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 tRNA^Met with S-nitroso-Hcy catalyzed by MetRS; and 3) transfer of S-nitroso-Hcy from S-nitroso-Hcy-tRNA^Met 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-tRNA synthetase (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.