HOMOCYSTEINE METABOLISM AND THE OXIDATIVE MODIFICATION OF PROTEINS AND LIPIDS

Altered homocysteine metabolism is implicated as a pathogenic factor i n atherogenesis, neoplasia, and aging. Hereditary enzymatic deficienci es and nutritional deficiencies of folate, pyridoxine, or cobalamin ar e associated with elevated blood homocysteine, accelerated atheroscler osis, and manifestations of aging. The failure of malignant cells to m etabolize homocysteine thiolactone to sulfate is attributed to deficie ncy of thioretinaco, a complex containing cobalamin, homocysteine thio lactone, and retinoic acid. The sulfhydryl group of homocysteine is be lieved to act catalytically with ferric or cupric ions in a mixed func tion oxidation system to generate hydrogen peroxide, oxygen radicals, and homocysteinyl radicals. These reactive species may interact with t he active site of enzyme protein to cause inactivation of catalytic ac tivity. Homocysteine thiolactone is oxidized to sulfate by a process i nvolving ascorbate, thioretinamide, and superoxide, under the control of thyroxine and growth hormone. Thioretinaco is believed to be the ac tive site of adenosine triphosphate (ATP) binding in oxidative phospho rylation with the participation of oxygen, ascorbate, proton gradient, and electron transport. Depletion of thioretinaco from mitochondrial and microsomal membranes may be associated with increased formation an d release of radical oxygen species within neoplastic and senescent ce lls. Specific proposals are made for investigating the importance of h omocysteine metabolism in the oxidative modification of proteins and l ipids.