Metabolism of amino acids

1. Metabolism of amino acids Vladimíra Kvasnicová

2. Classification of proteinogenic AAs-metabolic point of view • biosynthesis in a human body • nonessential(are synthesized) • essential(must be present in a diet) • degradation within cells • glucogenic(Glc can be formed from their carbon sceleton) • ketogenic(= AAs degraded to acetyl-CoA)

3. Essential amino acids „10“ • branched chain: Val, Leu, Ile • aromatic: Phe (→ Tyr), Trp • basic: His, Arg, Lys • sulfur-containing: Met (→ Cys) • other: Thr

4. Essential amino acids PVTTIMHALL • branched chain: Val, Leu, Ile • aromatic: Phe (→ Tyr),Trp • basic: His, Arg, Lys • sulfur-containing: Met (→ Cys) • other: Thr

5. Essential/conditionally essential/ nonessential amino acids essential: Val, Leu, Ile, Thr, Phe, Trp,His, Arg,Lys, Met noness.: Gly, Ala, Pro, Ser, Tyr, Asn, Gln, Asp, Glu, Cys

6. Essential/conditionally essential/ nonessential amino acids essential: Val, Leu, Ile, Thr, Phe, Trp,His, Arg,Lys, Met noness.: Gly, Ala, Pro, Ser, Tyr, Asn, Gln, Asp, Glu, Cys AAs ~ organically bound nitrogen dietary proteins proteosynthesis body proteins AAs pool N-compound synthes. de novo biosynthesis degradation (E,glc,fat)

7. Insertion of an inorganic nitrogen to organic comp.in a human metabolism The figure is from http://web.indstate.edu/thcme/mwking/nitrogen-metabolism.html (Jan 2007)

8. Synthesis of AAs in a human body- 5 substrates - • oxaloacetate→ Asp, Asn • -ketoglutarate→ Glu, Gln, Pro, (Arg) • pyruvate→ Ala • 3-phosphoglycerate→ Ser, Cys, Gly • Phe→ Tyr

9. Synthesis of AAs in a human body - important reactions - • transamination Pyr → Ala OA→ Asp -ketoGlt→ Glu • amidation Asp → Asn Glu → Gln • synthesis from other amino acids Phe → Tyr Ser → Gly Glu → Pro Met + Ser → Cys

10. Transamination reaction! REVERSIBLE ! enzymes: amino transferases coenzyme: pyridoxal phosphate (vit. B6 derivative) The figure is from http://web.indstate.edu/thcme/mwking/nitrogen-metabolism.html (Jan 2007)

11. Amino transferases important in medicine („transaminases“) alanine aminotransferase(ALT = GPT) aspartate aminotransferase(AST = GOT) 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

12. „amidation“of glutamate = side chain carboxylic group of Glu is converted to amide group GLUTAMINE = the most important transport form af amino nitrogen in blood glutamine synthetase 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

13. Synthesis of ASPARAGINE needs glutamine as–NH2 group donor (it is not ammonia as in the Gln synthesis) 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

14. Synthesis of Tyr from Phe The figure is from http://web.indstate.edu/thcme/mwking/amino-acid-metabolism.html (Jan 2007)

15. Synthesis of serine and glycine glycolysis The figure is from http://www.biocarta.com/pathfiles/GlycinePathway.asp(Jan 2007)

16. Formation of activated methionine= S-adenosylmethionine (SAM) SAM is used as –CH3 group donorin metabolic methylations The figure is from http://web.indstate.edu/thcme/mwking/amino-acid-metabolism.html (Jan 2007)

17. Synthesis of Cys from Met and Ser The figure is from http://web.indstate.edu/thcme/mwking/amino-acid-metabolism.html (Jan 2007)

18. The figure is from http://www.biocarta.com/pathfiles/Cysteine2Pathway.asp (Jan 2007)

19. Regeneration of Met (vitamins: folate+B12) B12 The figure is from http://web.indstate.edu/thcme/mwking/amino-acid-metabolism.html (Jan 2007)

20. Some amino acids are used for synthesis of other N-compound: • Gln, Asp, Gly → purines, pyrimidines • Gly → porphyrines, creatine (+ Arg and Met) • Arg → NO • Cys → taurine 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. Decarboxylation of AAs givesmonoamines(= biogenic amines) • Tyr → catecholamines(adrenaline, noradrenaline, dopamine) • Trp → serotonin (= 5-hydroxytryptamine) • His → histamine • Ser → etanolamine→ choline → acetylcholine • Cys → cysteamine Asp → -alanine Glu → -aminobutyrate (GABA) coenzyme A

22. Choose correct statement(s) • valine belongs among branched chain amino acids • serine contains thiol group in its side chain • glutamate belongs among essential amino acids • tryptophan is a precursor of catecholamines

23. Choose correct statement(s) • valine belongs among branched chain amino acids • serine contains thiol group in its side chain • glutamate belongs among essential amino acids • tryptophan is a precursor of catecholamines

24. Degradation of amino acids (AAs) • -NH2 group removing from AA • detoxification of the amino group • metabolism of carbon sceleton of AA • 7 products

25. 7 degradation products of AAs • pyruvateGly, Ala, Ser, Thr, Cys, Trp • oxaloacetateAsp, Asn • -ketoglutarate  Glu, Gln, Pro, Arg, His • succinyl-CoA  Val, Ile, Met, Thr • fumarate  Phe, Tyr • acetyl-CoA  Ile • acetoacetyl-CoA  Lys, Leu, Phe, Tyr, Trp glucogenic AAs ketogenic AAs

26. The entrance of amino acids into the citrate cycle The figure is from http://www.biocarta.com/pathfiles/glucogenicPathway.asp (Jan 2007)

27. An example of AA degradation to produce intermediate of the citrate cycle The figure is from http://www.biocarta.com/pathfiles/asparaginePathway.asp (Jan 2007)

28. Fate of amino nitrogen derived from AAs • in extrahepatic tissues • transamination(forms mainly Ala and Glu + 2-oxoacids) • deamination (only some AAs: Ser,Thr,His; releases NH3) • amidation Glu + NH3→ Gln (needs ATP) • in the liver • see a) • oxidative deamination of Glu(forms -ketoGlt + NH3)enzyme:glutamate dehydrogenase (GMD = GLD)

29. Glutamine is principaltransport form of amino nitrogen The figure is fromhttp://www.sbuniv.edu/~ggray/CHE3364/b1c25out.html (Dec 2006)

30. Transport of amino nitrogen from degraded muscle proteins excreted products 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

31. Glucose-alanine cycle 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

32. Metabolism of amino nitrogen The figure is from http://courses.cm.utexas.edu/archive/Spring2002/CH339K/Robertus/overheads-3/ch18_ammonia-transport.jpg (Jan 2007)

33. GLUTAMATE DEHYDROGENASE removes amino group from carbon skeleton of Glu in the liver 1. –NH2 from AAs was transfered by transamination →Glu 2. free ammonia is released by oxidative deamination of Glu The figure is from http://web.indstate.edu/thcme/mwking/nitrogen-metabolism.html (Jan 2007)

34. Transport and detoxification of amino nitrogen- SUMMARY - • aminotransferases→ glutamate or alanine • glutamine synthetase→ glutamine • glutaminase→ glutamate + NH4+ • glutamate dehydrogenase→2-oxoglutarate +NH4+ • liver: urea cycle→urea • kidneys: glutaminase→ glutamate + NH4+ → urine

35. The products can be formed from carbon skeleton of the amino acids: • aspartate → oxaloacetate • lysine → glucose • alanine → fat • glutamine →-ketoglutarate

36. The products can be formed from carbon skeleton of the amino acids: • aspartate → oxaloacetate • lysine → glucose • alanine → fat • glutamine →-ketoglutarate

37. Amino nitrogen released from carbon skeletons of AAs can be transported in blood as • NH4+ • alanine • glutamine • urea

38. Amino nitrogen released from carbon skeletons of AAs can be transported in blood as • NH4+ • alanine • glutamine • urea

39. Amino nitrogen released from carbon skeletons of AAs can be transported in blood as • NH4+physiologically up to 35 µmol/l(NH3 + H + NH4+) • alanine formed by transamination from pyruvate • glutamine the most important transport form of –NH2 • ureait is the end product of degradation of amino nitrogen (liver → kidneys → urine)

40. Urea (ornithine) cycle = detoxification pathway (NH3 is toxic for brain) • proceeds only in the liver • is localized in mitochondria /cytoplasm • carbamoyl phosphate synthetase I(= mitoch.) • can acidify the organism (consumes HCO3-) • needs energy(3 ATP, but 4 energy rich bonds) • is connected with citrate cycle through fumarate • urea is end product of –NH2 metabolism(→ urine)

41. Detoxification of ammonia in the liver The figure is from http://www.biocarta.com/pathfiles/ureacyclePathway.asp (Jan 2007)

42. Interconnection of the urea cycle with the citrate cycle The figure is from http://courses.cm.utexas.edu/archive/Spring2002/CH339K/Robertus/overheads-3/ch18_TCA-Urea_link.jpg(Jan 2007)

43. Regulation of urea cycle allosteric regulation + enzyme induction by protein rich diet or by metabolic changes during starvation Urea synthesis is inhibited by acidosis– HCO3- is saved

44. Detoxification of ammonia in a human body includes • urea cycle proceeding only in the liver • cleavage of glutamine in the liver and the kidneys • consumption of energy in a form of ATP • formation of ornithine from citrulline and carbamoyl phosphate

45. Detoxification of ammonia in a human body includes • urea cycle proceeding only in the liver • cleavage of glutamine in the liver and the kidneys • consumption of energy in a form of ATP • formation of ornithine from citrulline and carbamoyl phosphate