Protein homocysteinylation: possible mechanism underlying pathological consequences of elevated homocysteine levels

被引:333
作者
Jakubowski, H [1 ]
机构
[1] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Microbiol & Mol Genet, Newark, NJ 07103 USA
关键词
homocysteine thiolactone; atherosclerosis;
D O I
10.1096/fasebj.13.15.2277
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Homocysteine thiolactone, a cyclic thioester, is synthesized by certain aminoacyl-tRNA synthetases in editing or proofreading reactions that prevent translational incorporation of homocysteine into proteins. Although homocysteine thiolactone is expected to acylate amino groups in proteins, virtually nothing is known regarding reactivity of the thiolactone. Here it is shown that reactions of the thiolactone with protein lysine residues were robust under physiological conditions. In human serum incubated with homocysteine thiolactone, protein homocysteinylation was a major reaction that could be observed with as little as 10 nM thiolactone, Individual proteins were homocysteinylated at rates proportional to their lysine contents. Homocysteinylation led to protein damage, manifested as multimerization and precipitation of extensively modified proteins. Model enzymes, such as methionyl-tRNA synthetase and trypsin, were inactivated by homocysteinylation, Metabolic conversion of homocysteine to the thiolactone, protein homocysteinylation, and resulting protein damage may underlie involvement of Hey in the pathology of vascular disease.
引用
收藏
页码:2277 / 2283
页数:7
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