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| common sugar/phosphate compound to which all the major bases are attached. formed from ribose 5p by PRPP synthetase, which is activated by Pi and inhibited by purine nucleotides. purines form directly on it; pyrimidines form elsewhere and then attach to it. |
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| all newly synthesized nucleotides are |
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| ribonucleoside monophosphates, NMP |
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| specific kinases that typically use ATP as a phosphate donor (same for deoxy) = adenylate kinase, guanylate kinase, etc. |
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| less specific enzyme than NMP->NDP (same for deoxy) = nucleoside diphosphate kinase |
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| converts NDP to dNDP. donates necessary H, which it gets from thioredoxin, which gets H from NADPH. |
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| ribonucleotide reductase regulation |
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| allosterically by ATP (increased), dATP (decreased), dTTP, and dGTP (these two are specific) |
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| purine synthesis (precursors and step 1) |
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| CO2, several AAs (glycine, glutamine, aspartate), and N10-formylTHF donate carbons. first step = transamination: glutamine donates an amine group to PRPP, synthesizing 5'phosphoribosylamine (committed step). >>> hypoxanthine>IMP>AMP or GMP. |
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| regulation of synthesis of 5'phosphoribosylamine |
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| regulated by availability of PRPP. inhibitory feedback from GMP, AMP and IMP. energy from ATP is needed, carbons from N10formylTHF are needed. |
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| regulation of IMP>GMP or AMP |
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| both require 2 steps. both 1st steps end-product inhibited. ATP is converted to AMP to make GMP and vice versa. |
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| salvages IMP and GMP purine bases, attaching them to PRPP and converting them to NTP. |
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| salvages AMP purine base, attaching it to PRPP and converting it to ATP. |
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| x-linked, nearly complete deficiency of HGPRT. PRPP, hypoxanthine and guanine increase, IMP and GMP decrease. this stimulates purine synthesis = more hypoxanthine and guanine = uric acid = kidney stones, gouty arthritis and soft tissue deposition. motor dysfunction, cognitive defects, self-mutilation. |
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| dietary purines are typically degraded in intestine, not used to make nucleic acids. AMP>IMP. IMP and GMP lose phosphate groups, ribose is removed yielding hypoxanthine and guanine, both converted to xanthine and then uric acid. |
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| hyperuricemia = acute and chronic arthritis (MTP joint of big toe, soft tissues = tophi). aspiration of synovial fluid is needed for diagnosis, shows crystals under polarized light microscopy. |
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| most often caused by underexcretion (bad kidney function = secondary OR specific idiopathic problem = primary). may also be caused by overproduction of uric acid. most often idiopathic, but gene defect = lysch-nyhan. patients with high rates of cell turnover or metabolic disease may also become hyperuricemic. |
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| acute - antiinflammatory = ASA, colchicine (depolymerizes microtubules and thus decreases neutrophil movement). allopurinol and xanthine oxidase inhibit uric acid synthesis. probenecid and sulfinpyrazone increase renal excretion of uric acid. |
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| adenosine deaminase (converts to inosine to initiate degradation pathway) defect leads to build-up of adenosine. increased dATP inhibits ribonucleotide reductase. B and T and NK cells compromised = SCID (severe combined immunodeficiency disease). death by age 2 without treatment. |
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| 1. regulating step: cytosolic carbamoyl phosphate synthetase II. inhibited by UTP, activated by PRPP and ATP. next convert carbamoyl phosphate to orotate which is attached to PRPP to make OMP > UMP. UTP>CTP, dUMP>dTMP (with help of N5N10formylTHF). |
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| mostly degraded into highly soluble products |
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| dihydrofolate (DHF) > tetrahydrofolate (THF) via dihydrofolate reductase (DHFR). |
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| capable of reversibly accepting a carbon: purine synthesis, dTMP synthesis, methionine regeneration |
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| DHFR inhibitor = cancer treatment |
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| antimicrobial: competitively inhibits bacterial DHPS, which is necessary for bacterial THF synthesis |
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| inhibits bacterial DHFR = anti-microbial |
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| forms sugar backbone of nucleotide |
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| CPS I vs. II: cellular location, pathway, nitrogen source |
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| I: mitochondria, urea cycle, ammonia. II: cytosol, pyrimidine synthesis, glutamine |
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| when b12 deficient, n5methylTHF can't make THF and homocysteine can't make Met. system wants to make THF so everything backs up at n5methylTHF. is a type of megaloblastic anemia. mechanism? rbcs can't replicate, no dTMP? |
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| inadequate folate can be caused by |
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| dietary insufficiency, increased demand by lactation and pregnancy, poor absorption in the intestine, drugs like methotrexate |
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| low THF in first few weeks of fetal life; comes with anencephaly. is defective neural tube closing. |
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| low THF halts DNA synthesis in bone marrow - b12 required, causes pernicious anemia when defective which is similar to megaloblastic anemia, but won't respond to folate supplementation! |
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| thymidine analog, permanently binds and inhibits thymidylate synthase, blocking dUMP>dTMP |
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| all nucleotides! remember the formula for this |
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| what is the common NMP precursor to the pyrimidines |
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| major clinical consequences of insufficient folate |
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| megaloblastic anemia in adults, anencephaly and spina bifida in developing fetus |
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