Published In

Proceedings of the National Academy of Sciences

Document Type

Article

Publication Date

1-12-2010

Subjects

Oxidation, Homocysteine, Thiyl radicals

Abstract

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.

Description

Copyright 2013 National Academy of Sciences. This article contains supporting information online at http://www.pnas.org/cgi/content/full/0909737107/DCSupplemental

DOI

10.1073/pnas.0909737107

Persistent Identifier

http://archives.pdx.edu/ds/psu/9580

Included in

Chemistry Commons

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