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dc.contributor.authorBarta, Michael L.
dc.contributor.authorSkaff, D. Andrew
dc.contributor.authorMcWhorter, William J.
dc.contributor.authorHerdendorf, Timothy J.
dc.contributor.authorMiziorko, Henry M.
dc.contributor.authorGeisbrecht, Brian V.
dc.date.accessioned2016-09-16T16:23:34Z
dc.date.available2016-09-16T16:23:34Z
dc.date.issued2011-05-11
dc.identifier.citationBarta, M. L., Skaff, D. A., McWhorter, W. J., Herdendorf, T. J., Miziorko, H. M., & Geisbrecht, B. V. (2011). Crystal Structures of Staphylococcus epidermidis Mevalonate Diphosphate Decarboxylase Bound to Inhibitory Analogs Reveal New Insight into Substrate Binding and Catalysis. The Journal of Biological Chemistry, 286(27), 23900–23910. http://doi.org/10.1074/jbc.M111.242016en_US
dc.identifier.urihttp://hdl.handle.net/1808/21536
dc.description.abstractThe polyisoprenoid compound undecaprenyl phosphate is required for biosynthesis of cell wall peptidoglycans in Gram-positive bacteria, including pathogenic Enterococcus, Streptococcus, and Staphylococcus spp. In these organisms, the mevalonate pathway is used to produce the precursor isoprenoid, isopentenyl 5-diphosphate. Mevalonate diphosphate decarboxylase (MDD) catalyzes formation of isopentenyl 5-diphosphate in an ATP-dependent irreversible reaction and is therefore an attractive target for inhibitor development that could lead to new antimicrobial agents. To facilitate exploration of this possibility, we report the crystal structure of Staphylococcus epidermidis MDD (1.85 Å resolution) and, to the best of our knowledge, the first structures of liganded MDD. These structures include MDD bound to the mevalonate 5-diphosphate analogs diphosphoglycolyl proline (2.05 Å resolution) and 6-fluoromevalonate diphosphate (FMVAPP; 2.2 Å resolution). Comparison of these structures provides a physical basis for the significant differences in Ki values observed for these inhibitors. Inspection of enzyme/inhibitor structures identified the side chain of invariant Ser192 as making potential contributions to catalysis. Significantly, Ser → Ala substitution of this side chain decreases kcat by ∼103-fold, even though binding interactions between FMVAPP and this mutant are similar to those observed with wild type MDD, as judged by the 2.1 Å cocrystal structure of S192A with FMVAPP. Comparison of microbial MDD structures with those of mammalian counterparts reveals potential targets at the active site periphery that may be exploited to selectively target the microbial enzymes. These studies provide a structural basis for previous observations regarding the MDD mechanism and inform future work toward rational inhibitor design.en_US
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen_US
dc.rightsThis research was originally published in Journal of Biological Chemistry. Michael L. Barta,1, D. Andrew Skaff,1, William J. McWhorter, Timothy J. Herdendorf, Henry M. Miziorko and Brian V. Geisbrecht. Crystal Structures of Staphylococcus epidermidis Mevalonate Diphosphate Decarboxylase Bound to Inhibitory Analogs Reveal New Insight into Substrate Binding and Catalysis. Journal of Biological Chemistry. 2011; 286, 23900-23910. © the American Society for Biochemistry and Molecular Biology.en_US
dc.subjectEnzyme Catalysisen_US
dc.subjectEnzyme Inhibitorsen_US
dc.subjectEnzyme Mechanismsen_US
dc.subjectEnzyme Mutationen_US
dc.subjectEnzyme Structureen_US
dc.subjectEC 4.1.1.33en_US
dc.subjectGHMP Kinasesen_US
dc.subjectIsoprenoid Biosynthesisen_US
dc.subjectMevalonate 5-Diphosphate Decarboxylaseen_US
dc.subjectMevalonate Pathwayen_US
dc.titleCrystal Structures of Staphylococcus epidermidis Mevalonate Diphosphate Decarboxylase Bound to Inhibitory Analogs Reveal New Insight into Substrate Binding and Catalysisen_US
dc.typeArticleen_US
kusw.kuauthorBarta, Michael L.
kusw.kudepartmentHiguchi Biosciences Centeren_US
dc.identifier.doi10.1074/jbc.M111.242016en_US
kusw.oaversionScholarly/refereed, publisher versionen_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.rights.accessrightsopenAccess


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