1. Metabolism of amino acids Vladimíra Kvasnicová

2. Classification of proteinogenic AAs -metabolic point of view 1)biosynthesis in a human body  nonessential (are synthesized)  essential (must be present in a diet) 2)degradation within cells  glucogenic (Glc can be formed from their carbon sceleton)  ketogenic (= AAs degraded to acetyl-CoA)

3. Essential amino acids 1)branched chain: Val, Leu, Ile 2)aromatic: Phe ( → Tyr), Trp 3)basic: His, Arg, Lys 4)sulfur-containing: Met ( → Cys) 5)other: Thr „10“

4. Essential amino acids PVT TIM HALL 1)branched chain: Val, Leu, Ile 2)aromatic: Phe ( → Tyr), Trp 3)basic: His, Arg, Lys 4)sulfur-containing: Met ( → Cys) 5)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 proteinsproteosynthesis body proteins AAs poolN-compound synthes. de novo biosynthesisdegradation (E,glc,fat)

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

8. Synthesis of AAs in a human body - 5 substrates - 1.oxaloacetate → Asp, Asn 2.  -ketoglutarate → Glu, Gln, Pro, (Arg) 3.pyruvate → Ala 4.3-phosphoglycerate → Ser, Cys, Gly 5.Phe → Tyr

9. Synthesis of AAs in a human body - important reactions - 1.transamination Pyr → AlaOA → Asp  -ketoGlt → Glu 2.amidation Asp → AsnGlu → Gln 3.synthesis from other amino acids Phe → Tyr Ser → Gly Glu → Pro Met + Ser → Cys

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

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

12. glutamine synthetase „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 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 –NH 2 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. The figure is from http://web.indstate.edu/thcme/mwking/amino-acid-metabolism.html (Jan 2007)http://web.indstate.edu/thcme/mwking/amino-acid-metabolism.html Synthesis of Tyr from Phe

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

16. The figure is from http://web.indstate.edu/thcme/mwking/amino-acid-metabolism.html (Jan 2007)http://web.indstate.edu/thcme/mwking/amino-acid-metabolism.html Formation of activated methionine = S-adenosylmethionine (SAM) SAM is used as –CH 3 group donor in metabolic methylations

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

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

19. The figure is from http://web.indstate.edu/thcme/mwking/amino-acid-metabolism.html (Jan 2007)http://web.indstate.edu/thcme/mwking/amino-acid-metabolism.html B12 Regeneration of Met (vitamins: folate+B 12 )

20. Some amino acids are used for synthesis of other N-compound: 1)Gln, Asp, Gly → purines, pyrimidines 2)Gly → porphyrines, creatine (+ Arg and Met) 3)Arg → NO 4)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 gives monoamines (= biogenic amines) 1)Tyr → catecholamines (adrenaline, noradrenaline, dopamine) 2)Trp → serotonin (= 5-hydroxytryptamine) 3)His → histamine 4)Ser → etanolamine → choline → acetylcholine 5)Cys → cysteamine Asp →  - alanine Glu →  -aminobutyrate (GABA) coenzyme A

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

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

24. Degradation of amino acids (AAs) 1)-NH 2 group removing from AA 2)detoxification of the amino group 3)metabolism of carbon sceleton of AA  7 products

25. 7 degradation products of AAs 1.pyruvate  Gly, Ala, Ser, Thr, Cys, Trp 2.oxaloacetate  Asp, Asn 3.  -ketoglutarate  Glu, Gln, Pro, Arg, His 4.succinyl-CoA  Val, Ile, Met, Thr 5.fumarate  Phe, Tyr 6.acetyl-CoA  Ile 7.acetoacetyl-CoA  Lys, Leu, Phe, Tyr, Trp glucogenic AAs ketogenic AAs

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

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

28. Fate of amino nitrogen derived from AAs a)in extrahepatic tissues  transamination (forms mainly Ala and Glu + 2-oxoacids)  deamination (only some AAs: Ser,Thr,His; releases NH 3 )  amidation Glu + NH 3 → Gln (needs ATP) b)in the liver  see a)  oxidative deamination of Glu (forms  -ketoGlt + NH 3 ) enzyme: glutamate dehydrogenase (GMD = GLD)

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

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

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

34. Transport and detoxification of amino nitrogen - SUMMARY - aminotransferases → glutamate or alanine glutamine synthetase → glutamine glutaminase → glutamate + NH 4 + glutamate dehydrogenase → 2-oxoglutarate + NH 4 + liver: urea cycle → urea kidneys: glutaminase → glutamate + NH 4 + → urine

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

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

37. Amino nitrogen released from carbon skeletons of AAs can be transported in blood as a)NH 4 + b)alanine c)glutamine d)urea

38. Amino nitrogen released from carbon skeletons of AAs can be transported in blood as a)NH 4 + b)alanine c)glutamine d)urea

39. Amino nitrogen released from carbon skeletons of AAs can be transported in blood as a)NH 4 + physiologically up to 35 µmol/l (NH 3 + H +  NH 4 + ) b)alanine formed by transamination from pyruvate c)glutamine the most important transport form of –NH 2 d)urea it is the end product of degradation of amino nitrogen (liver → kidneys → urine)

40. Urea (ornithine) cycle = detoxification pathway (NH 3 is toxic for brain) proceeds only in the liver is localized in mitochondria /cytoplasm carbamoyl phosphate synthetase I (= mitoch.) can acidify the organism (consumes HCO 3 - ) needs energy (3 ATP, but 4 energy rich bonds) is connected with citrate cycle through fumarate urea is end product of –NH 2 metabolism ( → urine)

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

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

43. regulatory enzymeactivationinhibition carbamoyl phosphate synthetase I (= mitochondrial)  N-acetylglutamate N-acetylglutamate synthetase  arginine Regulation of urea cycle allosteric regulation + enzyme induction by protein rich diet or by metabolic changes during starvation Urea synthesis is inhibited by acidosis – HCO 3 - is saved

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

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