title: Three decades of the class A beta-lactamase acyl-enzyme.
abstract: The discovery that the mechanism of beta-lactam hydrolysis catalyzed by the class A (active site serine-dependent) beta-lactamases proceeds via an acyl-enzyme intermediate was made thirty years ago. Since this discovery, the active site circumstance that enables acylation of the active site serine and further enables hydrolytic deacylation of the acyl-serine intermediate, has received extraordinary scrutiny. The justification for this scrutiny is the direct relevance of the beta-lactamases to the manifestation of bacterial resistance to the beta-lactam antibiotics, and the subsequent (to the discovery of the beta-lactamase acyl-enzyme) recognition of the direct evolutionary relationship between the serine beta-lactamase acyl-enzyme, and the penicillin binding protein acyl-enzyme that is key to beta-lactam antibiotic activity. This short review describes the early events leading to the recognition that serine beta-lactamase catalysis proceeds via an acyl-enzyme intermediate, and summarizes several of the key mechanistic studies--including infrared spectroscopy, cryoenzymology, beta-lactam design, and x-ray crystallography--that have been exploited to understand this pivotal catalytic intermediate.
authors.affiliation: Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame IN 46556-5670, USA.
authors.forename: Jed F
authors.initials: JF
authors.lastname: Fisher
authors.forename: Shahriar
authors.initials: S
authors.lastname: Mobashery
mesh_terms: D001424:Bacterial Infections / Q000188:drug therapy; D001665:Binding Sites; D002384:Catalysis; D020134:Catalytic Domain; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D006801:Humans; D006868:Hydrolysis; D008956:Models, Chemical; D010406:Penicillins / Q000737:chemistry; D011487:Protein Conformation; D012694:Serine / Q000737:chemistry; D013055:Spectrophotometry, Infrared / Q000379:methods; D001618:beta-Lactamases / Q000737:chemistry* / Q000378:metabolism; D047090:beta-Lactams / Q000737:chemistry*
chemical_list: D010406:Penicillins; D047090:beta-Lactams; D012694:Serine; D001618:beta-Lactamases