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Nucleotide Metabolism II

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Nucleotide Metabolism II Nucleotide Metabolism II • Biosynthesis of deoxynucleotides • Salvage Pathway • Catabolism: Purines • Catabolism: Pyrimidines • Feedback inhibition in purine nucleotide biosynthesis CPS II • Cytosolic CPS II uses glutamine as the nitrogen donor to carbamoyl phosphate Regulation of pyrimidine synthesis •CPSII is allosterically regulated: PRPP and IMP are activators Several pyrimidines are inhibitors • Aspartate transcarbamoylase (ATCase) Important regulatory point in prokaryotes Catalyzes the first committed pathway step Allosteric regulators: CTP (-), CTP + UTP (-), ATP (+) • Regulation of pyrimidine nucleotide synthesis in E. coli Biosynthesis of deoxynucleotides • Uses diphosphates (ribo) • Ribonucleotide reducatase • 2 sub-units • R1- reduces, active and two allosteric sites (activity and specificity site) • R2- tyrosine radical carries electrons • removes 2' OH to H Ribonucleotide reductase reaction • removes 2' OH to H • Thioredoxin and NADPH used to regenerate sulfhydryl groups Thymidylate synthesis • UDP ------> dUMP • dUMP --------> dTMP • required THF • methylates uracil Regulation THF • Mammals cannot conjugate rings or synthesize PABA. • So must get in diet. • Sulfonamides effective in bacteria due to competitive inhibition of the incorporation of PABA Cancer Drugs • fluorouracil-- suicide inhibitor of Thy synthase • aminopterin • Methotrexate -- inhibits DHF reductase Salvage of Purines and Pyrimidines • During cellular metabolism or digestion, nucleic acids are degraded to heterocyclic bases • These bases can be salvaged by direct conversion to 5’-mononucleotides • PRPP is the donor of the 5-phosphoribosyl group • Recycling of intact bases saves energy (reduced nitrogen sources are scarce) Salvage Pathway • extra-hepatic tissues • free purines • APRT • HGPRT •Uracil • Salvage via Purine Nucleoside phosphorylase Lesch-Nyhan syndrome • Lack of HGPRT • x- linked • elevates PRPP • Increase de novo purine biosynthesis • overproduction of urate Catabolism: Purines • Dietary purines: mostly degraded • Purines produce urate • excreted in urine in mammals Degradation of uric acid Gout results from excess sodium urate • Gout is caused from overproduction or inadequate excretion of uric acid • Sodium urate is relatively insoluble and can crystallize in tissues • Gout can be caused by a deficiency of hypoxanthine-guanine phosphoribosyltransferase or defective regulation of purine biosynthesis Problems • Urate soluble 7 mg/dL at 37C • cooler extremities, crstallizes • synovial fluid • Gout Allopurinol is a treatment for gout • Allopurinol is converted in cells to oxypurinol, an inhibitor of xanthine dehydrogenase • Allopurinol prevents high levels of uric acid • Hypoxanthine, xanthine are more soluble Treatment • Allopurinol • inhibit xanthine oxidase • Chelates Mo 4+ • suicide inhibitor • deplete PRPP • secrete hypoxanthine/Xanthine, more soluble Pyrimidine Metabolism • Pyrimidine nucleotides are hydrolyzed to the nucleosides and Pi • Then thymine, uracil and (deoxy) ribose 1-phosphate are produced • Catabolism of the thymine and uracil bases ends with intermediates of central metabolism Catabolism: Pyrimidines • No problems • produce B-alanine, NH3, and CO2 Nucleotide Catabolism: disorders • SCID • ADA deficiency • Both B/T lymphocytes affected • elevated dATP 50-100x • inhibit ribonucleotide reductase • inhibit synthesis of other deoxynucleotides • pyrimidine starvation • no cell division Nucleotide Catabolism: disorders • PNP deficiency • T lymphocytes • elevated dGTP • inhibit ribonucleotide reductase • inhibit synthesis of other deoxynucleotides • no cell division .
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