Excess Homocysteine: A Key Factor In Cardiovascular Disease, Psychiatric Disorders, Cancer, Hip Fractures, And Alzheimer’s Disease
Homocysteine, a non-protein sulfur amino acid, is an intermediate product of the methionine cycle, also called the transulfuration methylation cycle (Figure 1) that closely links sulfur amino acid metabolism with key methylation reactions. Homocysteine is formed from the catabolism of S-adenosylmethionine or by the conversion of toxic homocysteine thiolactone to homocysteine by paraoxonase 1 (PON1), the same enzyme that detoxifies organophosphate pesticides. The clearance of homocysteine requires the presence of methyltetrahydrofolate, methylcobalamin, betaine, or pyridoxal-5-phosphate. Methylcobalamin is such a powerful methylating co-enzyme that it can methylate homocysteine directly to methionine without an associated enzyme.
Kilmer McCully was one of the first investigators to develop interest in the toxic effects of homocysteine as a major risk factor in atherosclerosis. After investigating cases of classic homocystinuria in patients who had abnormally increased of plasma total homocysteine and severe atherosclerosis even as a teenager, McCully began to investigate moderate elevations of homocysteine as a cause of atherosclerosis in a large section of the entire population. Individuals with the severe genetic deficiency of the enzyme cystathionine b-synthase had concentrations of total plasma homocysteine as high as 300 mmol/L. High homocysteine is also associated with other cardiovascular risk factors such as insulin resistance, metabolic syndrome, and type 2 diabetes mellitus. The optimum plasma homocysteine appears to be 6-7 micromoles/liter. The amino acid homocysteine has a sulfhydryl group that is hydrogenated (SH) while homocysteine in the oxidized state is bonded to another sulfhydryl group, either to another homocysteine in which the molecule is called homocystine or oxidized homocysteine or to the sulfhydryl group of another different protein or peptide (Figure 2). In the test performed at The Great Plains Laboratory, all forms of the molecule are converted to the reduced form with a free –SH group prior to quantitation.