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

Version 1

      Publication Details (including relevant citation   information):

    Macomber, L.; Minkara, M. S.; Hausinger, R.P.; Merz, K. M. Jr. Reduction of Urease Activity by Interaction with the Flap Covering Active Site.   Chem. Inf. Model. 2015, 55,   354-361.

      Abstract:

      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

      Address (URL): http://pubs.acs.org/doi/abs/10.1021/ci500562t