| Structural highlights
Function
BLC10_KLEAE Class C beta-lactamase which confers resistance to penicillins and cephalosporins (PubMed:15383166). Has benzylpenicillin-, ceftazidime-, nitrocefin- and imipenem-hydrolyzing activity (PubMed:16677302, PubMed:28242658).[1] [2] [3]
Publication Abstract from PubMed
Objectives: : Investigation into the adenylylation of the nucleophilic serine in AmpC BER and CMY-10 extended-spectrum class C beta-lactamases. Methods: : The formation and the stability of the adenylate adduct were examined by X-ray crystallography and MS. Inhibition assays for kinetic parameters were performed by monitoring the hydrolytic activity of AmpC BER and CMY-10 using nitrocefin as a reporter substrate. The effect of adenosine 5'-(P-acetyl)monophosphate (acAMP) on the MIC of ceftazidime was tested with four Gram-negative clinical isolates. Results: : The crystal structures and MS analyses confirmed the acAMP-mediated adenylylation of the nucleophilic serine in AmpC BER and CMY-10. acAMP inhibited AmpC BER and CMY-10 through the adenylylation of the nucleophilic serine, which could be modelled as a two-step mechanism. The initial non-covalent binding of acAMP to the active site is followed by the covalent attachment of its AMP moiety to the nucleophilic serine. The inhibition efficiencies ( k inact / K I ) of acAMP against AmpC BER and CMY-10 were determined to be 320 and 140 M -1 s -1 , respectively. The combination of ceftazidime and acAMP reduced the MIC of ceftazidime against the tested bacteria. Conclusions: : Our structural and kinetic studies revealed the detailed mechanism of adenylylation of the nucleophilic serine and may serve as a starting point for the design of novel class C beta-lactamase inhibitors on the basis of the nucleotide scaffold.
Structural and mechanistic insights into the inhibition of class C beta-lactamases through the adenylylation of the nucleophilic serine.,Kim MK, An YJ, Na JH, Seol JH, Ryu JY, Lee JW, Kang LW, Chung KM, Lee JH, Moon JH, Lee JS, Cha SS J Antimicrob Chemother. 2017 Mar 1;72(3):735-743. doi: 10.1093/jac/dkw491. PMID:27999057[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lee JH, Jung HI, Jung JH, Park JS, Ahn JB, Jeong SH, Jeong BC, Lee JH, Lee SH. Dissemination of transferable AmpC-type beta-lactamase (CMY-10) in a Korean hospital. Microb Drug Resist. 2004 Fall;10(3):224-30. PMID:15383166 doi:10.1089/mdr.2004.10.224
- ↑ Kim JY, Jung HI, An YJ, Lee JH, Kim SJ, Jeong SH, Lee KJ, Suh PG, Lee HS, Lee SH, Cha SS. Structural basis for the extended substrate spectrum of CMY-10, a plasmid-encoded class C beta-lactamase. Mol Microbiol. 2006 May;60(4):907-16. PMID:16677302 doi:10.1111/j.1365-2958.2006.05146.x
- ↑ Na JH, An YJ, Cha SS. GMP and IMP Are Competitive Inhibitors of CMY-10, an Extended-Spectrum Class C beta-Lactamase. Antimicrob Agents Chemother. 2017 Apr 24;61(5). pii: e00098-17. doi:, 10.1128/AAC.00098-17. Print 2017 May. PMID:28242658 doi:https://dx.doi.org/10.1128/AAC.00098-17
- ↑ Kim MK, An YJ, Na JH, Seol JH, Ryu JY, Lee JW, Kang LW, Chung KM, Lee JH, Moon JH, Lee JS, Cha SS. Structural and mechanistic insights into the inhibition of class C beta-lactamases through the adenylylation of the nucleophilic serine. J Antimicrob Chemother. 2017 Mar 1;72(3):735-743. doi: 10.1093/jac/dkw491. PMID:27999057 doi:https://dx.doi.org/10.1093/jac/dkw491
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