title: Pathophysiological consequences of homocysteine excess.
abstract: 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.
authors.affiliation: Department of Microbiology & Molecular Genetics, UMDNJ-New Jersey Medical School, International Center for Public Health, Newark, NJ 07101, USA. jakubows@umdnj.edu
authors.forename: Hieronim
authors.initials: H
authors.lastname: Jakubowski
mesh_terms: D001323:Autoantibodies / Q000276:immunology; D001798:Blood Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D016923:Cell Death; D004032:Diet; D004721:Endoplasmic Reticulum / Q000187:drug effects; D006710:Homocysteine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications* / Q000503:physiopathology*; D008239:Lysine / Q000378:metabolism; D008715:Methionine / Q000008:administration & dosage; D011485:Protein Binding
chemical_list: D001323:Autoantibodies; D001798:Blood Proteins; D006710:Homocysteine; D008715:Methionine; C007957:homocysteine thiolactone; D008239:Lysine