote: This material is copyrighted. All rights reserved. Edward Goljan. M.D. 2002 Lipid Disorders T Clinical Comments [Laboratory Findings ‘Type HT Te AD disorder with premoture _ ¢ Type ila: inereased LDL (often =260 « Fooniliel hyporeholester- ] CAD. « Achilles tendon xanth- | mgd) and cholesterol. normal TO. oh | omas pathognomonic, © Rav type Mb: increased LDL, cholesterol Pathogenesis: absent or | "statin” drugs and TG. defective LDL recoprors | « Acquired causes: diabetes, hypothyroidism, obstructive Jaundice, progesterone in birth) control pills Tepe til 7 Increased CAD Fisk. hyperu. | « Cholesterol and TG equaliy elevaced. + Familial cemia, « obesity, # diabetes. ‘e increase in chylomicron and IDi yiscose ~ galactose. * galactose metsbolism in sequence is as follons~ * galactose ~ galactokinase > galactose [-POs, ¢ galactose 1-POQ, ~ GALT (galactose rransferase) ~ UDP-glucose+ glucose 1-PO, = UDP-galactose, * glucose 1-PO: ~Noe: ‘This material is copyrighted. All rights reserved. Edward Goljan. M.D. 2002 phosphoghicomutase —> glucose 6-PO: (6 carbon intermediate) + glucose 6-PO, + glucose 6 phosphatase (sluconeogenie enzyme)» glucose. * galactokinase deficiency * benign AR disease, * positive urine Chinitest: Clinitest detects all reducing sugars except sucrose, which 1s not a reducing sugar. « galactosemia~ + AR disease with deficiency of GALT. excess galactose 28 converted ito the galactitol (polyol or alcohol sugar). which, like sorbitol. is osmoncally active: damages lens. nerve tissuc, CNS, liver, * excess galactose 1-PO, is toxic: cirrhosis. mental retardation. renal damage. neonatal hypoglycemia (lack ‘of glucose 6-PO,, 2 substrate for luconeogenesis). * Rx_is a lactose free diet for the first two yrs. + pregnant_women_ with ggactosernia can sunthesize lactose in their breast milk via the following zeactions: UDP-glucose ~ UDP--hexose epimerase > UDP-galactose, UDP-galactose - lactase synthetase» tactose = UDP Disorders in fructose metabolism: ¢ fructose metabolism in sequence * sucrose ~ sucrase —> glucose ~ fructose. * fructose =. fructokinase —> fructose 1-POs, * fructose. 1-PO, + aldolase B > gisceraldehyde 3 phosphate ~ dihydroxyacetone phosphate (DHAP. both are 3 carbon intermediates that are gluconeogenic substrates). ¢ fructose can ‘be synthesized from mannose (and ace versa) and sorbitol, # fructose is an essential nutrient for sperm stored in the seminal vesicles, © essential fructosuria~ * AR disease with missing fructokinase, * positive urine Clinitest due to fructose. © hereditary fructose _intolerance- * AR disease with a deficiency of aldolase B. + accumulation of fructose 1-PO., which is toxic to the liver (cirrhosis). » fasting hypoglycemia due. ‘a a decrease in 3 carbon intermediates for gluconeogenesis, * severe hypophosphatemia: excess fructose iraps phosphate in cells. depletion of ATP jeads 10 RBC hemolysis and rhabdomyolysis. rcs tas phos ine oer adMD) winch ira ore, carved inoue si eng a ermine maar agora the di Sorbitol: © osmotically active solute that is synthesized in those tissue comiaining aldose reductase which include— * lens. + ova. * seminal vesicles {note in the biochemical reaction listed below how olucose is converted into fructose in the seminal vesicles), * Schwann cells. * retina. * kidneys. ¢ aldose reductase converts glucose into sorbitol and sorbitol dehydrogenase converss sorbitol into noe ‘NADPH NADP NAD” NADH: iaeaie Sol ay Erste aldese reductase sorbitol dehydrogenase « in hyperglycemic statgs, like diabetes mellins, there is an excess of sorbitol produced it: the above tissucs leading to osmotic damage * cataracts, + peripheral neuropathy due to destruction of Schwann cells. * microaneurysms in retinal vessels due to destruction of pericytes Homocystinuria: + AR disease with a deficiency of cystathionine synthase, * metabolism of homocystine in sequence 1s a5 follows- * methionine ~ ATP —> S-adenosyimethionine (SAM) ~ snethy] acceptors ~ methyloransferase —» S-adenosythomocysteine ~ methylated products (donates methyl groups for 1 carbon transfers), * S-adenosythomecysteine ~ HO —> homocysteine ~ adenosine. * homocysteine + serine + cystathionine synthase —> cystathionine, ¢ in homocystinuria, both homocysteine and methionine are increased in serum, * SS of homocystinuria that resemble Marfan syndrome (example of genetic heterogeneity)~ * dislocated jens. + arachnodactvly. + eunuchoid, « distinetive features of homocystinurie~ + increase in plasms homocysteine levels leads to vessel damage/thrombosis (strokes. AMI), * mental retardation, increased urine homocysteine and increased serum/urine methionine ‘Alcaptonuria and hereditary tyrosimosis: » metabolism of phenylalanine 13 a8 folios + phenvislanine — phenvlalanine hydroxylase (deficient m PKL)—> tyrosine. + trosme —> 4 Eydroxypheny| pyruvate + homogentisate, + homogentisate ~ homogemisate oxidase (Getierent i aikaptonuria) —» maleylagetoacetate, * maleylacetoacetate + firmarylacetoacetate hydrolase (deficient in hereditary tyrosinemia} + fumarylacetoacetate. * fumarylacetoacetate — acetoacetat 38EEE TTIDSSS Note: This materiat is copyrighted. All rights reserved. Edward Goljan, M.D. 2002 ~ fumarate (present in TCA cycle). alkaptonuria~ + AR disease with an absence of homaze gxidase. + accumuistion of black, homogentisate pigment in joimts'cantilage leads to degenerative ‘oint disease, « urine tums black when oxidized upon exposure to light, « hereditary twrosinosis— + AR disease with 2 deficieney of fumarvlacetoacerate hydrolase, + increase in serum tsrosmne eabbage-ike odor. * cirrhosis with an extremely high incidence of hepatocellular carcinoma. + rena} disease (aminoaciduria). * death in the frst yr of life ~ Lysosomal storage diseases: « definition— * absence of degradi hydrolytic a glycosaminog| enzymes in lysosomes: «4 tain npads, ymes, + sccumulation of complex substrates in lysosome: sph: ‘cans, glycogen (Pompe's disease), « most are AR diseases with the exception of wo diseases, which are SXR- + Fabry's disease, + Hunter's discase. « biochemistry of lysosomes~ lysosomal enzymes are synthesized in the rough endoplasmic reticulum» en/yrnes are transported to the Golgi apparatus» enzymes undergo post-translational modification» enzymes are shosphorylated at one or more mannosyl residues to form mannose 6-phosphot which 1s attached to the side chains—» mannose 6-phosphate receptors on the inner of the Golgi apparatus membranes bind to the mannose 6-phosphate residues on the targeted lysosomal enzvraes—> small transport vesicles are pinched off the Golg: membrane that contain the reeepior- bound enzymes-> the vesicles fuse and release cazymes into lysasomies located in the cytosol—> receptors return to the Golgi apparatus to repeat the process over again + Glyeosaminoglyeans (GAGs) and their disorders: © GAGs— complexes of predominant branched. strongly negatively charged polysaccharide chains with repeating units of amino augars (D-giucosamine or D-galactosamine) and acid sugars (L-iduronic acid or D-glucuromie acid. « chondroitin sulfaie~ * most abundant GAG, + important component in cartilage. « heparan sulfate mainly responsible for the negative charge of the glomerular basement membrane, heparin— anticoagulant. © Keratan sulfate, # hyaluronic acid~ major component of synovial fluid Uoint Jubricant), ¢ dermatan sulfate + ground substance in heart valves that is increased m mitval valve prolapse. * increased in pretibial myxedema, * Hurler’s disease~ AR disease with a delicienes of t= Liduronidase. = lysosomal accumulation of dermanan‘heparan sulfate. « severe meatal retardation, + cosrse faciai features, + comeal clouding, + coronary artery disease: lipid accurnulates in coronary vessels. *vacuoles in peripheral blood leukoeytes, © Hunter's disease SXR disease *th a deficiency of |-iduronosulfete sulfatase, + lysosomal accemulation of dermatan’ heparan sulfate, * milder disease than Hurler's ~ — Sphingolipids and their disorders: » sphingolipids include~ * sphingomvelin. + cerebrosides, « gangliosides, ¢ sphingomyelin~ * involved in the synthesis of cell membranes in nerve tissue, sphingosing is the backbone of sphingomyelin. + sphingosine is used to produce ceramides. sphingosine ~ fatty acids — ceramide . © ceramide ~ phosphoryicholine-+ sphingomel ceramide ~ glucose or galactose—> gluco- or galactocerebrosides. # ceramide ~ oligosaccharides —» sanghosides, « Tay-Sachs disease- + AR with a deficiency of hexosarinidase (cr-subunit). a 4 ucleotide insertion leads to a frameshift mutation and an abnormal hexosaminidase. + lysosomal accumulation of GM. ganglioside, + common in Ashkenazi Jews, * normal at birth» severe mental retardation by 6 months. + blindness with a cherry red spot in the macula: common picture on USMLE, * no hepatosplenomegaly. + clectron microscopy exhibits whorled configurations 1» Jvsosomes that look exactly the same as lamellar bodies with surfactant in zype II pneumocytes. « Memann-Pick- AR disease with a deficiency of sphingomvelinase, ~ lysosomal accurmulanan of sphingomyelin: bubbly appearance in macrophages’ neurons. + mental retardation © heps:osplenomegaly, * EM exhibits zebra bodies in lysosomes: look hke zebra snipes. « Gaucher disease- + AR disease with deficiency of ghucocerebrosidase. + lysosomal accumulanon of shucgserebroside, fibrillary appearance (crumbled up newspaper} im macrophages. + adul: type associated wish massive hepatosplenomegaly and an increase in serum total acid phosphatase 39pum Now: “This material is copyrighted. All rights reserved. Edward Goljan. M.D. 2002 derived froma macrophages, + metachromatic leukodvstrophy- AR disease with # deficiency of Srslsulfatase A and a lysosomal accumulation of sulfatide: results im the synthesis of sbnormat crvelmn, + solfandes stein positive with metachromatic stains, * peripheral neuropathy. * urine Grrlsullitase activity decreased ‘ebsent, ¢ Krabbe diseases AR disease with & deficiency of Tgetosvleecamidase and « lysosomal accumulation of galsetgcergbroside: results inthe eyathesis cf an abnormal myelin, * progressive psychomotor retardation. * multinucleated globotd cells histiocytes) ia CNS. « Fabry disease + SXR disease with a deficiency of axgalactocerebrosidass ‘3 and am lysosomal accumulation of geramide trihexoside, > wagiokeratomas on skin. * bbypertension, * renal failure Glycogen synthesis (glycogenesis):« glycogen synthesis (glyengeness. occurs m the fed stale) 0 sequence * glucose ~ glucokinase —r G6-PO, * G6-FO.~ phosphoglucomuase ~ G1-POs.* GiPO. ~ UDP. glucose pprophosphorvlase—> UDP-glucose + UTP ~ PBs, * UDP-slucose = lelycogen synthetase (insulin enhanced, rate Hnnittne_enzyipel alveogen: branched chars polysaccharide of D-glucose residues with a-14 linkages. « alycogen syathetase produces o-1.3 Tinkages between the elucose zesidues by adding linkages to an already existing glycogen primer. © clucosy! 4:6 qyansferase makes branches by tensferring 5-8 glucosyl residues from the non: Feducing end of the fear giyeogen chain to another residue on the chain and attaching it (0 the cham by a a-1.6 linkas jen synthetase then adds glucose residues to the new non-reducins ‘ends on the branches and to the old non-reducing ends, « liver glycogen maintains blooe glucose during the facting state until its stores are cepleted~ gluconeogencsis is the most important factor ‘maintaining glucose in the fasting state, « muscle glycogen 1s used only by muscle Glycogenolysis: « glycogenolvsis occurs in the fasting state * glucagorvepinephrine activate auenviate cyclase > increases cyclic AMP (CAMP), * cAMP activates protem funase © phosphorylation inactivates glycogen synthase, + _ctivated protein’ kimase | sctvates phosphorylase Kinase, + activated phosphorylase kinase activates glycogen phosphorstase ‘A. « activated glycogen phosphorylase A (rate limiting enzyme, muscle and liver phosphorylases) Cleaves al-t bonds up to 4 glucose residues of a branch point. » glucosyl ¢4:4} transferase (debrancher enzvme) temoves 3 of the outer glucose residues that are left on the branch end Canefors them to the non-reducing end of another chain where giyeogen phosphorylase A cleaves Sif more glucose }-phosphates, * amylo- a-1.6 glucosidase (debrancier enzyme) cleaves off the femaining 1 glucose on the chain leaving behind a free glucose: ratio of glucose 1-PO: (0 fee glucose is ~1011, + glucose L-phosphate = phosphoglucomuzase—> glucose 6-phosphate, » Bose Gephosphate + glucose 6 phosphatase (gluconeogenic enzime deficient in von Gierke's)~ elosose « email amounts of glycogen are degraded in lysosomes by 0-1 4 glucosidase (acid msltase, which is deficient in Pompe's disease) Von Gierke's glycogenosis: © AR disease with a deficiency of piucose 6 phosphatase. 3 lucancogenic enzyme that is primarily located in the liver and kidneys, » glucose 1s decreased in jhe fasting state (fasting hypoglycemia) and glucose 6-phosphate accurmulates leading 10 ar tnereased synthesis of normal glycogen primarily tn the liver and kidneys (hepatorenomegals) « iyeogen excess in ren] tubules interferes with lactic acid and urie acid excretion—+ increased von sap metabolic acidosis and increased incidence of gout. stimlatonfests_for gluconeogenesis using slucagon, fructose, galactose cannot merease blond glucose owins 10 he sing glucose 6 phosphatase Pompe’s glycogenosis: « AR disease with a deficiency of the Iysosomal enzyme 1.4 slucosisase acid maltase}_ only glycogenosis that is a lysosomal storage disease. ¢ accumulation of normal clyenger. in lysosomes in multiple organs. « restrictive cardiomyopathy from glycogen deposition tp the heart is the MC CODNote: This material is copyrighted. All rights reserved. Edward Goljan, M.D. 2002 # — Meardles disease (glycogenosis): # AR disease with deficiency of muscle phosphorvlase, musc‘e giycogen cannot be degraded leading to reduced amounts of glucose for muscle ener; iy fatigue with cxercise (no ATP) leading to muscle cramps rhabdomyolysis — myotlobinurta, » absence of Jactic acid in blood after exercise. « norma) bload glucose: muscle oes not contribute 10 biood glucose, * enzyme assay of muscle confirms diagnosis~ compatible wich Tite » Debrancher aud brancher deficiencies: ¢ debranchersbrancher deficiencies are all associated with an accumulation of abnormal glycogen. * glucosyl 4:6 transferase (brancher} deficiency~ no branches on glycogen. # glacosy] (4:4) transferase debrancher deficiency~ * inerease in a—limit dextrins (small branched oligosaccharides) and decrease in tee glucose, + epinephrine challenge leads to an increase in a-limit dextrins and a decrease in free glucose. * amylo- a=. lucosidase debrancher deticrency~ decreased amounts of free glucose, since the remaining glucose cannot be cleaved off % — Glyeogenoses with fasting hypoglycemia: + yon Gierke’s. + deficiency of liver debrancher enzymes, « deficiency of liver phosphorylase % Sequence of collagen synthesis: « initial synthesis in fibroblasts~ + formation of polypeptide pro- aland pro-a? chains, * hvdroxvistion of proline and lysine by vitamin C: site for cross-linking ouiside the fibroblast. + glyeosvlation of lysine residues with glucose and galactose. * assembly of pro-c: chains- inter and intra chain disulfide bonds at C terminal extensions. * formetion of trple helix. + procollagen molecules vanslocated to Golgi apparatus for packaging and secretion. « extracellular synthesis of collagen- + procollagen molecule secreted into extracellular space, * procollagen peptidases cleave Nuerminal and C-terminal propeptides to release miple belix. + collagen molecules form fibrils, cross-linking of collagen fibrils to increase tenstle strength: Iysv! oxidase (copper is @ cofactor) is 2 cross-linking enzyme = TV infusion of thiamine (B1) in an alcoholic: « thiamine is a cofactor for pyruvate dehydrogenase. ackeroglutaraie dehydrogenase. and a-kefoacid dehydrogenase, * all these reactions produce NADH, which. in tore, generated 6 ATPS Types of mutations: point mutation of a single nucleotide base within a protein-coding gene may have 3 potential outcomes- ‘A. silent mutation: altered codon specifies the same amino acid without altering the phenotypic effec e.g.. UG (lysine) + CUG (lysine) B. missense mutation: altered codon specifies 2 different amino acid leading to variable phenorypie effects e.g, LUG (lysine) + UCG (serine) sickle cell disease/trait: point mutation occurs where adenine replaces thymidine causing valine to replace glutamic acid in the 6th position of the B-globin chain normal BehainDNA CIC sickle DNAB-chain CAC I Areplaces T]| | GAG GUG Glu Val ©. nonsense mutation: altered codon is @ stop codon (UAA. UAG. LGA) caus: premature termination during protein synthesis ¢.2.. UUG dlysme) ~r UAG (sto sodon) © Bethalassemia major: a point mutation produces 2 stop codon leadiag to termination of DNA transcription of B-globin chain 2. frameshift mutation~ A. caused by insertion or deletion of any number of nucleotides not divisible by 3 SeTese 61‘Note: This material is copyrighted. All rights reserved. Edward Goljan. M.D. 2002 Bi. shifts the reading frame during translation of mRNA Icading to a randomiy incorrect amino acid sequence and production of a truncated protein due 10 antroduiction of a premature stop codon mRNA: § GCC AAA AGU UAL UUG GCC3 ‘Ala Lys Ser Tyr Leu Aja delete A | 5) GCC AAA GUU AUU UGG 3' frameshift mutation Vai le Tp ‘Tay Sachs: (1) 4 base insertion produces a frameshift mutation (2) codes for defective hexosaminidase D._cystic fibrosis: (1) 3 base deletion with loss of phenylalanine on chromosome 7 this is net @ frameshift mutation since it is a multiple of 3 We lle Phe Gly Val normal DNA ATC ATC TTT GGT GTT CFDNA ATC AT- —T GGT GIT AIT. Ue Tie Gly Val (2) sranserbes a defective CF transmembrane regulator that disintegrates before it goes to the cell membrane + Glycine; » smallest amino acid, inhibitory neurotransmiter in spinal cord (blocked by town in setanus), synthesis of heme and collagen and bile salts and acids © Maniger alanine cycle during fasting, major substrate for gluconeogenesis (transaminated 710 pyruvate) Valine: « eosontial AA. « branched-chain amino acid, » not degraded in iver. ¢ uilized by muses «« increased in maple syrup urine disease = Lemeine: # essential AA. * branched-chain amino acid. « ulilized by muscic, « increased in maple syrup urine disease > — Isoleucine: # essential AA. # branched-chain amino acid, ‘muscle, « increased in maple syrup urine disease vs Methionine. = essential AA. © polypeptide chain instistion, ¢ methyl donor (as S-adenosy! methionine) + Profine. © helix breaker, * only amino acid with side chain attached to amino group. fiydroxylation ip collagen aided by ascorbie aid, « binding ste for cross-bridzes i collagen Phenylalanine: + essenta) AA. « increased in phenylketonuria (PKU). aromatic side chains: moreased in hepatic coma 2 Traprophan: « essential AA, ¢ serotoain,niscin, and melatonin precursor, ¢ aromatic sie chatns increased in hepatis cera = Cysteine: « forms disulfide bonds, + component of glutathione, an important entioxidant in RECS (deficient in G6PD deficiency) = Serine, « sngle-carbon donor: converted into glycine when carbon removed, + phosphorylated Py Tenases ‘Threonine: # essentia) AA. # phosphorylated by kinases © Tyrosine: » precursor of catecholamines, melanin, thyroid hormones. * phosphorsiates by {enases: important m second messengers, # aromatic side chains: merease in hepatic coma, ¢ mis be supplied in diet in phenylketonuria (PKU) ‘ot degraded in iver, © ketogenic. * pot degraded in liver, » utilized byNote: This material is copyrighted. All rights reserved. Edward Goljan, M.D, 2002 Asparagine: » insufficiently synthesized by neoplastic cells. » asparaginase used for treatment of teukemia Glutamine: » most abundant amino acid, ¢ major carrier of ammonia. * nitrogen donor in synthesis of purines and pyrimidines, # NH detoxification in brain and liver, ¢ amino group carrier wm skeletal muscle to other tissues in fasting state, « fuel for kidney. gut, and cells in wnmune system :n fasting state Lysine: « essential AA. # basic AA. © positive charge at pH 7, » ketogenic, « abundant in histones, + hydroxylation sn collagen aided by ascorbic acid, » binding site for cross-bridges in collagen Arginine: » essential AA. « basic AA, « positive charge at pH 7. ¢ essential for growth in children somulates growth hormone and insulin, » abundant in histones % Histidine: « essential AA. * basic AA, # positive charge at pH 7, « effective physiologic buffer. « residuc in hemoglobin coordinated to heme Fe", essential for growth in children. * zero charge at pH 740 © Aspartate: « acidic AA, ¢ strong negative charge at pH 7: important for binding properties of albumin, « forms oxaloacetate (substrate for gluconeogenesis} by transemination, Glutamate: « acidic AA. ¢ strong negative charge at pH 7: important for binding properties of albumin, # forms a-ketogtutarate by transamination © Know how to caleulate number of amino acids in a gene given the number of nucleotides in exons. introns. and S* UTR © — Genetic basis of mild B-thalassemia: primarily a splicing defect, severe thalassemia is a stop codon {nonsense mutation} © Effect of decreased LDL receptors on HMG CoA reductase: + normally, increased uptake of cholesterol in a cell decreases synthesis of LDL receptors and reduces gene transcription of HMG CoA reduccase resulting in less de novo cholesterol symthesis im the ceil, « decrease im LDL receptors decreases the uptake of cholesterol in the cell, therefore, less cholesterol causes increased transcription of HMG CoA reductase. hence an increase in cholesterol synthesis in the cell HIGH YIELD NOTES MICROBIOLOGY © Diphtberia toxin: « diphtheria toxin inhibits protein synthesis by ADP ribosylation of elongation factor 2. # anttoxin and erythromycin are the Rx of choice, # prevent with diphtheria toxoxd ‘immunization 2 Pseudomonas aeruginosa toxin: exotoxin A iabibits protein synthesis using the same mechanism 5 diphtheria toxin (See above) 2 Neisseria gonorrhoeae: © gram negative diplococcus, # endotoxin is lipooligasaccheride (not lipopolysaccharide like N. meningitidis), # oxidase positive contain cytochrome ¢. # chocolate agar~ modified Thayer-Marten . « pili + attach to smucosal surfaces, + resists phagocytosis by neutrophils. * antigente change responsible for repeated infections, # IgA protease— hydrolyzes seeretory IgA to make it easier 10 stick to vagina and urethra. # capsule protects against phagocytosis. ¢ sugar fermentation~ glucose (N. meningitidis is maltose and glucose), « plastmd ‘mediated penicillinase producing strains, « discharge in first week after sexual contact, ¢ RX— ceftriaxone or spectinomyein if allergic #0 penicillin © Francisella watarensis: « gram negative tod, # can survive in macrophages for prolonged periods. © antiphagocytc capsule, « vector~ tieks using @ wild rabbit reservoir. « MC transmisston— clean animal Tides (e.g, rabbits), # requires cysteine for growth, # Rx- streptomycin Campylobacter jejuni: + comma:S-shaped gram negative sods, « ingestion of contaminated poultry (ow! are reservoir), milk, or water. ¢ decreased gastric acidity increases chance of infection. © grows at 42°C. « MCC bacterial gastroenteritis in United States, some strains have enterotoxin