2021
DOI: 10.1016/j.jbc.2021.100799
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Local interactions with the Glu166 base and the conformation of an active site loop play key roles in carbapenem hydrolysis by the KPC-2 β-lactamase

Abstract: This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, a… Show more

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Cited by 16 publications
(19 citation statements)
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References 63 publications
(122 reference statements)
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“…Of the three distinct rotamers for the carbapenem 6α-1R-hydroxyethyl group, only position II allows the polar component (the hydroxyl group) to point out of the binding site, leading to lower reaction barriers. Position II is observed, both in Xray structures and during our QM/MM MD calculations, only for carbapenem complexes of carbapenem-hydrolyzing enzymes 38,56 .…”
Section: Discussionmentioning
confidence: 78%
See 1 more Smart Citation
“…Of the three distinct rotamers for the carbapenem 6α-1R-hydroxyethyl group, only position II allows the polar component (the hydroxyl group) to point out of the binding site, leading to lower reaction barriers. Position II is observed, both in Xray structures and during our QM/MM MD calculations, only for carbapenem complexes of carbapenem-hydrolyzing enzymes 38,56 .…”
Section: Discussionmentioning
confidence: 78%
“…Identification of factors contributing to carbapenemase activity may facilitate understanding of the basis for resistance mediated by such enzymes, and so provide a basis for antibiotic (re)design in order to overcome this growing clinical problem. Crystal structures in the PDB 38,43,46,[56][57][58][59][60] provide insight into active site interactions in the acyl-enzyme state, but the details of why some enzymes are able to efficiently hydrolyze carbapenems, rather than forming stable acyl-enzymes, are unclear. Answering this question requires analysis of reactivity of the acyl-enzymes.…”
Section: Discussionmentioning
confidence: 99%
“…Position II is observed, both in X-ray structures and during our QM/MM MD calculations, only for carbapenem complexes of carbapenem-hydrolyzing enzymes. 38,57 We further note the possibility that elimination of the hydroxyethyl group may, under some circumstances, occur on reaction with class A betalactamases. This would diminish the unfavorable hydroxyethyl-DW interactions seen in carbapenem-inhibited enzymes; although it has not been widely reported and is yet to be observed crystallographically.…”
Section: ■ Discussionmentioning
confidence: 97%
“…Identification of factors contributing to carbapenemase activity may facilitate understanding of the basis for resistance mediated by such enzymes, and, therefore, provide a basis for antibiotic (re)­design in order to overcome this growing clinical problem. Crystal structures in the PDB ,,, provide insight into active site interactions in the acyl-enzyme state, but the details of why some enzymes are able to efficiently hydrolyze carbapenems, rather than forming stable acyl-enzymes, are unclear. Answering this question requires an analysis of the reactivity of the acyl-enzymes.…”
Section: Discussionmentioning
confidence: 99%
“…The Glu316Gln lost the CtpA activity, while the Glu316Asp remained active, suggesting that carboxyl group on the side chain at this position is important to maintain the CtpA activity [ 72 ]. In the analyses of β-lactamase and Prc/Tsp, which are hydrolases belong to the same catalytic mechanism group, mutations at Glu166 of β-lactamase and Asp441 of Tsp, indicated similar behavior in each activity [ 76 , 77 ]. The catalytic involvement of these acidic residues near the catalytic dyads is still under debate and continuous consideration of the catalytic mechanism needed.…”
Section: Enzyme Involved In the D1 Processingmentioning
confidence: 99%