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Homocysteine, B vitamins, and risk of cardiovascular disease
  1. Desk F15, Department of Cardiology, The Cleveland Clinic Foundation
  2. 9500 Euclid Avenue, Cleveland, OH 44195, USA
  3. email:

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Homocysteine is a sulphur containing amino acid that plays an important role in methionine and folate metabolism.1 By receiving a methyl group from 5′-methyltetrahydrofolate, it is reconverted to methionine (fig 1), which is essential for many biochemical reactions critical to the formation of protein, nucleic acids, and creatinine. Reconversion of homocysteine to methionine also contributes to the maintenance of intracellular stores of tetrahydrofolate.

Figure 1

Pathways for the metabolism of homocysteine. Normal transsulfuration requires cystathionine β synthase with vitamin B6 as cofactor. Remethylation requires 5, 10-methylenetetrahydrofolate reductase and methionine synthase. The latter requires folate as cosubstrate and vitamin B12 (cobalamin) as cofactor. An alternative remethylation pathway also exists using the cobalamin independent betaine–homocysteine methyltransferase.

Homocysteine has become a target for many basic and clinical investigators because of a clinical syndrome described almost 40 years ago.2 ,3 The syndrome, homocystinuria, is an autosomal recessive disorder characterised by abnormalities of the long bones, ocular lens dislocation, mental retardation, and aggressive vascular disease, in particular venous thromboembolism. The underlying enzymological abnormality, a deficit of cystathionine β synthase, results in impairment of homocysteine transsulfuration. As a consequence, the concentrations of the amino acid in plasma may rise 20-fold from the normative range of 5–15 μmol/l. About 10 years after the discovery of homocystinuria it was hypothesised by McCully4 that high plasma homocysteine might be causally related to the vascular complications of the disease. In 1976, Wilcken and Wilcken5 studied patients without homocystinuria but with angiographically proved coronary artery disease. Using the methionine loading test, in which 0.1 mg/kg body weight of this amino acid is administered orally, they found that the prevalence of high circulating homocysteine concentrations, or hyperhomocysteinaemia, was higher than in normal controls. They concluded that people with a genetic susceptibility, namely carriers of the genetic mutation for cystathionine β synthase …

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