Inactivation of bacterial DD-peptidase by beta-sultams.

Anti-Bacterial Agents/chemistry; Bacterial Proteins/antagonists & inhibitors/metabolism; Binding Sites; Catalysis; Crystallography, X-Ray; Enzyme Inhibitors/chemistry; Enzyme Reactivators/chemistry; Enzyme Stability; Esters; Hydrogen-Ion Concentration; Hydrolysis; Hydroxylamine/chemistry; Serine/chemistry; Serine-Type D-Ala-D-Ala Carboxypeptidase/antagonists & inhibitors/metabolism; Spectrometry, Mass, Electrospray Ionization; Streptomyces/enzymology/growth & development; Substrate Specificity; Sulfhydryl Compounds/chemistry/metabolism; Sulfonamides/chemistry

Abstract :

[en] N-Acyl-beta-sultams are time-dependent, irreversible active site-directed inhibitors of Streptomyces R61 DD-peptidase. The rate of inactivation is first order with respect to beta-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 beta-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.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Llinas, Antonio

Ahmed, Naveed

Cordaro, Massimiliano

Laws, Andrew P

Frère, Jean-Marie ; Université de Liège - ULiège > Centre d'ingénierie des protéines

Delmarcelle, Michaël ; Université de Liège - ULiège > Centre d'ingénierie des protéines

Silvaggi, Nicholas R

Kelly, Judith A

Page, Michael I

Language :

English

Title :

Inactivation of bacterial DD-peptidase by beta-sultams.

Publication date :

2005

Journal title :

Biochemistry

ISSN :

0006-2960

eISSN :

1520-4995

Publisher :

American Chemical Society, Washington, United States - District of Columbia

Volume :

Issue :

Pages :

7738-46

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 26 October 2011

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Bibliography

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