Role of E166 in the imine to enamine tautomerization of the clinical beta-lactamase inhibitor sulbactam.
Mechanism-based inhibitors of class A beta-lactamases, such as sulbactam, undergo a complex series of chemical reactions in the enzyme active site. Formation of a trans-enamine acyl-enzyme via a hydrolysis-prone imine is responsible for transient inhibition of the enzyme. Although the imine to enamine tautomerization is crucial to inhibition of the enzyme, there are no experimental data to suggest how this chemical transformation is catalyzed in the active site. In this report, we show that E166 acts as a general base to promote the imine to enamine tautomerization.
Kalp
Matthew
M
Department of Biochemistry, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA. mdk16@case.edu
Buynak
John D
JD
Carey
Paul R
PR
D000588:Amines / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D007097:Imines / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D013059:Spectrum Analysis, Raman; D013329:Structure-Activity Relationship; D013407:Sulbactam / Q000737:chemistry* / Q000378:metabolism*; D065093:beta-Lactamase Inhibitors
D000588:Amines; D004791:Enzyme Inhibitors; D007097:Imines; D065093:beta-Lactamase Inhibitors; D013407:Sulbactam