Metabolism of amino acids Vladimíra Kvasnicová

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)

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“

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

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

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)

The figure is from (Jan 2007) Insertion of an inorganic nitrogen to organic comp. in a human metabolism

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

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

The figure is from (Jan 2007) Transamination reaction ! REVERSIBLE ! enzymes: amino transferases coenzyme: pyridoxal phosphate (vit. B6 derivative)

The figure was adopted from Devlin, T. M. (editor): Textbook of Biochemistry with Clinical Correlations, 4th ed. Wiley ‑ Liss, Inc., New York, ISBN 0 ‑ 471 ‑ ‑ 2 alanine aminotransferase (ALT = GPT) aspartate aminotransferase (AST = GOT) Amino transferases important in medicine („transaminases“)

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, ISBN 0 ‑ 471 ‑ ‑ 2

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, ISBN 0 ‑ 471 ‑ ‑ 2

The figure is from (Jan 2007) Synthesis of Tyr from Phe

The figure is from (Jan 2007) Synthesis of serine and glycine glycolysis

The figure is from (Jan 2007) Formation of activated methionine = S-adenosylmethionine (SAM) SAM is used as –CH 3 group donor in metabolic methylations

The figure is from (Jan 2007) Synthesis of Cys from Met and Ser

The figure is from (Jan 2007)

The figure is from (Jan 2007) B12 Regeneration of Met (vitamins: folate+B 12 )

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, ISBN 0 ‑ 471 ‑ ‑ 2

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

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

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

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

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

The figure is from (Jan 2007) The entrance of amino acids into the citrate cycle

The figure is from (Jan 2007) An example of AA degradation to produce intermediate of the citrate cycle

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)

Glutamine is principal transport form of amino nitrogen The figure is from (Dec 2006)

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, ISBN 0 ‑ 471 ‑ ‑ 2

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, ISBN 0 ‑ 471 ‑ ‑ 2

The figure is from (Jan 2007) Metabolism of amino nitrogen

The figure is from (Jan 2007) 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

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

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

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

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

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

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)

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)

The figure is from (Jan 2007) Detoxification of ammonia in the liver

The figure is from (Jan 2007) Interconnection of the urea cycle with the citrate cycle

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

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

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