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Reduction of Urease Activity by Interaction with the Flap Covering the Active Site

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† ∥ Department of Microbiology & Molecular Genetics, Biomedical Physical Sciences Building and Department of Biochemistry & Molecular Biology, Biomedical Physical Sciences Building, Michigan State University, Room 2215, 567 Wilson Road, East Lansing, Michigan 48824, United States
§ Department of Chemistry and Quantum Theory Project, University of Florida, 2328 New Physics Building, P.O. Box 118435, Gainesville, Florida 32611-8435, United States
Institute for Cyber Enabled Research and Department of Chemistry, Chemistry Building, Michigan State University, Room 283B, 578 South Shaw Lane, East Lansing, Michigan 48824, United States
*Phone: 517-355-9715, E-mail: [email protected]
Cite this: J. Chem. Inf. Model. 2015, 55, 2, 354–361
Publication Date (Web):January 16, 2015
https://doi.org/10.1021/ci500562t
Copyright © 2015 American Chemical Society

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    Abstract

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    With the increasing appreciation for the human microbiome coupled with the global rise of antibiotic resistant organisms, it is imperative that new methods be developed to specifically target pathogens. To that end, a novel computational approach was devised to identify compounds that reduce the activity of urease, a medically important enzyme of Helicobacter pylori, Proteus mirabilis, and many other microorganisms. Urease contains a flexible loop that covers its active site; Glide was used to identify small molecules predicted to lock this loop in an open conformation. These compounds were screened against the model urease from Klebsiella aerogenes, and the natural products epigallocatechin and quercetin were shown to inhibit at low and high micromolar concentrations, respectively. These molecules exhibit a strong time-dependent inactivation of urease that was not due to their oxygen sensitivity. Rather, these compounds appear to inactivate urease by reacting with a specific Cys residue located on the flexible loop. Substitution of this cysteine by alanine in the C319A variant increased the urease resistance to both epigallocatechin and quercetin, as predicted by the computational studies. Protein dynamics are integral to the function of many enzymes; thus, identification of compounds that lock an enzyme into a single conformation presents a useful approach to define potential inhibitors.

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