Homocysteine is a non-proteogenic amino acid synthesized intracellularly by removal of the N-methyl group from the essential amino acid methionine. Homocysteine is exported from cells into the blood, where it exists mainly as an oxidized disulfide species, either as a dimer or bound to cysteine residues of serum proteins. The reduced form of homocysteine ('free' homocysteine) can be metabolized into cysteine via the transsulfuration pathway; however, it can also undergo intramolecular cyclization, forming the highly reactive pro-oxidant homocysteine thiolactone. Subsequent N-homocysteinylation of protein lysine residues by the reactive thiolactone disrupts protein conformation, leading to formation of cytotoxic protein aggregates. Homocysteinylated proteins may also act as autoantigens, triggering arterial inflammation and atherosclerosis. Elevated plasma homocysteine concentration is a clinical biomarker for increased risk of cardiovascular disease, ischemic stroke and myocardial infarction. Severely elevated homocysteine levels (hyperhomocysteinemia) are correlated with a 4-fold increase in mortality due to heart attack and a 16-fold increase in the likelihood of recurrent stroke.