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J Nutr. 2006 Jun;136(6 Suppl):1741S-1749S.

Pathophysiological consequences of homocysteine excess.

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  • Department of Microbiology & Molecular Genetics, UMDNJ-New Jersey Medical School, International Center for Public Health, Newark, NJ 07101, USA. jakubows@umdnj.edu


Elevated level of the nonprotein amino acid homocysteine (Hcy) is a risk factor for cardiovascular diseases, neurodegenerative diseases, and neural tube defects. However, it is not clear why excess Hcy is harmful. To explain Hcy toxicity, the "Hcy-thiolactone hypothesis" has been proposed. According to this hypothesis, metabolic conversion of Hcy to a chemically reactive metabolite, Hcy-thiolactone, catalyzed by methionyl-tRNA synthetase is the first step in a pathway that contributes to Hcy toxicity in humans. Plasma Hcy-thiolactone levels are elevated in human subjects with hyperhomocysteinemia caused by mutations in CBS or MTHFR genes. Plasma and urinary Hcy-thiolactone levels are also elevated in mice fed a high-methionine diet. Hcy-thiolactone can be detrimental because of its intrinsic ability to form N-Hcy-protein adducts, in which a carboxyl group of Hcy is N-linked to epsilon-amino group of a protein lysine residue. This article reviews recent studies of Hcy-thiolactone and N-Hcy-protein in the human body, including their roles in autoimmune response, cellular toxicity, and atherosclerosis. Potential utility of Hcy-thiolactone, N-Hcy-protein, or anti-N-Hcy-protein autoantibodies as markers of Hcy excess is discussed.

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