Inactivation of Bacterial DD-Peptidase by β-Sultams

Antonio Llinás, Naveed Ahmed, Massimiliano Cordaro, Andrew P. Laws, Jean Marie Frère, Michael Delmarcelle, Nicholas R. Silvaggi, Judith A. Kelly, Michael I. Page

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30 Citations (Scopus)

Abstract

N-Acyl-β-sultams are time-dependent, irreversible active site-directed inhibitors of Streptomyces R61 DD-peptidase. The rate of inactivation is first order with respect to β-sultam concentration, and the second-order rate constants show a dependence on pH similar to that for the hydrolysis of a substrate. Inactivation is due to the formation of a stable 1:1 enzyme-inhibitor complex as a result of the active site serine being sulfonylated by the β-sultam as shown by ESI-MS analysis and by X-ray crystallography. A striking feature of the sulfonyl enzyme is that the inhibitor is not bound to the oxyanion hole but interacts extensively with the "roof" of the active site where the Arg 285 is located.

Original languageEnglish
Pages (from-to)7738-7746
Number of pages9
JournalBiochemistry
Volume44
Issue number21
Early online date7 May 2005
DOIs
Publication statusPublished - 31 May 2005

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    Llinás, A., Ahmed, N., Cordaro, M., Laws, A. P., Frère, J. M., Delmarcelle, M., Silvaggi, N. R., Kelly, J. A., & Page, M. I. (2005). Inactivation of Bacterial DD-Peptidase by β-Sultams. Biochemistry, 44(21), 7738-7746. https://doi.org/10.1021/bi050110o