Genetic determinants of homocysteine thiolactonase activity in humans: implications for atherosclerosis

A metabolite of homocysteine (Hcy), the thioester Hcy thiolactone, damages proteins by modifying their lysine residues which may underlie Hcy-associat ed cardiovascular disease in humans. A protein component of high density li poprotein, Hcy thiolactonase (HTase) hydrolyzes thiolactone to Hcy. Thiolac tonase is a product of the polymorphic PON1 gene, also involved in detoxifi cation of organophospates and implicated in cardiovascular disease. Polymor phism in PON1 affects the detoxifying activity of PON1 in a substrate-depen dent manner. However, how PON1 polymorphism affects HTase activity is unkno wn. Here we report a strong association between the thiolactonase activity and PON1 genotype in human populations. High thiolactonase activity was ass ociated with L55 and R192 alleles, more frequent in blacks than in whites. Low thiolactonase activity was associated with M55 and Q192 alleles, more f requent in whites than in blacks. High thiolactonase activity afforded bett er protection against protein homocysteinylation than low thiolactonase act ivity. These results suggest that variations in HTase may play a role in Hc y-associated cardiovascular disease. (C) 2001 Federation of European Bioche mical Societies. Published by Elsevier Science B.V. All rights reserved.