Molecular basis of homocysteine toxicity in humans.
Because of its similarity to the protein amino acid methionine, homocysteine (Hcy) can enter the protein biosynthetic apparatus. However, Hcy cannot complete the protein biosynthetic pathway and is edited by the conversion to Hcy-thiolactone, a reaction catalyzed by methionyl-transfer RNA synthetase in all organisms investigated, including human. Nitrosylation converts Hcy into a methionine analogue, S-nitroso-Hcy, which can substitute for methionine in protein synthesis in biological systems, including cultured human endothelial cells. In humans, Hcy-thiolactone modifies proteins posttranslationally by forming adducts in which Hcy is linked by amide bonds to epsilon-amino group of protein lysine residues (Hcy-epsilonN-Lys-protein). Levels of Hcy bound by amide or peptide linkages (Hcy-N-protein) in human plasma proteins are directly related to plasma 'total Hcy' levels. Hcy-N-hemoglobin and Hcy-N-albumin constitute a major pool of Hcy in human blood, larger than 'total Hcy' pool. Hcy-thiolactone and Hcy-thiolactone-hydrolyzing enzyme, a product of the PON1 gene, are present in human plasma. Modification with Hcy-thiolactone leads to protein damage and induces immune response. Autoantibodies that specifically recognize the Hcy-epsilonN-Lys-epitope on Hcy-thiolactone-modified proteins occur in humans. The ability of Hcy to interfere with protein biosynthesis, which causes protein damage, induces cell death and elicits immune response, is likely to contribute to the pathology of human disease.
Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, International Center for Public Health, 225 Warren Street, Newark, New Jersey 07101, USA. jakubows@umdnj.edu
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D006710:Homocysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000502:physiology / Q000633:toxicity*; D006801:Humans; D011506:Proteins / Q000737:chemistry
D011506:Proteins; D006710:Homocysteine; C079202:S-nitrosohomocysteine; C007957:homocysteine thiolactone