Protein homocysteinylation: a new mechanism of atherogenesis?
An increased concentration of homocysteine is an important risk factor of atherosclerosis; however, the mechanism of the proatherogenic effect of this amino acid is not yet known. Studies performed during the last two decades suggest that the atherogenic effect of homocysteine may be accounted for by homocysteine thiolactone (HCTL). Homocysteine is nonspecifically activated by methionyl-tRNA synthetase; however, it is not transferred to tRNA and incorporated into proteins, but is transformed to a cyclic thioester, homocysteine thiolactone. HCTL is highly reactive and acylates free amino groups of protein lysine residues, the process referred to as protein N-homocysteinylation. Various plasma proteins are homocysteinylated in vitro and in vivo. Homocysteinylation results in the incorporation of additional thiol groups which may alter the physicochemical properties and biological activity of proteins. In particular, homocysteinylation of low-density lipoproteins (LDLs) increases their susceptibility to oxidation and accelerates their uptake by macrophages. In addition, homocysteinylated LDL elicit humoral immune response. Anti-homocysteinyllysine antibodies are detected in plasma of healthy humans and their titer is elevated in patients with ischemic heart disease or ischemic cerebral stroke. Homocysteine thiolactone is hydrolyzed to homocysteine by paraoxonase (PON), a calcium-dependent esterase synthesized in the liver and contained in plasma high-density lipoproteins (HDLs). Protein homocysteinylation may contribute to accelerated atherogenesis in individuals with hyperhomocysteinemia.
Bełtowski
Jerzy
J
Department of Pathophysiology, Medical University, Lublin, Poland. jerzy.beltowski@am.lublin.pl
D000818:Animals; D050197:Atherosclerosis / Q000503:physiopathology*; D006710:Homocysteine / Q000031:analogs & derivatives / Q000378:metabolism*; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism
D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D006710:Homocysteine; C007957:homocysteine thiolactone