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Metabolism of purines and pyrimidines

Metabolism of purines and pyrimidines. Vladimíra Kvasnicová. Structure of purine and pyrimidine nucleotides. nucleo tide = ester of phosphoric acid and a nucleo side nucleo side = N-containing base + monosaccharide -N-glycosidic bond between base and saccharide

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Metabolism of purines and pyrimidines

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  1. Metabolism of purines and pyrimidines Vladimíra Kvasnicová

  2. Structure of purine and pyrimidine nucleotides • nucleotide= ester of phosphoric acid and a nucleoside • nucleoside= N-containing base + monosaccharide • -N-glycosidic bondbetween base and saccharide • nucleotide bases: aromatic heterocycles • purines: pyrimidine + imidazol ring • pyrimidines: pyrimidine ring

  3. PURINE BASES Obrázek je převzat z učebnice: Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  4. ribonucleosidedeoxyribonucleoside N-glycosidic bond Obrázek je převzat z učebnice: Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  5. ribonucleotidedeoxyribonucleotide Obrázek je převzat z učebnice: Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  6. PYRIMIDINE BASES Obrázek je převzat z učebnice: Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  7. ribonucleosidesdeoxyribonucleoside Obrázek je převzat z učebnice: Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  8. Ribonucleotides * N-glycosidic bond * ester bond * anhydride bond Obrázek je převzat z učebnice: Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  9. Classification of nucleotides • purine nucleotides:contain adenine, guanine, hypoxanhine or xanthine • pyrimidine nucleosides:contain cytosine, uracil or thymine • ribonucleotides(saccharide = ribose) • deoxyribonukleotidy(saccharide = deoxyribose) • formed by reduction of ribonucleoside diphosphates (NADPH)

  10. Purine nucleotides • include an aromatic cycle in the structure • can contain either adenine or thymine • include N-glycosidic bond • are composed of a nucleoside bound to phosphoric acid by an anhydride bond

  11. Purine nucleotides • include an aromatic cycle in the structure • can contain either adenine or thymine • include N-glycosidic bond • are composed of a nucleoside bound to phosphoric acid by an anhydride bond

  12. Pyrimidine nucleotides • include an imidazol ring in the structure • include thymidine- and cytidine monophosphate • contain an ester bond • can include 3 phosphate groups in their structure

  13. Pyrimidine nucleotides • include an imidazol ring in the structure • include thymidine- and cytidine monophosphate • contain an ester bond • can include 3 phosphate groups in their structure

  14. Occurrence of nucleotides • essential for all cells • mainly 5´-nucleosidedi and triphosphates • ribonucleotides: concentration of a sum of them is constant (mM), only their ratio varies(main ribonucleotide of cells: ATP) • deoxyribonucleotides: their concentration depends on a cell cycle (µM)

  15. Properties of nucleotides • strong absorption of UV radiation (260 nm) • purines are less stable under acidic conditions than pyrimidines • polar terminal phosphate groups • alternative names: adenylate or adenylic acid, ...

  16. Nucleotides in a metabolism 1) energetic metabolism ATP = principal form of chemical energy available to cells – „as money of the cell“ (30 kJ/mol / spliting off phosphate) • phosphotransferase reactions (kinases) • muscle contraction, active transport 2) monomeric units of RNA and DNA • substrates: nucleoside triphosphates 3) physiological mediators • cAMP, cGMP („second messengers“)

  17. 4) components of coenzymes • NAD, NADP, FAD, CoA 5) activated intermediates • UDP-Glc, GDP-Man, CMP-NANA • CDP-choline, ethanolamine, diacylglycerol • SAM  methylation • PAPS  sulfatation 6) allosteric efectors - regulation of key enzymes of metabolic pathways

  18. 3´-phosphoadenosine-5´-phosphosulfate (PAPS) used as the sulfate donor in metabolic reactions (sulfatation) Obrázek je převzat z http://web.indstate.edu/thcme/mwking/amino-acid-metabolism.html (leden 2007)

  19. Purine and pyrimidine nucleotides can be used • as nucleoside triphosphates for nucleic acid synthesis • in energetic metabolism of cells • for activation of metabolic intermediates of saccharides and lipids • in enzymatic reactions: some coenzymes are nucleotides

  20. Purine and pyrimidine nucleotides can be used • as nucleoside triphosphates for nucleic acid synthesis • in energetic metabolism of cells • for activation of metabolic intermediates of saccharides and lipids • in enzymatic reactions: some coenzymes are nucleotides

  21. PRPP = 5-phosphoribosyl-1-pyrophosphate • common substrate of both purine and pyrimidine synthesis • its synthesis is a key reaction of synthesis of the nucleotides • PRPP-synthetase is regulated by feed back inhibition by nucleoside di and triphosphates • precursors: * ribose-5-phosphate (from HMPP) * ribose-1-phosphate(phosphorolysis of nucleosides)

  22. function: • regulation of nucleotide synthesis • substrate of nucleotide synthesis PRPP = PRDP Obrázek je převzat z učebnice: Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  23. Synthesis of purine nucleotides • de novo= new building of a nucleotide rings • salvage reactions=synthesis from bases or nucleosides • less energy need than for de novo synthesis • they inhibit de novo synthesis • substrates: a) base (adenine, guanine, hypoxanthine) PRPP b) ribonucleosides ATP

  24. Synthesis of purine nucleotides de novo • high consumption of energy (ATP) • cytoplasm of many cells, mainly in the liver • substrates: * 5-phosphoribosyl-1-diphosphate (= PRDP = PRPP) * amino acids (Gln, Gly, Asp) * tetrahydrofolate derivatives, CO2 • coenzymes: * tetrahydrofolate (= THF) * NAD+

  25. important intermediates: • 5´-phosphoribosylamine • inosine monophosphate (IMP) • products: nucleoside monophosphates (AMP, GMP) • interconversion of purine nucleotides: • via IMP = common precursor of AMP and GMP (inosine monophosphate: base = hypoxanthine)

  26. Synthesis of purine nucleotides CYTOPLASM Obrázek převzat z http://web.indstate.edu/thcme/mwking/nucleotide-metabolism.html (leden 2007)

  27. IMP AMP GMP Obrázek je převzat z učebnice: Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  28. Obrázek je převzat z učebnice: Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  29. Synthesis of pyrimidine nucleotides • de novo= new building of a nucleotide rings • salvage reactions=synthesis from bases or nucleosides • substrates: a) * base (not cytosine) * PRPP b) * ribonucleosides * ATP

  30. Synthesis of pyrimidine nucleotidesde novo • cytoplasm of cells (exception: one enzyme is found at mitochondria /dihydroorotate-DH) • substrates: * carbamoyl phosphate (Gln,CO2,2ATP) * aspartate * PRPP * methylene-THF (only for thimidine) Karbamoyl phosphate is formed in urea synthesis as well(only in mitochondria of hepatocytes)

  31. important intermediates: * orotic acid * orotidine monophosphate (OMP) * uridine monophosphate (UMP) • products: * cytidine triphosphate (from UTP) * deoxythimidine monophosphate (from dUMP)

  32. Synthesis of pyrimidine nucleotides CYTOPLASM mitochondrion Obrázek převzat z http://web.indstate.edu/thcme/mwking/nucleotide-metabolism.html (leden 2007)

  33. Obrázek je převzat z učebnice: Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  34. Synthesis of 2-deoxyribonucleotides enzyme: ribonucleotide reductase+ small protein „thioredoxin“ Obrázek je převzat z učebnice: Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  35. Synthesis of thymidine monophosphate Obrázek je převzat z učebnice: Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  36. Regulation of nucleotide synthesis • PRPP-synthetase is inhibited by both purine and pyrimidine nucleoside di- and triphosphates • nucleotide synthesis: feed back inhibition • nucleoside diphosphate reductase:activated bynucleoside triphosphates, inhibited bydeoxyadenosine triphosphate (dATP)

  37. Regulation of nucleotide synthesis

  38. Degradation of purines and pyrimidines • exogenous:mostly not used for resynthesis • endogenous: • enzymes * nucleases (split off nucleic acids) * nucleotidases (...nucleotides) * nucleoside phosphorylases (nucleosides) * deaminase (adenosine) * xanthinoxidase (hypoxanthine, xanthine) inhibited by allopurinol (pharmacology)

  39. Degradation of purines „uric acid“

  40. Degradation of pyrimidines

  41. products: • purines→ NH3, uric acid – it has antioxidative properties(partially excreted with urine; failure: hyperuricemia, gout) physiological range: serum 220 – 420 µmol/l (men) 140 – 340 µmol/l (women) urine 0,48 – 5,95 mmol/l • pyrimidines: C, U →-alanine, CO2, NH3T → -aminoisobutyrate, CO2, NH3

  42. Principal differences between metabolism of purines and pyrimidines

  43. Synthesis of nucleotides • uses products of pentose cycle • includes phosphoribosyl diphosphate (PRDP = PRPP) as a substrate • needs derivatives of folic acid • proceeds in a cytoplasm only

  44. Synthesis of nucleotides • uses products of pentose cycle • includes phosphoribosyl diphosphate (PRDP = PRPP) as a substrate • needs derivatives of folic acid • proceeds in a cytoplasm only

  45. Synthesis of purine nucleotides • uses ammonia as a nitrogen donor • proceeds in a cytoplasm • can start from nucleosides produced by degradation of nucleic acids • includes uric acid as an intermediate

  46. Synthesis of purine nucleotides • uses ammonia as a nitrogen donor • proceeds in a cytoplasm • can start from nucleosides produced by degradation of nucleic acids • includes uric acid as an intermediate

  47. Synthesis of pyrimidine nucleotides • starts by the reaction: PRDP + glutamine • proceeds only in a cytoplasm of cells • includes orotic acid as an intermediate • includes inosine monophosphate as an intermediate

  48. Synthesis of pyrimidine nucleotides • starts by the reaction: PRDP + glutamine • proceeds only in a cytoplasm of cells • includes orotic acid as an intermediate • includes inosine monophosphate as an intermediate

  49. In a degradation of purine nucleotides • ammonia is released • CO2 is produced • the enzyme xanthine oxidase participates • uric acid is produced as the end product

  50. In a degradation of purine nucleotides • ammonia is released • CO2 is produced • the enzyme xanthine oxidase participates • uric acid is produced as the end product

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