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Premium member Presentation Transcript Nucleic Acid Metabolism: Nucleic Acid Metabolism Nucleotides Essential for all cells Carriers of activated intermediates in carbohydrate, lipids and proteins CoA FAD NAD NADP Energy Carriers ATP Inhibiting or activating enzymes DNA RNANucleotide Structure: Nucleotide Structure Ribose Sugar Ribose Deoxyribose Base Purines Pyrimidines Nucleoside Base plus sugar Nucleotide E.g., AMP, ADP, ATPNomenclature: Nomenclature DNA Purine Bases Adenine Guanine Purine Nucleosides Adenosine Guanosine DNA Nucleotides (Purine) dAMP (deoxyadenylate) dGMP (deoxyguanylate) RNA Nucleotides (Purine) Adenylate (AMP) Guanylate (GMP)Nomenclature Continued: Nomenclature Continued DNA Pyrimidine Bases Thymine Cytosine (Also RNA) DNA Pyrimidine Nucelosides Thymidine Cytidine DNA Pyrimidine Nucleotides (dTMP) deoxythymidylate (dCMP) deoxycytidylate RNA Pyrimidine Nucleotides (CMP) cytidylate (UMP) uridylatePRPP 5-Phosphoribosyl 1-Pyrophosphate: PRPP 5-Phosphoribosyl 1-Pyrophosphate Addition of the ribose sugar component HMP ATP Required Mg ++ Pi activates and nucleosides inhibitPyrimidine Synthesis: Pyrimidine Synthesis UMP (Uridine 5-monophosphate) to UTP Precursor to CTP Occurs on mitochondria inner membrane Carbamoyl phosphate synthetase II Different from CPS I CPS I uses free ammonia CPS II uses glutamine for amino sourceCarbamoyl Phosphate Synthetase II: Carbamoyl Phosphate Synthetase IIFormation of Uridine 5’-phosphate: Formation of Uridine 5’-phosphateEnzymes of Pyrimidine Biosynthesis: Enzymes of Pyrimidine BiosynthesisUTP to CTP Conversion: UTP to CTP Conversion CTP Synthetase ReactionConversion of Ribonucleotides to Deoxyribonucleotides: Conversion of Ribonucleotides to Deoxyribonucleotides Ribonucleotide reductase NADP Thioredoxin reductase Example is production of dCDPAllosteric Inhibition of Ribonucleotide Reductase: Allosteric Inhibition of Ribonucleotide Reductase ATP activates dATP inhibitsThymidylate Biosynthesis: Thymidylate Biosynthesis Substrates and Vitamins dUMP Folate (N5, N10,-Methylene-THF) Glycine/Serine NADPConversion of dUMP to dTMP:Overall: Conversion of dUMP to dTMP:Overall 5-fluorouracil MethotrexateThymidylate Pathway:Specific: Thymidylate Pathway:SpecificThymidylate Synthesis and Cancer Chemotherapy: Thymidylate Synthesis and Cancer Chemotherapy Thymidylate synthase is target for fluorouracil Action is 5-fluorouracil (5-FU)is converted to 5-fluoro-2’-deoxyuridylate (dUMP structural analog) Then 5-fluoro-2’-deoxyuridylate binds to the enzyme Thymidylate Synthase and undergoes a partial reaction where part of the way through 5-fluoro-2’-deoxyuridylate forms a covalent bridge between Thymidylate Synthase and N 5 , N 10 -Methylene THF and is an irreversible inhibition. Normally, the enzyme, Thymidylate Synthase and the vitamin would NOT be linked together permanently This type of inhibition is called “ suicide-based enzyme inhibition ” because the inhibitor participates in the reaction causing the enzyme to react with the compound producing a compound that inactivates the enzyme itself .Fluorouracil Pathway: Fluorouracil Pathway Suicide inhibition because Flurouracil does not directly inhibit enzyme.Methotrexate: Methotrexate Competitive inhibitor of Dihydrofolate Reductase Used in, Acute lymphoblastic leukemia Osteosarcoma in children Solid tumor treatment Breast, head, neck, ovary, and bladder Prevents regeneration of tetrahydrofolate and removes activity of the active forms of folateLeucovorin Rescue Strategy in Methotrexate Chemotherapy: Leucovorin Rescue Strategy in Methotrexate Chemotherapy Patients given sufficient methotrexate that if were not followed by Leucovorin (N 5 -methenyl-THF) would be fatal. All neoplastic cells are killed Patients are “rescued” (6-36 hours) by the Leucovorin (Folate) otherwise would die due to permanent tetrahydrofolate shutdown. Tumor resistance to methotrexate can occur in patients who have “gene amplification” of dihydrofolate reductase (in tumor cells) More dihydrofolate reductase is produced by more than the normal active genes usually present in normal cells.Purine Biosynthesis: Purine Biosynthesis IMP (Inosine Monophosphate) Precursor to GMP and AMP Utilizes (Substrates) Glycine Glutamine ATP Folate (N 10 -formyl-THF) Aspartate CO 2 PRPP amidotransferase is rate limiting Inhibited by AMP and GMPIMP Pathway: IMP PathwayIMP to AMP and GMP: IMP to AMP and GMP Glutamine, NAD, ATP used in GMP production Aspartate, GTP used AMP productionAMP and GMP Pathway: AMP and GMP PathwayNucleotide Pyrimidine Catabolism: Nucleotide Pyrimidine Catabolism Degradation of pyrimidine metabolites UMP, CMP, TMP End products are acetyl-CoA and Propionyl-CoA Ribose sugar component may be converted to ribose-5-phosphate which is a substrate for PRPP Synthetase Ribose sugar component may be further catabolized in HMP pathwayPyrimidine Catabolic Pathway: Pyrimidine Catabolic PathwayPurine Catabolism: Purine CatabolismRegulation of Nucleotide Metabolism: Regulation of Nucleotide Metabolism Pyrimidine Regulation Primary regulatory step is Carbamoyl Phosphate via Carbamoyl Phosphate Synthetase II Purine RegulationAction of Allopurinol: Action of Allopurinol Allopurinol is purine base analog Three mechanisms Allopurinol is oxidized to alloxanthine by xanthine dehydrogenase Then Allopurinol and alloxanthine are inhibitors of xanthine dehydrogenase This inhibition decreases urate formation Then concentrations of Allopurinol and alloxanthine increase but do not precipitate as urate does. Allopurinol and alloxanthine are excreted into the urineAction of Allopurinol:Pathway: Action of Allopurinol:PathwayBiosythesis of Nucleotide Coenzymes: Biosythesis of Nucleotide Coenzymes CoA OTC is pantothenate Uses ATP, CTP, CysteineCoenzyme A Pathway: Coenzyme A PathwayFMN and FAD: FMN and FAD OTC is riboflavin Consumes ATP You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.