Unravelling the mechanism of intracellular oxidation of thiols by (N‐Cl)‐Taurine1. (5th August 2013)

• Record Type: Journal Article
• Authors: Fernández, M. I.; García, M. V.; Armesto, X. L.; Canle López, M.; Arturo Santaballa, J.; Page, Michael I.
• Is Part Of: Journal of physical organic chemistry. Volume 26:Number 12(2013:Dec.)
• Page Start: 1098
• Page End: 1104
• Publication Date: 2013-08-05
• Subjects: Chemistry, Physical organic -- Periodicals; 547.1
• DOI: 10.1002/poc.3181
• Languages: English
• ISSNs: 0894-3230

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Myeloperoxidase, a heme enzyme stored in high amounts in neutrophils and monocytes, produces <named-content id="d307e525" content-type="chemicalTechnology" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">reactive oxygen species</named-content> that are involved in the innate mammalian response to infection; among these, the most reactive is HOCl, generated by oxidation of Cl<sup>−</sup> in the presence of H<sub>2</sub>O<sub>2</sub>. This powerful oxidant reacts very fast with protein side chains and peptide bonds. Taurine (<sup>−</sup>O<sub>3</sub>SCH<sub>2</sub>CH<sub>2</sub>NH<sub>3</sub><sup>+</sup>), present in high concentrations in human neutrophils, traps the HOCl to yield (<italic>N</italic>‐Cl)‐Taurine, much less toxic and reactive; it is a long‐lived oxidant which contributes to the killing of pathogenic organisms and plays a role in the inflammatory response. Kinetic data suggest that (<italic>N</italic>‐Cl)‐Tau reacts with cysteine and glutathione, two relevant thiols in mammals, <italic>via</italic> two pathways: direct oxidation (<named-content id="d307e574" content-type="reactionType" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">chlorination</named-content>) of the thiolate by (<italic>N</italic>‐Cl)‐Tau involving general‐acid <named-content id="d307e584" content-type="reactionType" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">catalysis</named-content>, and, the major one, (<italic>N</italic>‐Cl)‐Tau <named-content id="d307e590" content-type="reactionType" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">hydrolysis</named-content> followed by fast chlorine transfer from the so‐formed HOCl/ClO<sup>−</sup> mixture to the corresponding thiolate, despite the highly unfavorable <named-content id="d307e603" content-type="reactionType" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">hydrolysis</named-content> equilibrium (K<sub>H</sub> =10<sup>−8</sup>M). Scavenging of HOCl by strong nucleophiles like thiolates opens an effective reactive channel. Theoretical calculations, at the B3LYP/6‐311++G(d, p) level of theory and using the SMD model to simulate aqueous salvation, agree with the experimental behavior, predicting that both the chlorine and the proton are almost half transferred at the transition state in the direct, general‐acid catalyzed, <named-content id="d307e616" content-type="reactionType" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">chlorination</named-content> of the thiolate by (<italic>N</italic>‐Cl)‐Tau. Under physiological conditions, the <named-content id="d307e625" content-type="reactionType" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">hydrolysis</named-content> of (<italic>N</italic>‐Cl)‐Tau is the main responsible of the oxidation of intracellular thiols far away from the site of HOCl enzymatic production. Copyright © 2013 John Wiley & Sons, Ltd.</p> </abstract>