4jpm

Publication Abstract from PubMed

The inhibition of the class A SHV-1 beta-lactamase by 7-(tert-butoxycarbonyl)methylidenecephalosporin sulfone was examined kinetically, spectroscopically, and crystallographically. An 1.14A 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 -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.

beta-Lactamase Inhibition by 7-Alkylidenecephalosporin Sulfones: Allylic Transposition and Formation of an Unprecedented Stabilized Acyl-Enzyme.,Rodkey EA, McLeod DC, Bethel CR, Smith KM, Xu Y, Chai W, Che T, Carey PR, Bonomo RA, van den Akker F, Buynak JD J Am Chem Soc. 2013 Nov 12. PMID:24219313^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.