The molecular basis of homocysteine thiolactone-mediated vascular disease.
Accumulating evidence suggests that a metabolite of homocysteine (Hcy), the thioester Hcy-thiolactone, plays an important role in atherogenesis and thrombosis. Hcy-thiolactone levels are elevated in hyperhomocysteinemic humans and mice. The thioester chemistry of Hcy-thiolactone underlies its ability to form isopeptide bonds with protein lysine residues, which impairs or alters the protein's function. Protein targets for the modification by Hcy-thiolactone in human blood include fibrinogen, low-density lipoprotein, and high-density lipoprotein. Protein N-homocysteinylation leads to pathophysiological responses, including increased susceptibility to thrombogenesis caused by N-Hcy-fibrinogen, and an autoimmune response elicited by N-Hcy-proteins. Chronic activation of these responses in hyperhomocysteinemia over many years could lead to vascular disease. This article reviews recent evidence supporting the hypothesis that Hcy-thiolactone contributes to pathophysiological effects of Hcy on the vascular system.
Jakubowski
Hieronim
H
Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, International Center for Public Health, Newark, NJ 07101-1709, USA. jakubows@umdnj.edu
D005340:Fibrinogen / Q000378:metabolism; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D011506:Proteins / Q000378:metabolism; D014652:Vascular Diseases / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology
D011506:Proteins; D006710:Homocysteine; D005340:Fibrinogen; C007957:homocysteine thiolactone