Over 25 years ago, McCully reported that elevated plasma homocyst (e) ine concentrations can cause atherosclerotic vascular disease (1). His postmortem analysis of several patients with elevated plasma homocyst (e) ine due to rare inborn errors of metabolism showed severe atherosclerosis. Abundant epidemiologic evidence has since confirmed McCully’s original hypothesis, with elevated plasma homocyst (e) ine concentrations conferring an independent, increased risk for coronary, cerebrovascular, and peripheral vascular atherosclerotic disease (2, 3).

Homocysteine is a sulfur-containing amino acid formed during the metabolism of methionine. Once synthesized, homocysteine may undergo remethylation to methionine in a reaction catalyzed by methylenetetrahydrofolate homocysteine methyltransferase (methionine synthetase), which uses methyltetrahydrofolate as a methyl donor and cobalamin as an essential cofactor (4). Alternatively, homocysteine can enter the transsulfuration pathway when cysteine synthesis is required or in the presence of excess methionine. In this pathway, homocysteine first condenses with serine to form cystathionine in a rate-limiting reaction catalyzed by cystathionine--synthase and requiring pyridoxal 5-phosphate; cystathionine--lyase then catalyzes the hydrolysis of cystathionine to yield-ketobutyrate and cysteine in another reaction requiring pyridoxal 5-phosphate.