Novel mechanism of hydrolysis of therapeutic beta-lactams by Stenotrophomonas maltophilia L1 metallo-beta-lactamase

J Biol Chem. 2001 Sep 7;276(36):33638-44. doi: 10.1074/jbc.M105550200. Epub 2001 Jul 6.

Abstract

Stopped-flow tryptophan fluorescence under single turnover and pseudo-first-order conditions has been used to investigate the kinetic mechanism of beta-lactam hydrolysis by the Stenotrophomonas maltophilia L1 metallo-beta-lactamase. For the cephalosporin substrates nitrocefin and cefaclor and the carbapenem meropenem, a substantial quench of fluorescence is observed on association of substrate with enzyme. We have assigned this to a rearrangement event subsequent to formation of an initial collision complex. For the colorimetric compound nitrocefin, decay of this dark inter- mediate represents the overall rate-determining step for the reaction and is equivalent to decay of a previously observed state in which the beta-lactam amide bond has already been cleaved. For both cefaclor and meropenem, the rate-determining step for hydrolysis is loss of a second, less quenched state, in which, however, the beta-lactam amide bond remains intact. We suggest, therefore, that the mechanism of hydrolysis of nitrocefin by binuclear metallo-beta-lactamases may be atypical and that cleavage of the beta-lactam amide bond is the rate-determining step for breakdown of the majority of beta-lactam substrates by the L1 enzyme.

MeSH terms

  • Catalysis
  • Cefaclor / metabolism
  • Cephalosporins / metabolism
  • Cephalosporins / pharmacology
  • Dose-Response Relationship, Drug
  • Hydrolysis*
  • Indicators and Reagents / pharmacology
  • Kinetics
  • Meropenem
  • Models, Chemical
  • Spectrometry, Fluorescence
  • Stenotrophomonas maltophilia / enzymology*
  • Temperature
  • Thienamycins / metabolism
  • Time Factors
  • Tryptophan / metabolism
  • Ultraviolet Rays
  • beta-Lactamases / metabolism*

Substances

  • Cephalosporins
  • Indicators and Reagents
  • Thienamycins
  • Cefaclor
  • Tryptophan
  • beta-lactamase L1
  • beta-Lactamases
  • nitrocefin
  • Meropenem