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Computational design of effective, bioinspired HOCl antioxidants: The role of intramolecular Cl+ and H+ shifts
journal contribution
posted on 2023-05-17, 18:13 authored by Karton, A, O'Reilly, RJ, Pattison, DI, Davies, MJ, Radom, LThe enzyme myeloperoxidase generates significant amounts of hypochlorous acid (HOCl) at sites of inflammation to inflict oxidative damage upon invading pathogens. However, excessive production of this potent oxidant is associated with numerous inflammatory diseases. Recent kinetic measurements suggest that the endogenous antioxidant carnosine is an effective HOCl scavenger. On the basis of computational modeling, we suggest a possible mechanism for this antioxidant activity. We find that a unique structural relationship between three adjacent functional groups (imidazole, carboxylic acid, and terminal amine) enables an intramolecular chlorine transfer to occur. In particular, two sequential proton shifts are coupled with a Cl+ shift converting the kinetically favored product (chlorinated at the imidazole nitrogen) into the thermodynamically favored product (chlorinated at the terminal amine) effectively trapping the chlorine. We proceed to design systems that share similar structural features to those of carnosine but with even greater HOCl-scavenging capabilities.
History
Publication title
Journal of the American Chemical SocietyVolume
134Issue
46Pagination
19240-19245ISSN
0002-7863Department/School
School of Natural SciencesPublisher
American Chemical SocietyPlace of publication
1155 16Th St, Nw, Washington, USA, Dc, 20036Rights statement
Copyright 2012 American Chemical SocietyRepository Status
- Restricted