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Homocysteine (left) and methionine (right) are related by demethylation and remethylation. Remethylation is a major step in the conversion of homocysteine to the essential amino acid methionine . The remethylation process involves the enzyme methionine synthase (MS), which requires vitamin B 12 as a cofactor, and also depends indirectly on ...
The production of homocysteine through transsulfuration allows the conversion of this intermediate to methionine, through a methylation reaction carried out by methionine synthase. The reverse pathway is present in several organisms, including humans, and involves the transfer of the thiol group from homocysteine to cysteine via a similar ...
In the body, homocysteine can be recycled into methionine or converted into cysteine with the aid of vitamin B 6, B 9, and B 12. [ 3 ] High levels of homocysteine in the blood ( hyperhomocysteinemia ) is regarded as a marker of cardiovascular disease, likely working through atherogenesis , which can result in ischemic injury .
Methylenetetrahydrofolate reductase (MTHFR) is the rate-limiting enzyme in the methyl cycle, and it is encoded by the MTHFR gene. [5] Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine.
MTHFR is the rate-limiting enzyme in the methyl cycle, which includes the conversion of homocysteine into methionine. Defects in variants of MTHFR can therefore lead to hyperhomocysteinemia. [9] There are two common variants of MTHFR deficiency. In the more significant of the two, the individual is homozygous for the 677T polymorphism.
The recovery of methionine from homocysteine by transmethylation is depicted in reaction 4. The transmethylation cycle is depicted in reactions 1–4. Transmethylation is a biologically important organic chemical reaction in which a methyl group is transferred from one compound to another.
In humans it is encoded by the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase). [5] [6] Methionine synthase forms part of the S-adenosylmethionine (SAMe) biosynthesis and regeneration cycle, [7] and is the enzyme responsible for linking the cycle to one-carbon metabolism via the folate cycle.
Betaine (N,N,N-trimethylglycine) is used to reduce concentrations of homocysteine by promoting the conversion of homocysteine back to methionine, i.e., increasing flux through the re-methylation pathway independent of folate derivatives (which is mainly active in the liver and in the kidneys). The re-formed methionine is then gradually removed ...