The essential (indispensable) amino acids must be supplied in the diet because their carbon skeletons cannot be synthesized in the human body, whereas the nonessential amino acids can be synthesized from common intermediates of the central metabolic pathways within the cell (i.e., glycolysis, the pentose phosphate pathway and the TCA cycle). As long as the keto-analogs are present, almost all amino acids can be generated by the process of transamination. The exceptions are threonine and lysine. Threonine is a poor substrate for mammalian transaminase enzymes, whereas the keto-analog of lysine, a-oxo-e-aminocaproate, is unstable and cyclizes spontaneously to pipecolic acid.
Glutamic acid, glutamine, proline, and arginine
Glutamic acid is synthesized by transamination of 2-oxoglutarate, a TCA cycle intermediate. This reaction represents the first stage in the catabolism of many other amino acids, particularly the branched-chain amino acids. Vitamin B6 is a cofactor for all transamination (aminotransferase) reactions. Gluta-mine is made from glutamic acid and ammonium in an energy-requiring reaction catalyzed by glutamine synthetase. The synthesis of glutamine plays an important role in the removal of the ammonium glutamate phosphate glutamic-p-semialdehyde —»- A1-pyrroline-5-carboxylat^ —proline
N-acetyl N-acetyl N-acetyl N-acetyl ithi glutamate p-glutamyl phosphate glutamic-p-semialdehyde ornithine orni ine arginine
Figure 2 Synthesis and catabolism of proline and arginine. Solid lines indicate biosynthetic pathways; broken lines indicate catabolic pathways.
formed in peripheral tissues by deamination of amino acids as it is transported to the liver and used for urea synthesis.
Glutamic acid can be phosphorylated to 7-gluta-myl phosphate by ATP, and this can then be dephosphorylated to glutamic-7-semialdehyde. This undergoes nonenzymic cyclization to A1-pyroline-5-carboxylate, which can then be reduced to proline (Figure 2).
Arginine is made from ornithine via the reactions of the urea cycle. Ornithine can theoretically be made by transamination of glutamic-7-semialdehyde, but as mentioned previously this cyclizes spontaneously to pyroline-5-carboxylate. Thus, in practice glutamate is first acetylated by acetyl CoA to N-acetyl glutamate so that when this is converted to N-acetyl glutamic-7-semialdehyde the amino group is blocked and cannot cyclize. The N-acetyl glutamic-7-semialdehyde is then transaminated to N-acetyl ornithine, and this is deacetylated to ornithine (Figure 2).
Aspartic acid and asparagine Aspartic acid is derived from transamination of oxaloacetic acid, a TCA cycle intermediate. As with glutamic acid synthesis, this represents a common mechanism for removing amino groups from many other amino acids. Asparagine is made from aspartic acid by transfer of the amide group from glutamine.
Alanine Alanine is made by transamination of pyruvic acid, which is generated by glycolysis.
Serine and glycine Serine and glycine are readily interconvertible via methylene tetrahydrofolate, which either condenses with a glycine molecule to yield serine or is cleaved to yield glycine and tetrahydrofolate (Figure 3). However, there are also separate biosynthetic pathways for both molecules. Glycine can be synthesized by transamination of glyoxylate, which arises from the pentose phosphate pathway. Serine can be made by dephosphorylation of 3-phosphoserine, which is made by sequential dehydrogenation and transamination of 3-phospho-glycerate, a glycolytic intermediate (Figure 3).
Histidine Histidine is synthesized by a relatively long pathway that has no branch points and does not lead to the formation of any other important intermediates. The main precursors are phosphori-bosyl pyrophosphate and ATP, with the a-amino group arising by transamination from glutamate (Figure 4).
Cysteine In man and other animals, cysteine can only be synthesized from the essential amino acid methionine. Methionine reacts with ATP to form S-adenosylmethionine, an important methylating agent within the cell. Transfer of the methyl group results in the formation of S-adenosylhomocysteine, which is then converted to homocysteine. Homocys-teine can condense with serine to form cystathio-nine, which is then cleaved by cystathionase to yield cysteine (Figure 5).
An alternative fate for homocysteine is remethyla-tion to methionine. The methyl donor for this reaction can be either methyltetrahydrofolate, in a
3-phosphoglycerate glyoxylate 3-hydroxyphosphoglycerate
THF glycine r glycine « * methylene THF serine t T
2-oxopropanol 2-amino-3-oxobutyrate ; +
Figure 3 Synthesis and catabolism of glycine, serine, and threonine. Solid lines indicate biosynthetic pathways; broken lines indicate catabolic pathways. THF, tetrahydrofolate.
urocanic acid T
4-imidazolone-5-propionic acid T
formiminoglutamic acid T
Figure 4 Synthesis and catabolism of histidine. Solid lines indicate biosynthetic pathways; broken lines indicate catabolic pathways.
S-adenosylmethionine —- *-*- S-adenosylhomocysteine reaction for which vitamin B12 is a cofactor, or betaine. Remethylation seems to be quite sensitive to folate status, and plasma homocysteine is becoming accepted as a biomarker of nutritional status with respect to folate.
Homocystinuria is an important inborn error of metabolism that is caused by impaired activity of cystathionine synthetase, the enzyme that catalyzes the condensation of homocysteine with serine. One of the consequences of homocystinuria is premature cardiovascular disease. There is considerable evidence that milder elevations of plasma homocys-teine, caused by poorly active variants of the methylenetetrahydrofolate reductase enzyme (which is required to make the methyl donor methyltetrahy-drofolate) or by low folic acid status, may be an important risk factor for cadiovascular disease throughout the population.
Tyrosine In mammals, including man, tyrosine can only be formed by hydroxylation of the essential amino acid phenylalanine. The inborn error of metabolism phenylketonuria is caused by a failure of the enzyme phenylalanine hydroxylase.
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