New insights into the regulation of methyl group and homocysteine metabolism

Abstract

Hepatic folate, methyl group, and homocysteine metabolism are interrelated pathways that when disrupted are associated with numerous pathologies. Maintenance of normal methyl group and homocysteine homeostasis is dependent on the balance between: S-adenosylmethionine (SAM)-dependent transmethylation, which utilizes methyl groups and produces homocysteine; remethylation of homocysteine back to methionine by folate-dependent and -independent mechanisms; and homocysteine catabolism via the transsulfuration pathway. Recent studies have demonstrated that hormonal imbalance is a factor in the control of key proteins that regulate these pathways. A diabetic state is characterized by increased expression of specific methyltransferases that utilize SAM-derived methyl groups and produce homocysteine. Although the supply of methyl groups from the folate-dependent 1-carbon pool appears to be diminished under diabetic conditions, the increased production of homocysteine is compensated for by stimulation of folate-independent remethylation and catabolism by transsulfuration, resulting in hypohomocysteinemia. Similar changes have been observed with glucocorticoid administration and in a growth hormone-deficient model, which can be prevented by insulin and growth hormone treatment, respectively. Taken together, these reports clearly indicate that hormonal regulation is a major factor in the metabolic control of folate, methyl groups, and homocysteine, thereby providing a potential link between the pathologies associated with these pathways and hormonal imbalance.