{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["VanPelt J"],"funding":["NIH","NIGMS NIH HHS"],"pagination":["167150"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8453075"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["433(19)"],"pubmed_abstract":["The resistance of Gram-negative bacteria to β-lactam antibiotics stems mainly from β-lactamase proteins that hydrolytically deactivate the β-lactams. Of particular concern are the β-lactamases that can deactivate a class of β-lactams known as carbapenems. Carbapenems are among the few anti-infectives that can treat multi-drug resistant bacterial infections. Revealing the mechanisms of their deactivation by β-lactamases is a necessary step for preserving their therapeutic value. Here, we present NMR investigations of OXA-24/40, a carbapenem-hydrolyzing Class D β-lactamase (CHDL) expressed in the gram-negative pathogen, Acinetobacter baumannii. Using rapid data acquisition methods, we were able to study the \"real-time\" deactivation of the carbapenem known as doripenem by OXA-24/40. Our results indicate that OXA-24/40 has two deactivation mechanisms: canonical hydrolytic cleavage, and a distinct mechanism that produces a β-lactone product that has weak affinity for the OXA-24/40 active site. The mechanisms issue from distinct active site environments poised either for hydrolysis or β-lactone formation. Mutagenesis reveals that R261, a conserved active site arginine, stabilizes the active site environment enabling β-lactone formation. Our results have implications not only for OXA-24/40, but the larger family of CHDLs now challenging clinical settings on a global scale."],"journal":["Journal of molecular biology"],"pubmed_title":["Arginine Modulates Carbapenem Deactivation by OXA-24/40 in Acinetobacter baumannii."],"pmcid":["PMC8453075"],"funding_grant_id":["R01 GM123338"],"pubmed_authors":["Rose HA","Graney S","Kovrigina E","Leonard DA","Dempster K","Peng JW","VanPelt J","Graney E","Braynard S","Stoffel S","Staude MW"],"additional_accession":[]},"is_claimable":false,"name":"Arginine Modulates Carbapenem Deactivation by OXA-24/40 in Acinetobacter baumannii.","description":"The resistance of Gram-negative bacteria to β-lactam antibiotics stems mainly from β-lactamase proteins that hydrolytically deactivate the β-lactams. Of particular concern are the β-lactamases that can deactivate a class of β-lactams known as carbapenems. Carbapenems are among the few anti-infectives that can treat multi-drug resistant bacterial infections. Revealing the mechanisms of their deactivation by β-lactamases is a necessary step for preserving their therapeutic value. Here, we present NMR investigations of OXA-24/40, a carbapenem-hydrolyzing Class D β-lactamase (CHDL) expressed in the gram-negative pathogen, Acinetobacter baumannii. Using rapid data acquisition methods, we were able to study the \"real-time\" deactivation of the carbapenem known as doripenem by OXA-24/40. Our results indicate that OXA-24/40 has two deactivation mechanisms: canonical hydrolytic cleavage, and a distinct mechanism that produces a β-lactone product that has weak affinity for the OXA-24/40 active site. The mechanisms issue from distinct active site environments poised either for hydrolysis or β-lactone formation. Mutagenesis reveals that R261, a conserved active site arginine, stabilizes the active site environment enabling β-lactone formation. Our results have implications not only for OXA-24/40, but the larger family of CHDLs now challenging clinical settings on a global scale.","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 Sep","modification":"2026-05-08T11:29:39.846Z","creation":"2025-02-19T00:47:49.521Z"},"accession":"S-EPMC8453075","cross_references":{"pubmed":["34271009"],"doi":["10.1016/j.jmb.2021.167150"]}}