Synchrotron Radiation Provides a Plausible Explanation for the Generation of a Free Radical Adduct of Thioxolone in Mutant Carbonic Anhydrase II |
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Authors: | Sippel Katherine H Genis Caroli Govindasamy Lakshmanan Agbandje-McKenna Mavis Kiddle James J Tripp Brian C McKenna Robert |
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Affiliation: | Department of Biochemistry and Molecular Biology, P.O. Box 100245, College of Medicine, University of Florida, Gainesville, Florida 32610. |
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Abstract: | Thioxolone acts as a prodrug in the presence of carbonic anhydrase II (CA II), whereby the molecule is cleaved by thioester hydrolysis to the carbonic anhydrase inhibitor, 4-mercaptobenzene-1,3-diol (TH0). Thioxolone was soaked into the proton transfer mutant H64A of CA II in an effort to capture a reaction intermediate via X-ray crystallography. Structure determination of the 1.2 ? resolution data revealed the TH0 had been modified to a 4,4'-disulfanediyldibenzene-1,3-diol, a product of crystallization conditions, and a zinc ligated 2,4-dihydroxybenzenesulfenic acid, most likely induced by radiation damage. Neither ligand was likely a result of an enzymatic mechanism. |
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