Mona Minkara - Inhibition of Urease by Modification of a Cysteinyl Residue in the Flap Covering the Active Site

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      Publication Details (including relevant citation   information):

      Macomber, L.; Minkara, M. S.;   Hausinger, R. P.; Merz, K. M. Jr. “Inhibition of Urease by   Modification of a Cysteinyl Residue in the Flap Covering the   Active Site” Chem. Inf. Model, submitted for   publication.


        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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