Methoxistasis: integrating the roles of homocysteine and folic acid in cardiovascular pathobiology

Abstract

Over the last four decades, abnormalities in the methionine-homocysteine cycle and associated folate metabolism have garnered great interest due to the reported link between hyperhomocysteinemia and human pathology, especially atherothrombotic cardiovascular disease. However, clinical trials of B-vitamin supplementation including high doses of folic acid have not demonstrated any benefit in preventing or treating cardiovascular disease. In addition to the fact that these clinical trials may have been shorter in duration than appropriate for modulating chronic disease states, it is likely that reduction of the blood homocysteine level may be an oversimplified approach to a complex biologic perturbation. The methionine-homocysteine cycle and folate metabolism regulate redox and methylation reactions and are, in turn, regulated by redox and methylation status. Under normal conditions, a normal redox-methylation balance, or "methoxistasis", exists, coordinated by the methionine-homocysteine cycle. An abnormal homocysteine level seen in pathologic states may reflect a disturbance of methoxistasis. We propose that future research should be targeted at estimating the deviation from methoxistasis and how best to restore it. This approach could lead to significant advances in preventing and treating cardiovascular diseases, including heart failure.

Figure 1

Methionine-homocysteine cycle is closely linked to redox balance, methylation, and sulfur amino-acid metabolism. Abbreviations: THF—tetrahydrofolate; 5MeTHF—5′ methyl tetrahydrofolate; BHMT—betaine homocysteine methyltransferase; DMG—dimethyl glycine; MS—methionine synthase; GNMT—glycine N-methyl transferase; CGL—cystathionine γ-lyase; and CBS—cystathionine β synthase.

Figure 2

Folate metabolism and methionine-homocysteine cycle. Abbreviations: DHFR—dighydrofolate reducatse; SHMT—serine hydroxymethyl transferase; MTHFR—methylene tetrahydrofolate reductase; MTHFD—N⁵,N¹⁰-methylene tetrahydrofolate dehydrogenase; MTHFC—N⁵,N¹⁰-methenyl tetrahydrofolate cyclohydrolase; FTHFS—Formyl tetrahydrofolate synthase; CBS—cystathionine beta synthase; TS—thymidylate synthase; UTP—deoxy uridine monophosphate; dTMP—deoxy thymidine monophosphate; SAM—S-adenosylmethionine; and SAH—S-adenosyl homocysteine.

Figure 3

Methoxistasis: the close interrelationship between redox status and methylation balance is disturbed in pathologic states.