期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：2
页码：551-554
DOI：10.1073/pnas.0909737107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Elevated levels of homocysteine are associated with several major diseases. However, it is not clear whether homocysteine is a marker or a causative agent. The majority (ca. 80%) of the homocysteine present in humans is protein bound. The study of the posttranslational modification of proteins by homocysteine and its cyclic congener, homocysteine thiolactone, is emerging as an area of great current interest for unraveling the ongoing "mediator/marker controversy" [Jacobsen DW (2009) Clin Chem 55:1-2]. Interestingly, many of the pathologies associated with homocysteine are also linked to oxidative stress. In the current study, chemical evidence for a causal relationship between homocysteine-bound proteins and oxidative damage is presented. For example, a reproducible increase in protein carbonyl functionality occurs as a consequence of the reaction of human serum albumin with homocysteine thiolactone. This occurs at physiological temperature upon exposure to air without any added oxidants or free-radical initiators. Alpha-amino acid carbon-centered radicals, well-known precursors of protein carbonyls, are shown to form via a hydrogen atom transfer process involving thiolactone-derived homocystamides. Model peptides in buffer as well as native proteins in human blood plasma additionally exhibit properties in keeping with the homocystamide-facilitated hydrogen atom transfer and resultant carbon-centered radicals.
