Homocysteine: Overview of Biochemistry, Molecular Biology, and Role in Disease Processes

ABSTRACT

Homocysteine is derived from the essential amino acid methionine and plays a vital role in cellular homeostasis in man. Homocysteine levels depend on its synthesis, involving methionine adenosyltransferase, S-adenosylmethionine-dependent methyltransferases such as glycine N-methyltransferase, and S-adenosylhomocysteine hydrolase; its remethylation to methionine by methionine synthase, which requires methionine synthase reductase, vitamin B₁₂, and 5-methyltetrahydrofolate produced by methylenetetrahydrofolate reductase or betaine methyltransferase; and its degradation by transsulfuration involving cystathionine β-synthase. The control of homocysteine metabolism involves changes of tissue content or inherent kinetic properties of the enzymes. In particular, S-adenosylmethionine acts as a switch between remethylation and transsulfuration through its allosteric inhibition of methylenetetrahydrofolate reductase and activation of cystathionine β-synthase. Mutant alleles of genes for these enzymes can lead to severe loss of function and varying severity of disease. Several defects lead to severe hyperhomocysteinemia, the most common form being cystathionine β-synthase deficiency, with more than a hundred reported mutations. Less severe elevations of plasma homocysteine are caused by folate and vitamin B₁₂ deficiency, and renal disease and moderate hyperhomocysteinemia are associated with several common disease states such as cardiovascular disease. Homocysteine toxicity is likely direct or caused by disturbed levels of associated metabolites; for example, methylation reactions through elevated S-adenosylhomocysteine.

KEYWORDS

Homocysteine - enzymes - genes - inherited metabolic disorder - S-adenosylmethionine

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