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 10 4) sulfur-containing: Met ( Cys) 5) other: Thr
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 AAs ~ organically bound nitrogen dietary proteins proteosynthesis body proteins AAs pool N-compound synthes. de novo biosynthesis degradation (E,glc,fat)
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)
Synthesis of AAs in a human body - 5 substrates - 1. oxaloacetate Asp, Asn 2. α-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 Ala OA Asp α-ketoglt Glu 2. amidation Asp Asn Glu Gln 3. synthesis from other amino acids Phe Tyr Ser Gly Glu Pro Met + Ser Cys
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)
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
amidation of glutamate = side chain carboxylic group of Glu is converted to amide group glutamine synthetase 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
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
Synthesis of Tyr from Phe The figure is from http://web.indstate.edu/thcme/mwking/amino-acid-metabolism.html (Jan 2007)
glycolysis Synthesis of serine and glycine The figure is from http://www.biocarta.com/pathfiles/glycinepathway.asp (Jan 2007)
Formation of activated methionine = S-adenosylmethionine (SAM) SAM is used as CH 3 group donor in metabolic methylations The figure is from http://web.indstate.edu/thcme/mwking/amino-acid-metabolism.html (Jan 2007)
Synthesis of Cys from Met and Ser The figure is from http://web.indstate.edu/thcme/mwking/amino-acid-metabolism.html (Jan 2007)
The figure is from http://www.biocarta.com/pathfiles/cysteine2pathway.asp (Jan 2007)
B12 Regeneration of Met (vitamins: folate+b 12 ) The figure is from http://web.indstate.edu/thcme/mwking/amino-acid-metabolism.html (Jan 2007)
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
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 β-alanine coenzyme A Glu γ-aminobutyrate (GABA)
TEST / Choose correct statement(s) a) valine is a branched chain amino acid b) serine contains thiol group in its side chain c) glutamate is an essential amino acid 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. α-ketoglutarate Glu, Gln, Pro, Arg, His 4. succinyl-coa Val, Ile, Met, Thr 5. fumarate Phe, Tyr 6. acetyl-coa Ile glucogenic AAs ketogenic AAs 7. acetoacetyl-coa Lys, Leu, Phe, Tyr, Trp
The entrance of amino acids into the citrate cycle The figure is from http://www.biocarta.com/pathfiles/glucogenicpathway.asp (Jan 2007)
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)
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 α-ketoglt + NH 3 ) enzyme: glutamate dehydrogenase (GMD = GLD)
Glutamine is principal transport form of amino nitrogen The figure is from http://www.sbuniv.edu/~ggray/che3364/b1c25out.html (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, 1997. ISBN 0-471-15451-2
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, 1997. ISBN 0-471-15451-2
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)
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 The figure is from http://web.indstate.edu/thcme/mwking/nitrogen-metabolism.html (Jan 2007)
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
TEST / The products can be formed from carbon skeleton of the amino acids: a) aspartate oxaloacetate b) lysine glucose c) alanine fat d) glutamine α-ketoglutarate
TEST / Amino nitrogen released from carbon skeletons of AAs can be transported in blood as a) NH + 4 b) alanine c) glutamine d) urea
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)
Detoxification of ammonia in the liver The figure is from http://www.biocarta.com/pathfiles/ureacyclepathway.asp (Jan 2007)
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)
Regulation of urea cycle allosteric regulation + enzyme induction by protein rich diet or by metabolic changes during starvation regulatory enzyme carbamoyl phosphate synthetase I (= mitochondrial) activation N-acetylglutamate inhibition N-acetylglutamate synthetase arginine Urea synthesis is inhibited by acidosis HCO 3- is saved
TEST / 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