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Metabolism of purines and pyrimidines

Metabolism of purines and pyrimidines. Vladimíra Kvasnicová. The figure was found at http://www.mahidol.ac.th/mahidol/ra/rapa/mong/26uric.jpg (Jan 2008). PURINE BASES.

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Metabolism of purines and pyrimidines

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  1. Metabolism of purines and pyrimidines Vladimíra Kvasnicová The figure was found at http://www.mahidol.ac.th/mahidol/ra/rapa/mong/26uric.jpg (Jan 2008)

  2. PURINE BASES The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  3. PYRIMIDINE BASES The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  4. 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

  5. ribonucleosidedeoxyribonucleoside N-glycosidic bond The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  6. ribonucleosidesdeoxyribonucleoside The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  7. Ribonucleotides * N-glycosidic bond * ester bond * anhydride bond The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  8. ribonucleotidedeoxyribonucleotide The figure was adopted from 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 nucleotides:contain cytosine, uracil or thymine • ribonucleotides(saccharide = ribose) • deoxyribonukleotidy(saccharide = deoxyribose) • formed by reduction ofribonucleoside diphosphates (NADPH)

  10. 3´-phosphoadenosine-5´-phosphosulfate (PAPS) used as the sulfate donor in metabolic reactions (sulfatation) The figure was found at http://web.indstate.edu/thcme/mwking/amino-acid-metabolism.html (Jan 2007)

  11. 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, ...

  12. Purine and pyrimidine 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)

  13. 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

  14. Synthetic analogs of purines and pyrimidines are usedin chemotherapy The figure was adopted from Harper´s Illustrated Biochemistry 26th ed./ R.K.Murray; McGraw-Hill Companies, 2003, ISBN 0-07-138901-6.

  15. 3) physiological mediators • cAMP, cGMP („second messengers“) Cyclic adenosine monophosphate (cAMP) The figure was found at http://www.benbest.com/health/cycAMP.gif (Jan 2008)

  16. 4) components of coenzymes • NAD+, NADP+, FAD, CoA The figures were found at http://lxyang.myweb.uga.edu/bcmb8010/pic/NAD+.gif a http://oregonstate.edu/instruct/bb450/stryer/ch14/Slide26.jpg (Jan 2008)

  17. 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. PRDP = 5-fosforibosyl-1-diphosphate = the substrate for synthesis of bothpurines and pyrimidines The figure was found at http://ead.univ-angers.fr/~jaspard/Page2/COURS/2N2NH3aaetUree/2Figures/9AAaromatiques/8PRPP.gif (Jan 2008)

  19. PRPP = 5-phosphoribosyl-1-diphosphate • its synthesis is a key reaction of synthesis of the nucleotides • PRPP-synthetaseis regulated by feed back inhibition by nucleoside di- and triphosphates • precursors: * ribose-5-phosphate (from HMPP) * ribose-1-phosphate(phosphorolysis of nucleosides)

  20. function: • regulation of nucleotide synthesis • substrate of nucleotide synthesis PRPP = PRDP The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  21. 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

  22. Synthesis of purine nucleotides CYTOPLASM The figure was found at http://web.indstate.edu/thcme/mwking/nucleotide-metabolism.html (Jan 2007)

  23. IMP AMP GMP The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  24. The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  25. Folate is a vitamin– it is not synthesized in human cells Bacteria can synthesize the folate:sulfonamides are analogs of PABA→ bacteriostatic effect The figure was found at http://www.dentistry.leeds.ac.uk/biochem/MBWeb/mb2/part1/aacarbon.htm (Jan 2008)

  26. cytostatics The figure was found at http://oregonstate.edu/instruct/bb450/lecturenoteskevin/enzymesoutline.html (Jan 2008)

  27. Activation of folate(reduction) Dihydrofolate reductase can be inhibited by Methotrexate The figure was found at http://www.dentistry.leeds.ac.uk/biochem/postgrad/fol-red.gif (Jan 2008)

  28. Derivatives of tetrahydrofolate The figure was found at http://www.dentistry.leeds.ac.uk/biochem/postgrad/thftypes.gif (Jan 2008)

  29. Serin is the principal donor of methylene group The figure was found at http://www.med.unibs.it/~marchesi/glycine_synth.gif (Jan 2008)

  30. Folate in a metabolism The figure was found at http://www.prema-eu.org/folatepathway/fig1.gif (Jan 2008)

  31. Synthesis of purine nucleotides de novo(I) • 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+

  32. Synthesis of purine nucleotides de novo(II) • 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)

  33. 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

  34. Synthesis of pyrimidine nucleotides CYTOPLASM mitochondrion The figure was found at http://web.indstate.edu/thcme/mwking/nucleotide-metabolism.html (Jan 2007)

  35. The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  36. Synthesis of thymidine monophosphate The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley‑Liss, Inc., New York, 1997. ISBN 0‑471‑15451‑2

  37. Synthesis of pyrimidine nucleotidesde novo(I) • 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)

  38. Synthesis of pyrimidine nucleotides de novo(II) • important intermediates: * orotic acid (pyrimidine derivative) * orotidine monophosphate (OMP) * uridine monophosphate (UMP) • products: * cytidine triphosphate (from UTP) * deoxythimidine monophosphate (from dUMP)

  39. Synthesis of 2-deoxyribonucleotides protein NADP+ NADPH+H+ protein The reaction is catalyzed byribonucleotide reductase The figure was found at http://www.chm.bris.ac.uk/motm/vitaminb12/ribred.gif (Jan 2008)

  40. Regulation of nucleotide synthesis • PRPP-synthetaseis 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)

  41. Regulation of synthesisof purine nucleotides The figure was found at http://www.med.unibs.it/~marchesi/purine_synth_reg.gif (Jan 2008)

  42. Regulation of synthesisof pyrimidine nucleotides The figure was found at http://www.med.unibs.it/~marchesi/pyrimidine_synth_reg.gif (Jan 2008)

  43. Regulation of nucleotide synthesis

  44. 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(substrates: hypoxanthine, xanthine) inhibited by allopurinol(pharmacology)

  45. Degradation of purines The figure was found at http://www.med.unibs.it/~marchesi/purine_degradation.gif (Jan 2008)

  46. URIC ACIDketo and enol form • salts of uric acid = urates • pH of blood: mononatrium urate

  47. The figure was adopted from Color Atlas of Biochemistry / J. Koolman, K.H.Röhm. Thieme 1996. ISBN 0-86577-584-2

  48. Degradation of pyrimidines

  49. freeradicals SUMMARY: • 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 The figures were adopted from http://www.uni-koeln.de/med-fak/biochemie/biomed/versuche/v07/abb05.gif and http://www.healerpatch.com/images/gout.jpg (Jan 2008)

  50. Principal differences between metabolism of purines and pyrimidines

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