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posted 21. November 2004 06:40
PLoS Biology Published November 16, 2004
From a PLoS Primer
Exploiting Thiol Modifications
Patricia J. Kiley* , Gisela Storz
*To whom correspondence should be addressed. E-mail: pjkiley@wiscmail.wisc.edu
Abbreviations: H2O2, hydrogen peroxide; O2, molecular oxygen; O2−, superoxide; •OH, hydroxyl radical
DOI: 10.1371/journal.pbio.0020400
Copyright: © 2004 Kiley and Storz. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Citation: Kiley PJ, Storz G (2004) Exploiting Thiol Modifications. PLoS Biol 2(11): e400.
As the premier biological electron acceptor, molecular oxygen (O2) serves a vital role in fundamental cellular functions, including the process of aerobic respiration. Nevertheless, with the beneficial properties of O2 comes the inadvertent formation of reactive oxygen species, including superoxide (O−2), hydrogen peroxide (H2O2), and hydroxyl radical (•OH); these differ from O2 in having one, two, and three additional electrons, respectively (Figure 1). Cells also encounter elevated levels of these reactive oxygen species when they are released by animals, plants, and insects as a defense against detrimental organisms such as microbial pathogens. Reactive oxygen species can damage cells in many ways: by inactivating proteins, damaging nucleic acids, and altering the fatty acids of lipids, which leads in turn to perturbations in membrane structure and function. The accumulation of this oxidative damage underlies the formation of many disease states in humans. It is postulated that tissue injury by these reactive oxygen species accumulates over a long period of time and plays roles in the aging process and the development of heart disease, diabetes, chronic inflammatory diseases, cancer, and several neurodegenerative diseases (Halliwell 1999).
Many organisms have evolved strategies to remove reactive oxygen species and repair damage, which have enabled them to prosper from the tremendous oxidizing potential of O2 without succumbing to oxidative damage. Bacteria, yeast, and mammalian cells all induce the synthesis of global regulatory responses to survive oxidative insults. The consequences of oxidative stress and the corresponding defense responses have been extensively studied in Escherichia coli. For ease of study in the laboratory, the stress responses are often provoked by the external addition of chemical oxidants that specifically elevate the levels of reactive oxygen species within cells, or by the use of mutant strains that disrupt the normal “homeostatic mechanisms” for removing reactive oxygen species or the damage they do. While this primer focuses on a particular set of protective and regulatory protein modifications induced by oxidative stress in E. coli, it should be noted that many of the same mechanisms are present in other organisms; some specific examples from other species will also be described.
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Another component to the oxidative stress response is the reduction of oxidized thiols that arises through one of the mechanisms described below. The tripeptide glutathione and the thiol reductants glutaredoxin and thioredoxin are key to the restoration of thiols to their reduced state (SH) (Fernandes and Holmgren 2004). E. coli contains three glutaredoxins that utilize the reducing power of glutathione to catalyze the reduction of disulfide bonds (–S–S–) in the presence of NADPH and glutathione reductase. There are two thioredoxins in E. coli that also function to reduce disulfide bonds. Reduced thioredoxin is regenerated by thioredoxin reductase and NADPH. The fact that NADPH is required to maintain the reduced state of glutathione and thioredoxin indicates that the response to oxidative stress is coupled to the physiological status of core pathways that generate NADPH.
Regulatory Roles of Thiol Modifications
As mentioned above, proteins—in particular, the thiols of cysteines—are the major targets of H2O2. The reaction of cysteinyl thiolates with H2O2 can lead to the formation of different modifications, such as sulfenic acid (–SOH), sulfinic acid (–SO2H), and sulfonic acid (–SO3H), as well as disulfide bond formation (–S–S–) and glutathione conjugation (–S–GSH) (Jacob et al. 2004; Poole et al. 2004) (Figure 2). These modifications often alter the structure and function of the protein. Recent progress in this field points to a common chemistry in the reaction of H2O2 with thiolates through the initial formation of sulfenic acid. In the case of proteins that have a nearby cysteinyl residue, a disulfide bond forms between the two sulfur atoms. The sulfenated cysteinyl residue also can react with a cysteinyl residue on another protein or with glutathione, leading to a mixed disulfide. If no cysteinyl residue is nearby, the sulfenated cysteine can be further oxidized to sulfinic or sulfonic acid, or it can remain in the sulfenic acid state. All but the sulfinic and sulfonic acid modifications are readily reversible by reduction, using proteins such as thioredoxin or glutaredoxin; though sulfinic acid reductase activities have recently been identified in yeast and mammalian cells (denoted sulfiredoxin and sestrin, respectively) (Biteau et al. 2003; Budanov et al. 2004).
Read the Entire Primer at PloS Biology
[ 03. December 2004, 20:35: Message edited by: ISCID News Editor ]
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