Protein N-homocysteinylation: implications for atherosclerosis.
Elevated levels of homocysteine (Hcy) are associated with various human pathologies, including cardiovascular disease. However, it is not exactly known why Hcy is harmful. A plausible hypothesis is that the indirect incorporation of Hcy into protein, referred to as protein N-homocysteinylation, leads to cell damage. A translational pathway involves: 1) reversible S-nitrosylation of Hcy with nitric oxide produced by nitric oxide synthase; 2) aminoacylation of tRNAMet with S-nitroso-Hcy catalyzed by MetRS; and 3) transfer of S-nitroso-Hcy from S-nitroso-Hcy-tRNAMet into growing polypeptide chains at positions normally occupied by methionine. Subsequent transnitrosylation leaves Hcy in the protein chain. A post-translational pathway involves: 1) metabolic conversion of Hcy to thiolactone by methionyl-tRNAsynthetase (MetRS), and 2) acylation of protein lysine residues by Hcy thiolactone. The levels of Hcy thiolactone and N-homocysteinylated protein in human vascular endothelial cells depend on the ratio of Hcy/Met, levels of folic acid, and HDL, factors linked to cardiovascular disease. HDL-associated human serum Hcy thiolactonase/paraoxonase hydrolyzes thiolactone to Hcy, thereby minimizing protein N-homocysteinylation. Variations in Hcy thiolactonase may play an important role in Hcy-associated human cardiovascular disease.
Jakubowski
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Department of Microbiology & Molecular Genetics, UMDNJ-New Jersey Medical School, Newark 07103, USA. jakubows@umdnj.edu
D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000209:etiology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000378:metabolism*; D006801:Humans; D008715:Methionine / Q000378:metabolism; D008954:Models, Biological; D011506:Proteins / Q000378:metabolism*
D011506:Proteins; D006710:Homocysteine; C079202:S-nitrosohomocysteine; D008715:Methionine; C007957:homocysteine thiolactone