Homocysteine in the Pathogenesis of Chronic Glaucoma

1.1 Metabolic pathway Methionine is one of four amino acids that form succinyl CoA. This sulphur containing amino acid is the source of homocysteine (Hcy). It is converted to S-adenosylmethionine (SAM), the major methyl-group donor in one–carbon metabolism. The synthesis of SAM occurs when methionine condenses with adenosine triphosphate (ATP) by the hydrolysis of all three phosphate bonds. The methyl group attached to the tertiary group in SAM is activated and can be transferred to a variety of acceptor molecules, such as noradrenaline in the synthesis of adrenaline. The reaction product S-adenosylhomocysteine (SAH) is a simple thioether, analogous to methionine. The resulting loss of free energy accompanying the reaction makes the methyl transfer essentially irreversible. Next is the hydrolysis of SAH to Hcy and adenosine. Homocysteine has two fates. If there is a deficiency of methionine, Hcy may be re-methylated to methionine. If stores of methionine are adequate, Hcy may enter the trans-sulphuration pathway, where it is converted to cysteine. The re-synthesis of methionine occurs with the acceptance of a methyl group from N5-methyltetrahydrofolate (N5-methyl-THF) in a reaction that requires methyl-cobalamin, a coenzyme derived from cobalamin (vitamin B12). The methyl group is transferred from the B12 derivative to Hcy, and vitamin B12 is recharged from N5-methyl-THF. The synthesis of cysteine occurs when Hcy combines with serine, forming cystathionine, which is hydrolysed to α ketobutyrate and cysteine. This sequence has the net effect of converting serine to cysteine and Hcy to α ketobutyrate, which is oxidatively decarboxylated to form propionyl CoA. Because Hcy is synthesised from the essential amino acid methionine, cysteine is not an essential amino acid so long as methionine is available (Figure 1). Under normal metabolic circumstances, there is a strict balance between Hcy formation and elimination. Usually about 50% of the Hcy formed is re-methylated to methionine. When protein or methionine intake is in excess, the trans-sulfuration pathway catabolises a larger proportion. If there is an increased formation of Hcy relative to its consumption, Hcy is excreted from the cells. This can be detected as an increased level of Hcy in plasma/serum or in the urine.