Figure 1.

Homocysteine metabolism: methionine – folate cycle and the folate shuttle Hcy is an intermediate metabolic product of methionine metabolism. Once methionine is demethylated, producing Hcy it can be further catabolized to cystathionine and cysteine via the transsulfuration pathway. This transsulfuration pathway is dependent on the cystathionine beta synthase enzyme (CBS) and vitamin B₆. Human vascular cells lack the CBS enzyme and therefore the transsulfuration pathway is not present. In the remethylation cycle termed the Methionine – Folate Cycle, folic acid (folate) serves as the methyl donor to convert Hcy to Methionine. This reaction is dependent on the Methionine Synthase (MS) enzyme and the cofactor vitamin B₁₂. Folate serves not only as a methyl donor but also as hydrogen and an electron donor. This hydrogen and electron donation capability renders folate as a dual source for stabilization of the tetrahydrobiopterin (BH₄) Cofactor of the endothelial nitric oxide synthase (eNOS) reaction producing the quintessential endothelial nitric oxide (eNO) and the additional function of being a local endothelial microenvironment antioxidant. These findings have led to the hypothesis of a Folate Shuttle phenomenon. As can be seen there may exist a relative endogenous endothelial folate deficiency resulting in a toxic effect of Hcy accumulation within endothelial cells as a result of this Folate Shuttle.