HUMAN HOMOCYSTEINE CATABOLISM - 3 MAJOR PATHWAYS AND THEIR RELEVANCE TO DEVELOPMENT OF ARTERIAL OCCLUSIVE DISEASE

Two separate metabolic pathways that methylate homocysteine to methion ine are known in humans, utilizing, respectively, 5-methyltetrahydrofo late and betaine as methyl donors, Deficiency of the folate-dependent methylation system is linked to hyperhomocysteinemia. Our data suggest that this deficiency leads to concurrent metabolic down-regulation of homocysteine transsulfuration that may contribute to hyperhomocystein emia. By contrast, no instances have been reported of hyperhomocystein emia resulting from deficiencies of betaine-dependent homocysteine met hylation. Long-term betaine supplementation of 10 patients, who had py ridoxine-resistant homocystinuria and gross hyperhomocysteinemia due t o deficiency of cystathionine beta-synthase activity, caused a substan tial lowering of plasma homocysteine, which has now been maintained fo r periods of up to 13 years. Betaine had to be taken regularly because the effect soon disappeared when treatment was stopped. In conclusion , depressed activity of the transsulfuration pathway may contribute to hyperhomocysteinemia because of primary deficiencies of enzymes of ei ther the transsulfuration or of the folate-dependent methylation pathw ays. Stimulation of betaine-dependent homocysteine remethylation cause s a commensurate decrease in plasma homocysteine that can be maintaine d as long as betaine is taken.