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Nucleotide Metabolism

Nucleotide Metabolism. C483 Spring 2013. 1. A ribose sugar is added to ________ rings after their synthesis and to ________ rings during their synthesis. A) purine; pyrimidine B) pyrimidine; purine C) purine; purine D) pyrimidine; pyrimidine

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Nucleotide Metabolism

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  1. Nucleotide Metabolism C483 Spring 2013

  2. 1. A ribose sugar is added to ________ rings after their synthesis and to ________ rings during their synthesis. A) purine; pyrimidine B) pyrimidine; purine C) purine; purine D) pyrimidine; pyrimidine 2. The first nucleotide product in the de novo biosynthetic pathway of purines is A) AMP. B) GMP. C) IMP. D) XMP. 3. Which of the following statements is false concerning purine synthesis? N7 is from glycine C2 is from carbon dioxide (bicarbonate) N3 is from glutamine C8 is from 10-formylTHF.

  3. 4. Which is a precursor in the de novosynthesize CTP? A) CMP. B) GMP. C) TMP. D) UMP. Which of the following is not a role of a catalytic sulfur atom in ribonucleotidereductase? Proton donor Radical stabilization Redox reaction Covalent catalysis 6. Dihydrofolatereductase and thymidylatesynthetase are major targets for anticancer drugs because A) these enzymes are unique in cancer cells. B) cancer cells lack sufficient amounts of these enzymes. C) cancer cells grow rapidly and are very dependent upon the activities of these enzymes. D) they donate one-carbon groups. E) All of the above.

  4. Terminology of Nucleic Acids • Nucleotide • Nucleoside • Nucleobase • AMP • ADP • ATP • dAMP

  5. Some Examples of Nucleotides UDP-Glucose ATP NAD+ FAD GTP CoA S-AM

  6. DeNovo Synthesis

  7. DeNovo Synthesis of Purines • Form activated ribose • Form 5-phospho ribosylamine • Build IMP from precursors • Synthesis of AMP and GMP

  8. PRPP • Pentose phosphate pathway • 2 ATP equivalents • Over production of PRPP is one cause of gout because PRPP stimulates the next step…

  9. 5-phosphoribosylamine • First step of purine biosynthesis • Glutamine is N donor • Regulated • Activation by PPRP • Increased purine levels • Degradation of purines leads to compound which can cause gout

  10. Purine Pathway • Don’t need to know details, order • Know precursors • N from Asp, Gln • C from THF, Gly, CO2 • Cost • 2 ATP eq for PRPP • 5 more ATP steps Know this figure!

  11. Purines • Two distinct strategies for amination • Mechanisms • Regulation • Feedback to 5-phospho ribosylamine • Branchpoint regulation

  12. Compare/Contrast • Purine biosynthesis • Salvage is a major pathway • Base synthesized while attached to ribose • IMP is common intermediate for AMP and GMP, but itself is not a typical nucleotide • Pyrimidine biosynthesis • De novo is a major pathway • Base is synthesized, then attached to ribose • UMP, a typical nucleic acid, is converted into other pyrimidines

  13. De novo Pyrimidine Synthesis • First step regulated (compare to urea cycle) • Asp is different than purine—whole molecule is incorporated

  14. Further Modifications • Interconversion of nucleotides (mono, di, tri phosphates) • Reduction to form deoxynucleotides • Methylation to form dTMP

  15. Nucleotide Interconversions • Fast, reversible, driven by high [ATP] • NMPNDP catalyzed by specific nucleoside monophosphate kinase • NDPNTP catalyzed by nonspecific kinase • AMP + ATP  ADP + ADP important in energy balance

  16. Deoxyribonucleotides • Deoxygenation occurs on diphosphates • One enzyme affects all transformations [dUDP]

  17. RibonucleotideReductase • Sulfur does amazing chemistry! • Stable radical • Proton donor • Redox reagent • NADPH is ultimate source of reducing

  18. Regulation of Reductase • One enzyme balances needs of cell via regulation of activity and selectivity • Be able to explain why this table makes sense

  19. Methylation • dTMP is made from dUMP • Key step in replicating cells • Therapeutic target for anti-cancer drugs • Two key enzymes

  20. Thymidylate Synthase • Methylene-THF acts as a “methyl” donor • Donates methylene • And hydride • Fascinating chemistry! • Sulfur is covalent catalyst • Internal 1,3-hydride shift • THF is left as DHF

  21. 5-Fluorouracil • Incorporated into monophosphate nucleotide in body • Mechanism based inhibitor (Trojan Horse) • Forms covalent link to enzyme like normal • No elimination possible because proton replaced with fluorine

  22. DHF reductase • DHF must be reduced back to THF to be a viable cofactor • Second chemotherapy target • Competitive inhibitor that is structurally similar to THF would end methylation process

  23. Review of Purines • Knowing blue in figure will help with chapter summary

  24. Review of Pyrimidines • Knowing blue in figure will help with chapter summary

  25. Catabolism • Less important than other catabolic processes • not a major energy source • Lots of salvage • Serves to clear excess • In humans, purines  uric acid (excreted) • In humans, pyrimidines  acetyl CoA, succinyl CoA for some energy gain

  26. Severe Combined Immunodeficiency Syndrome (SCIDS) • Deficiency of adenosine deaminase • First step in catabolism • High levels of dATP lead to low levels of dNTP • No DNA kills fast growing T-cells *

  27. Answers • B • C • B • D • D • C

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