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Cited by 289

The DOI matches its Crossref record; 157 of the 157 references it cites were found in a registry or an index.

Factors Affecting Protein Thiol Reactivity and Specificity in Peroxide Reduction

Ferrer-Sueta, Gerardo, Manta, Bruno, Botti, Horacio, Radi, Rafael, Trujillo, Madia, Denicola, Ana·2011·Chemical Research in Toxicology
DOI 10.1021/tx100413v
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Abstract

Protein thiol reactivity generally involves the nucleophilic attack of the thiolate on an electrophile. A low pK(a) means higher availability of the thiolate at neutral pH but often a lower nucleophilicity. Protein structural factors contribute to increasing the reactivity of the thiol in very specific reactions, but these factors do not provide an indiscriminate augmentation in general reactivity. Notably, reduction of hydroperoxides by the catalytic cysteine of peroxiredoxins can achieve extraordinary reaction rates relative to free cysteine. The discussion of this catalytic efficiency has centered in the stabilization of the thiolate as a way to increase nucleophilicity. Such stabilization originates from electrostatic and polar interactions of the catalytic cysteine with the protein environment. We propose that the set of interactions is better described as a means of stabilizing the anionic transition state of the reaction. The enhanced acidity of the critical cysteine is concurrent but not the cause of catalytic efficiency. Protein stabilization of the transition state is achieved by (a) a relatively static charge distribution around the cysteine that includes a conserved arginine and the N-terminus of an α-helix providing a cationic environment that stabilizes the reacting thiolate, the transition state, and also the anionic leaving group; (b) a dynamic set of polar interactions that stabilize the thiolate in the resting enzyme and contribute to restraining its reactivity in the absence of substrate; but upon peroxide binding these active/binding site groups switch interactions from thiolate to peroxide oxygens, simultaneously increasing the nucleophilicity of the attacking sulfur and facilitating the correct positioning of the substrate. The switching of polar interaction provides further acceleration and, importantly, confers specificity to the thiol reactivity. The extraordinary thiol reactivity and specificity toward H(2)O(2) combined with their ubiquity and abundance place peroxiredoxins, along with glutathione peroxidases, as obligate hydroperoxide cellular sensors.

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Metadata

Authors
Ferrer-Sueta, G., Manta, B., Botti, H., Radi, R., Trujillo, M., & Denicola, A.
Venue
Chemical Research in Toxicology
Publisher
American Chemical Society (ACS)
Published
2011-03-10
Volume
24
Issue
4
Pages
434-450
ISSN
  • 0893-228X (ISSN-L)
  • 1520-5010
DOI
10.1021/tx100413v
OpenAlex
W1998294214
Cited by
289
References
157
FWCI
8.23
Type
journal article
Language
en
Open access
closed

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