期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 135, 期 49, 页码 18358-18369出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja403598g
关键词
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资金
- Robert A. Welch Foundation [N-0871]
- NIH [AI062968, R01AI072219, R01AI063517, R01AI100560, GM54072]
- Louis Stokes Cleveland Department of Veterans Affairs Medical Center
- VISN 10 Geriatric Research, Education, and Clinical Care Center (VISN 10) of the Department of Veterans Affairs
The inhibition of the class A SHV-1 beta-lactamase by 7-(tert-butoxycarbonyl)methylidenecephalosporin sulfone was examined kinetically, spectroscopically, and crystallographically. An 1.14 angstrom X-ray crystal structure shows that the stable acyl-enzyme, which incorporates an eight-membered ring, is a covalent derivative of Ser70 linked to the 7-carboxy group of 2-H-5,8-dihydro-1,1-dioxo-1,5-thiazocine-4,7-dicarboxylic acid. A cephalosporin-derived enzyme complex of this type is unprecedented, and the rearrangement leading to its formation may offer new possibilities for inhibitor design. The observed acyl-enzyme derives its stability from the resonance stabilization conveyed by the beta-aminoacrylate (i.e., vinylogous urethane) functionality as there is relatively little interaction of the eight-membered ring with active site residues. Two mechanistic schemes are proposed, differing in whether, subsequent to acylation of the active site serine and opening of the beta-lactam, the resultant dihydrothiazine fragments on its own or is assisted by an adjacent nucleophilic atom, in the form of the carbonyl oxygen of the C7 tert-butyloxycarbonyl group. This compound was also found to be a submicromolar inhibitor of the class C ADC-7 and PDC-3 beta-lactamases.
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