11 metabolism of amino acids, purine and pyrimidine bases

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11 metabolism of amino acids, purine and pyrimidine bases

  1. 1. Metabolism of amino acids, purine and pyrimidine bases
  2. 2. Amino acids (AAs)Sources of AAs:• diet• synthesis de novo• protein degradationdietary proteins proteosynthesisbody proteins AAs pool N-compound synthes.de novo biosynthesis degradation(E,glc,fat)
  3. 3. Biosynthesis of amino acids (AA)Humans can synthesize only 10 Essential AA Nonessential AAof the 20 AA. Arg AlaEssential AA = AA that cannot His Asnbe synthesized „de novo“. Theymust be obtained from diet. Ile AspNonessential AA: Leu CysAla is synthesized from Lys Glnpyruvate. Met GluCys is synthesized from Met Phe Glyand Ser. Thr ProTyr is formed by hydroxylationfrom Phe. Trp Ser Val Tyr
  4. 4. Synthesis of AAs in a human body - 5 substrates -1. oxaloacetate → Asp, Asn2. -ketoglutarate → Glu, Gln, Pro, (Arg)3. pyruvate → Ala4. 3-phosphoglycerate → Ser, Cys, Gly5. Phe → Tyr
  5. 5. Synthesis of thyrosine from phenylalanineFigure is found at http://themedicalbiochemistrypage.org/amino-acid-metabolism.html#tyrosine
  6. 6. Formation of activated methionine = S-adenosylmethionine (SAM) SAM is used as –CH3 group donor in metabolic methylationsFigure is found at http://themedicalbiochemistrypage.org/amino-acid-metabolism.html#cysteine
  7. 7. Synthesis of Cys from Met and SerFigure is found at http://themedicalbiochemistrypage.org/amino-acid-metabolism.html#cysteine
  8. 8. Degradation of AA20 different multienzyme sequences exist for catabolismof AAs. All common 20 AAs are converted to only7 compounds:• pyruvate• acetyl-CoA• acetoacetyl-CoA• α-ketoglutarate• succinyl-CoA• fumarate• oxaloacetate
  9. 9. Three types of reactions are typical for degradation of AAs:1. Transamination2. Deamination3. Decarboxylation
  10. 10. Transamination= an exchange of –NH2 between amino acid and α-ketoacidThese reactions are catalyzed by transaminases (aminotransferases).Most of them require α-ketoglutarate as an acceptor of –NH2.Coenzyme of transaminases: pyridoxal phosphate (vit. B6 derivative)Figure is found at http://web.indstate.edu/thcme/mwking/nitrogen-metabolism.html
  11. 11. Aminotransferases (transaminases) important in medicineAlanine aminotransferase (ALT) Aspartate aminotransferase (AST)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
  12. 12. Deamination e. g. oxidative deamination of Glu Glu → α-ketoglutarate by glutamate dehydrogenaseFigure is found at http://www.sbuniv.edu/~ggray/CHE3364/b1c25out.html
  13. 13. Decarboxylation→ primary aminesa) decarboxylation of His → histamineb) decarboxylation of Trp → serotoninc) decarboxylation of Tyr → epinephrine and norepinephrined) decarboxylation of Glu → GABA (γ-aminobutyrate)Figure is found at http://www.sbuniv.edu/~ggray/CHE3364/b1c25out.html
  14. 14. Ammonia transport and detoxificationGlutamine (Gln) is the major transport form of ammonia. Figure is found at http://www.sbuniv.edu/~ggray/CHE3364/b1c25out.html
  15. 15. Glucose-Alanine cycleFigure is found at http://www.sbuniv.edu/~ggray/CHE3364/b1c25out.html
  16. 16. Urea cycle (ornithine cycle)• substrates: NH4+, HCO3-, Asp, ATP• product: urea• function: synthesis of non-toxic urea• subcellular location: mitochondria and cytosol• organ location: liver• regulatory enzyme: carbamoyl phosphate synthetase I
  17. 17. Urea cycle (ornithine cycle) lFigure is found at http://web.indstate.edu/thcme/mwking/nitrogen-metabolism.html
  18. 18. The fate of carbon skeletons of AA during catabolism• The strategy of the cell is to convert carbon skeletons to compounds useful in gluconeogenesis or CAC.• Glucogenic AAs = AA that can form any of intermediates of carbohydrate metabolism Gly, Ala, Ser, Cys, Thr → pyruvate Glu, Pro, Arg, His → Glu → α-ketoglutarate Met, Ile, Val → succinyl-CoA• Ketogenic AAs are converted to acetyl-CoA and acetoacetyl-CoA. They yield ketone bodies. Leu, Lys● Glucogenic-ketogenic AAs = Thr, Phe, Tyr, Ile
  19. 19. Figure is found at http://www.biocarta.com/pathfiles/glucogenicPathway.asp F
  20. 20. De novo synthesis of purine nucleotidesFigure is found at http://web.indstate.edu/thcme/mwking/nucleotide-metabolism.html
  21. 21. Important notes about biosynthesis of purine nucleotides• Subcellular location: cytoplasm• PRPP = phosphoribosyl pyrophosphate is derived from ribose-5-P• IMP = inosine monophosphate serves as the common precursor of AMP and GMP synthesis• Gln, Gly, Asp are donors of C and N atoms• CO2 is a source of C• C1 units are transferred via tetrahydrofolate„Salvage pathway“:• purines from normal turnover of cellular NA can be converted to nucleoside triphosphates• substrates: purine bases, PRPP, ATP
  22. 22. Degradation of purine nucleotides→ uric acid is formed by enzyme xanthine oxidase
  23. 23. De novo synthesis of pyrimidine nucleotidesFigure is found at http://web.indstate.edu/thcme/mwking/nucleotide-metabolism.html
  24. 24. Important notes about synthesis of pyrimidine nucleotides• Carbamoyl phosphate is formed from Gln and CO2 (2 ATP are consumed). This reaction is catalyzed by carbamoyl-P synthetase II (cytosolic enzyme) = regulatory step• pathway occurs in cytoplasm but formation of orotate occurs in mitochondrion → orotate is linked by PRPP → OMP → UMP• UMP → UTP → CTP TTP TTP● UTP inhibits regulatory enzyme, activator is PRPP„Salvage pathway“:● pyrimidine nucleosides are phosphorylated (ATP) to nucleotides
  25. 25. Degradation of pyrimidine bases→ β-amino acids are formed

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