Nucleic acid metabolism lecture nam04

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Transcript of Nucleic acid metabolism lecture nam04

  1. 1. Dr. Aga Syed Sameer Lecturer (Demonstrator) Department of Biochemistry, Medical College, Sher-I-Kashmir Institute of Medical Sciences, Bemina, Srinagar, Kashmir, 190010. India. Nucleic Acid Metabolism Pyrimidine Metabolism
  2. 2. Pyrimidine Biosynthesis UMP (Uridine Monophosphate) Precursor to TMP and CTP Utilizes (Substrates) One Aspartate -NH3 of Glutamine CO2 is recycled (Used in 1st step and released back in last) Water molecule NAD+ ATPs (Two : Till UMP Synthesis) Methyl group of THF + GTP {dTMP Synthesis} NH3 of Glutamine + ATP (2 Equivalent) {CTP Synthesis}
  3. 3. 2 ATP + HCO3 - + Glutamine + H2O CO O PO3 -2 NH2 Carbamoyl Phosphate NH2 C N H CH CH2 C COO O HO O Carbamoyl Aspartate HN C N H CH CH2 C COO O O Dihydroorotate HN C N H C CH C COO O O Orotate HN C N C CH C COO O O HH CH2 OH OH H H O O2- O3P Orotidine-5'-monophosphate (OMP) HN C N CH CH C O O HH CH2 OH OH H H O O2- O3P Uridine Monophosphate (UMP) 2 ADP + Glutamate + Pi Carbamoyl Phosphate Synthetase II Aspartate Transcarbamoylase (ATCase) Aspartate Pi H2O Dihydroorotase Quinone Reduced Quinone Dihydroorotate Dehydrogenase PRPP PPi Orotate Phosphoribosyl Transferase CO2 OMP Decarboxylase Pyrimidine Biosynthesis
  4. 4. Enzymes and Reactions 2 condensation Rxns: form carbamoyl aspartate and dihydroorotate (intramolecular) Dihydroorotate dehydrogenase (FMN) is an intra- mitochondrial enzyme; oxidizing power comes from ubiquinone reduction Attachment of base to ribose ring is catalyzed by OPRT; PRPP provides ribose-5-P. OMP Decarboxylase enhances the rate of decarboxylation by a factor of 2x1023 Channeling: Enzymes 1, 2, and 3 are on same chain; Enzymes 5 and 6 are on same chain
  5. 5. CTP and UTP synthesis UMP is then converted UDP & UTP The conversion takes place by the action of Nucleoside Mono/Di Phosphate Kinases. CTP formed from UTP via CTP Synthetase driven by ATP hydrolysis Glutamine provides amide nitrogen
  6. 6. Conversion of Ribonucleotides to Deoxyribonucleotides Ribonucleotide reductase NADP Thioredoxin reductase
  7. 7. Regulation of RNRs ATP activates dATP Inhibits
  8. 8. dTMP synthesis dUMP formed; produces dTMP via Thymidylate Synthetase N5,N10 Methylene THF provides methyl group THF is first reduced and then methylated
  9. 9. dTMP synthesis
  10. 10. Regulation Differs between bacteria and animals Bacteria regulation at ATCase rxn Animals regulation at carbamoyl phosphate synthetase II UDP and UTP inhibit enzyme; ATP and PRPP activate it Also UMP and CMP competitively inhibit OMP Decarboxylase
  11. 11. Degradation of Pyrimidines CMP and UMP degraded to bases similarly to purines Dephosphorylation Deamination Glycosidic bond cleavage Uracil reduced in liver, forming -Alanine Is then converted to malonyl-CoA used in fatty acid synthesis for energy metabolism dTMP is degraded to -Amino Isobutyrate Is then converted to methyl malonyl-CoA used in fatty acid synthesis for energy metabolism
  12. 12. Cancer is a clonal disorder. It is composed of malignant cells of several distinguishable characteristics such as: immortality, faster growth, unable to establish cell-cell interaction, propensity to invade, metastasize and grow in an abnormal cellular environment. Hanahan D and Weinberg RA. The hallmarks of cancer. Cell. 2000; 100:57-70. Cancer
  13. 13. Molecules Implicated in Colorectal Cancer Pathogenesis In Kashmiri Population Aga Syed Same
  14. 14. Anti-Folate Drugs Cancer cells consume dTMP quickly for DNA replication Interfere with Thymidylate Synthase rxn to decrease dTMP production (fluorodeoxyuridylate irreversible inhibitor) also affects rapidly growing normal cells (hair follicles, bone marrow, immune system, intestinal mucosa) Dihydrofolate reductase step can be stopped competitively (DHF analogs) Anti-Folates: Aminopterin, methotrexate, trimethoprim
  15. 15. 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 N5, N10-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
  16. 16. Thymidylate Synthesis and Cancer Chemotherapy
  17. 17. 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 folate