Amino Acid Metabolism

David A. Bender, Senior Lecturer, Department of Biochemistry and Molecular Biology, University College London, London, UK; Assistant Faculty Tutor (Life Sciences, Medical) and Sub-Dean (Teaching), Royal Free and University College Medical School.

“Summing Up: Recommended.  Upper-division undergraduates through professionals.”  (Choice, 1 March 2013)“Bender writes succinctly and clearly, in a manner which serves well for quick referencing or for reading whole chapters at a time. The chapters are well organised and arranged logically.”  (Phenotype, 1 February 2013)

• Figures xiii Tables xviiPreface xix1 Nitrogen Metabolism 11.1 Nitrogen fixation 31.1.1 Nitrogenase 51.1.1.1 The nitrogen fixation gene cluster 71.1.1.2 Regulation of nitrogenase by the availability of fixed nitrogen and ATP 71.1.1.3 Protection of nitrogenase against oxygen 91.1.1.4 Respiratory protection in aerobic microorganisms 91.1.1.5 Conformational changes in nitrogenase 101.1.1.6 Heterocyst formation in filamentous cyanobacteria 101.1.1.7 Symbiotic Rhizobium spp. in root nodules 101.2 Nitrification and denitrification 111.2.1 The anammox (ANaerobic AMMonium OXidation) reaction 121.3 The incorporation of fi xed nitrogen into organic compounds 121.3.1 Utilization of nitrite and nitrate in plants 121.3.2 Incorporation of ammonium into organic compounds 131.3.2.1 Reductive amination – the glutamate pathway of ammonium incorporation 141.3.2.2 Glutamate dehydrogenase 161.3.2.3 Mammalian glutamate dehydrogenase 171.3.2.4 Glutamate synthase – the glutamine pathway of ammonium incorporation 181.3.2.5 Synthesis of aspartate and asparagine 211.4 The synthesis and catabolism of purine and pyrimidine nucleotides 231.4.1 Purine synthesis 261.4.1.1 Phosphoribosyl pyrophosphate (PRPP) synthetase 281.4.1.2 PRPP amidotransferase 301.4.2 Purine catabolism and salvage 311.4.2.1 Adenosine deaminase deficiency – severe combined immune deficiency 341.4.2.2 Gout and hyperuricaemia 351.4.2.3 HGPRT deficiency – the Lesch-Nyhan syndrome 371.4.3 Pyrimidine synthesis 381.4.3.1 Orotic aciduria 421.4.4 Pyrimidine catabolism and salvage 431.5 Deamination of amino acids 451.5.1 Amino acid oxidases 451.5.2 Amine oxidases 471.5.3 Glutamate and alanine dehydrogenases 481.5.4 Non-oxidative deamination of amino acids 491.5.5 Glutaminase and asparaginase 501.6 Excretion of nitrogenous waste 511.6.1 Uricotelic and purinotelic species 511.6.2 Ureotelic species 521.6.2.1 Urea synthesis 521.6.2.2 Inborn errors of metabolism affecting the urea synthesis cycle 571.6.2.3 Entero-hepatic circulation of urea 591.6.2.4 Canavanine 601.7 Other nitrogenous compounds in human urine 611.7.1 Aminoacidurias 62Further reading 652 Nitrogen Balance and Protein Turnover – Protein and Amino Acids in Human Nutrition 672.1 Nitrogen balance and protein requirements 672.1.1 Protein digestion and absorption 692.1.2 Protein digestibility and unavailable amino acids in dietary proteins 742.1.3 Obligatory nitrogen losses 752.1.4 Dynamic equilibrium and tissue protein turnover 762.1.5 Tissue protein catabolism 772.1.5.1 Lysosomal autophagy 782.1.5.2 Ubiquitin and the proteasome 792.1.5.3 Active site proteolysis of apo-enzymes 812.1.6 Whole body protein turnover 812.1.6.1 The constant infusion, labelled precursor method 822.1.6.2 The constant infusion, labelled end product method 822.1.6.3 Rates of whole-body protein turnover 832.1.6.4 The catabolic drive and amino acid oxidation 832.1.6.5 The energy cost of protein turnover 842.1.6.6 Diurnal variation in protein turnover 852.2 Requirements for individual amino acids 862.2.1 Nitrogen balance studies 892.2.2 Isotope tracer studies 902.2.3 Control of protein synthesis by the availability of amino acids 912.2.4 Protein quality (protein nutritional value) 922.2.4.1 Biological assays of protein quality 932.2.4.2 Chemical analysis and protein quality 942.3 The fate of amino acid carbon skeletons and the thermic effect of protein 942.4 Inter-organ metabolism of amino acids 992.5 Transport of amino acids across membranes 1002.5.1 Families of amino acid transporters 1012.5.1.1 Dipeptide transport 104Further reading 1043 The Role of Vitamin B6 in Amino Acid Metabolism 1053.1 Pyridoxal phosphate-dependent reactions 1063.1.1 Families of pyridoxal phosphate-dependent enzymes 1113.2 Amino acid racemases 1123.2.1 Bacterial alanine racemase 1123.2.2 Eukaryotic serine racemase 1133.2.3 D-Aspartate in eukaryotes 1143.2.4 D-Amino acids in aquatic invertebrates 1153.2.5 D-Amino acids in gene-encoded peptides and proteins 1153.3 Transamination 1173.3.1 Dual substrate recognition in transaminases 1203.3.2 Aspartate transaminase and the malate-aspartate shuttle 1203.4 Decarboxylation and side-chain elimination and replacement reactions 1223.4.1 Transamination of decarboxylases and enzymes catalyzing side-chain  limination reactions 1223.5 Pyruvate-containing enzymes 1243.6 Vitamin B6 defi ciency and dependency 125Further reading 1284 Glycine, Serine and the One-Carbon Pool 1294.1 Sources of glycine 1304.1.1 Choline as a source of glycine 1304.1.2 Glycine transaminase 1324.2 The interconversion of glycine and serine 1324.2.1 Serine hydroxymethyltransferase 1334.2.2 The glycine cleavage system 1354.2.3 Serine hydroxymethyltransferase and the glycine cleavage system in photosynthetic tissue 1364.2.4 Non-ketotic and ketotic hyperglycinaemia 1374.3 Glycine oxidase and glyoxylate metabolism 1384.3.1 Primary hyperoxaluria 1404.4 One-carbon metabolism 1414.5 Serine biosynthesis 1414.6 Serine catabolism 1444.6.1 Serine transamination 1444.6.2 Serine deaminase 1454.7 Peptidyl glycine hydroxylase (peptide α-amidase) 1464.8 5-Aminolevulinic acid and porphyrin synthesis 1474.8.1 Porphyrias – diseases of porphyrin synthesis 1514.9 Selenocysteine 152Further reading 1545 Amino Acids Synthesized from Glutamate: Glutamine, Proline, Ornithine, Citrulline and Arginine 1575.1 Synthesis of 5-aminolevulinic acid from glutamate in plants 1595.2 The catabolism of glutamate 1605.3 Glutamine 1615.3.1 Indirect formation of glutamine-tRNA 1635.3.2 Glutaminases 1645.3.2.1 Glutamine-dependent amidotransferases 1645.3.3 Transglutaminases 1655.4 Glutathione and the γ-glutamyl cycle 1685.4.1 Glutathione peroxidases 1705.4.2 Glutathione reductase 1715.4.3 Glutathione S-transferases 1715.4.4 Glutathione synthesis 1745.4.4.1 Glutamate cysteine ligase 1745.4.4.2 Glutathione synthetase 1755.4.5 The γ-glutamyl cycle 1765.5 Glutamate decarboxylase and the GABA shunt 1785.5.1 Glutamate decarboxylase 1805.5.2 Alternative pathways of GABA synthesis 1815.5.3 GABA catabolism 1835.6 Glutamate carboxylase and vitamin K-dependent post-synthetic modification of proteins 1845.6.1 Vitamin K-dependent proteins in blood clotting 1875.6.2 Osteocalcin and matrix Gla protein 1895.6.3 Vitamin K-dependent proteins in cell signalling – Gas-6 and protein S 1905.7 Proline 1905.7.1 Proline synthesis and catabolism 1925.7.1.1 Δ1-pyrroline-5-carboxylate reductase and proline oxidase 1925.7.1.2 Hydroxyproline catabolism 1945.7.2 Peptide prolyl hydroxylase 1965.7.2.1 The hypoxia-inducible factor 1985.8 The polyamines 1985.8.1 Ornithine decarboxylase 1995.8.2 S-Adenosylmethionine decarboxylase and polyamine synthesis 2015.8.3 Polyamine catabolism and the interconversion pathway 2035.8.4 Hypusine 2045.9 Arginine, citrulline and ornithine 2055.9.1 Arginine biosynthesis 2065.9.1.1 The role of citrulline in arginine biosynthesis in mammals 2085.9.2 Arginine catabolism in microorganisms 2095.9.3 Nitric oxide 2105.9.3.1 Nitric oxide synthase 2115.9.3.2 Arginase and the control of arginine availability for nitric oxide synthesis or polyamine synthesis 2145.9.4 Agmatine 2165.9.5 Post-synthetic methylation of arginine in proteins 2175.9.6 Post-synthetic formation of citrulline in proteins 2185.9.7 Creatine 219Further reading 2226 Amino Acids Synthesized from Aspartate: Lysine, Methionine (and Cysteine), Threonine and Isoleucine 2256.1 Regulation of the pathway of amino acid synthesis from aspartate 2276.1.1 Aspartate kinase 2286.1.1.1 Aspartate kinase in post-synthetic modification of proteins 2306.1.1.2 Aspartic semialdehyde dehydrogenase 2306.1.2 Homoserine dehydrogenase 2306.1.3 Homoserine kinase 2316.1.4 Threonine synthase 2326.1.5 Threonine catabolism 2326.1.5.1 Threonine deaminase 2346.2 Lysine 2356.2.1 Lysine biosynthesis in bacteria and plants – the diaminopimelate pathway 2366.2.1.1 Diaminopimelate and dipicolinate in sporulating bacteria 2386.2.2 Lysine biosynthesis in yeasts and fungi – the α-amino adipic acid pathway 2396.2.3 Lysine catabolism 2426.2.3.1 The saccharopine pathway of lysine catabolism 2436.2.3.2 The pipecolic acid pathway of lysine catabolism 2456.2.4 Post-synthetic modifi cation of lysine in proteins 2456.2.4.1 Hydroxylysine, lysine aldehyde (allysine) and cross-links in collagen and elastin 2476.2.4.2 Methyl lysine 2496.2.4.3 Pyrrolysine 2516.2.5 Carnitine 2526.3 Methionine and cysteine 2556.3.1 Methionine biosynthesis 2566.3.1.1 Cystathionine γ-synthase and cystathionine β-lyase 2586.3.1.2 Methionine synthase 2596.3.1.3 S-Methylmethionine in plants 2606.3.2 S-Adenosylmethionine and the methylation cycle 2606.3.2.1 Glycine N-methyltransferase 2636.3.2.2 Megaloblastic anaemia and the methyl folate trap 2646.3.2.3 Methionine γ-lyase 2646.3.3 Transsulphuration and cysteine synthesis in animals 2656.3.3.1 Homocystinuria, hyperhomocysteinaemia and cardiovascular disease 2666.3.4 Ethylene synthesis in plants 2686.3.5 Radical SAM enzymes 2716.3.6 Hydrogen sulphide 2726.3.7 Taurine and the catabolism of cysteine 273Further reading 2767 The Branched-Chain Amino Acids: Leucine, Isoleucine and Valine 2797.1 Synthesis of the branched-chain amino acids 2807.1.1 Acetohydroxyacid synthase 2827.1.2 Acetohydroxyacid reducto-isomerase, dihydroxyacid dehydratase and transamination of the oxo-acids 2837.1.3 Leucine synthesis 2847.1.3.1 The pyruvate pathway of isoleucine synthesis 2867.2 Mammalian catabolism of the branched-chain amino acids 2877.2.1 Branched-chain amino acid transaminases 2897.2.2 Branched-chain 2-oxo-acid dehydrogenase 2907.2.2.1 Maple syrup urine disease 2937.2.3 Branched-chain acyl CoA dehydrogenases 2937.2.4 Leucine catabolism 2957.2.5 Isoleucine catabolism 2967.2.6 Valine catabolism 2977.2.7 Biotin-dependent carboxylation reactions 2997.2.7.1 Multiple carboxylase deficiency 300Further reading 3028 Histidine 3058.1 Biosynthesis of histidine 3068.2 Histidine catabolism 3108.2.1 The urocanic acid pathway of histidine catabolism 3118.2.1.1 The histidine load test (FIGLU test) for folate nutritional status 3148.2.2 The hydantoin propionate pathway 3158.2.3 The transaminase pathway of histidine catabolism 3168.3 Histamine 3168.3.1 Bacterial histamine poisoning (scombroid poisoning) 3178.3.2 Histidine decarboxylase 3188.3.3 Histamine catabolism 3198.4 Methylhistidine 3218.5 Carnosine and related histidine-containing peptides 321Further reading 3229 The Aromatic Amino Acids: Phenylalanine, Tyrosine and Tryptophan 3239.1 Biosynthesis of phenylalanine, tyrosine and tryptophan 3249.1.1 The shikimate pathway 3259.1.2 Synthesis of phenylalanine and tyrosine 3289.1.3 Synthesis of tryptophan 3319.1.3.1 The trp operon 3339.2 Metabolism of phenylalanine and tyrosine 3359.2.1 Phenylalanine ammonia lyase and lignin biosynthesis in plants 3359.2.2 Polyphenol biosynthesis in plants 3389.2.3 Phenylalanine hydroxylase and phenylketonuria 3399.2.4 The catecholamines: dopamine, noradrenaline and adrenaline 3429.2.4.1 Parkinson’s disease and inhibitors of dopa decarboxylase 3469.2.4.2 Catabolism of the catecholamines 3469.2.5 Tyrosinase and melanin synthesis 3499.2.6 The thyroid hormones, thyroxine and tri-iodothyronine 3529.3 Catabolism of phenylalanine and tyrosine 3559.4 Metabolism of tryptophan 3579.4.1 Auxin (indoleacetic acid) 3579.4.2 Indole formation 3589.4.3 Serotonin and melatonin 3599.4.3.1 Melatonin synthesis and catabolism 3629.4.4 The kynurenine pathway of tryptophan metabolism 3639.4.4.1 Regulation of tryptophan dioxygenase 3659.4.4.2 Kynurenine metabolism 3679.4.4.3 Kynureninase and the tryptophan load test for vitamin B6 nutritional status 3689.4.4.4 De novo synthesis of NAD 3699.4.5 Pellagra 3709.4.5.1 The pellagragenic effect of excess dietary leucine 3729.4.5.2 Inborn errors of tryptophan metabolism 3729.4.5.3 Carcinoid syndrome 3739.4.5.4 Drug-induced pellagra 3739.5 Quinone cofactors in amine oxidases 374Further reading 375Bibliography 377Index 431