Amino Acid Metabolism Lecture Series 2 (PDF)

9/22/24 AMINO ACID METABOLISM INTRODUCTION 1 Biosynthesis of amino acids, showing the connections to glycolysis/gluconeogenesis and the citric acid cycle 2 1 ...

9/22/24 AMINO ACID METABOLISM INTRODUCTION 1 Biosynthesis of amino acids, showing the connections to glycolysis/gluconeogenesis and the citric acid cycle 2 1  9/22/24 Biosynthesis of amino acids, showing the connections to glycolysis/gluconeogenesis and the citric acid cycle 3 Aspartate 4 2  9/22/24 Phosphorylation of aspartate * These enzymes are missing in animals 5 Lysine, Methionine and Threonine Aspartate is the precursor for the synthesis of lysine, methionine, and threonine i. The first step in the pathway is the phosphorylation of aspartate in a reaction catalysed by aspartate kinase ii. In the second step, aspartyl phosphate is converted to aspartate β- semialdehyde catalysed by aspartate semialdehyde dehydrogenase These two enzymes are present in bacteria , protists and fungi and plants but they are missing in animals. The first two reactions leading to aspartate β-semialdehyde are common to the formation of all three amino acids 6 3  9/22/24 Lysine, Methionine and Threonine iii) Homoserine is formed from aspartate β-semialdehyde and is a branch point for the formation of threonine and methionine iv) Threonine is derived from homoserine in two steps, one of which requires pyridoxal phosphate (PLP) In the methionine pathway, homoserine is converted to homocysteine in three steps The sulfur atom of homocysteine then accepts a methyl group derived from 5-methyl-THF forming methionine The enzyme that catalyses this reaction is homocysteine methyltransferase, one of the few enzymes that requires cobalamin Homocysteine methyltransferase is found in mammals but its activity is low and homocysteine supply is limited Thus methionine remains an essential amino acid in the pathway 7 Methionine and phenylalanine are respectively precursors of cysteine and tyrosine The latter amino acids can become essential if adequate amounts of the former are not supplied in the diet Arginine is a conditionally essential amino acid. Although synthesized in the body, the amounts are not adequate during growth 8 4  9/22/24 Aspartate 9 Aspartate and Asparagine Oxaloacetate is the amino group acceptor in a transamination reaction that produces aspartate The enzyme that catalyzes this reaction is aspartate transaminase Asparagine is synthesized in most species by an ATP-dependent transfer of the amide nitrogen of glutamine to aspartate in a reaction catalysed by asparagine synthetase 10 5  9/22/24 11 Alanine, Valine, Leucine and Isoleucine Pyruvate is the amino group acceptor in the synthesis of alanine by a transamination reaction Pyruvate is also a precursor in the synthesis of the branched chain amino acids valine, leucine and isoleucine i. The first step in the branched chain pathway is the synthesis of α-ketobutyrate from threonine ii. Pyruvate combines with α-ketobutyrate in a series of three reactions leading to the branched chain intermediate α-keto-β-methylvalerate This intermediate is converted to isoleucine in a transamination reaction 12 6  9/22/24 Alanine, Valine, Leucine and Isoleucine iv) The same enzyme that catalyses the synthesis of α-keto-β- methylvalerate also catalyses the synthesis of α-ketoisovalerate by combining two molecules of pyruvate v) α-ketoisovalerate is converted directly to valine by valine transaminase vi) α-ketoisovalerate is converted to leucine via 4 reactions 13 Glutamate, Glutamine, Arginine and Proline You have already learnt that glutamate and glutamine are formed from the citric acid cycle intermediate, α-ketoglutarate The carbon atoms of proline and arginine also come from α-ketoglutarate , via glutamate Proline is synthesized from glutamate by a four-step pathway in which the 5-carboxylate group of glutamate is reduced to an aldehyde The glutamate 5-semialdehyde intermediate undergoes non-enzymatic cyclization to a Schiffs base, 5-carboxylate, that is reduced by a pyridine nucleotide coenzyme to produce proline 14 7  9/22/24 15 Serine, Glycine and Cysteine These three amino acids are derived from the glycolytic/gluconeogenic intermediate 3- phosphoglycerate 16 8  9/22/24 Serine, Glycine and Cysteine First, the secondary hydroxyl substituent of 3-phosphoglycerate is oxidized to a keto group, forming 3-phosphohydroxypyruvate This compound undergoes transamination with glutamate to form 3-phosphoserine and α-ketoglutarate Finally, 3-phosphoserine is hydrolysed to give serine and Pi 17 Biosynthesis of glycine Serine is a major source of glycine via a reversible reaction catalysed by serine hydroxymethyltransferase 18 9  9/22/24 The biosynthesis of cysteine from serine Occurs in two steps in bacteria and plants First an acetyl group from acetyl CoA is transferred to the β-hydroxyl substituent of serine forming O-acetylserine. Next sulphide, displaces the acetate group,and cysteine is formed 19 Biosynthesis of amino acids, showing the connections to glycolysis/gluconeogenesis and the citric acid cycle 20 10