Coordination geometries of metal ions in d- or l-captopril-inhibited metallo-beta-lactamases.
d- and l-captopril are competitive inhibitors of metallo-beta-lactamases. For the enzymes from Bacillus cereus (BcII) and Aeromonas hydrophila (CphA), we found that the mononuclear enzymes are the favored targets for inhibition. By combining results from extended x-ray absorption fine structure, perturbed angular correlation of gamma-rays spectroscopy, and a study of metal ion binding, we derived that for Cd(II)1-BcII, the thiolate sulfur of d-captopril binds to the metal ion located at the site defined by three histidine ligand residues. This is also the case for the inhibited Co(II)1 and Co(II)2 enzymes as observed by UV-visible spectroscopy. Although the single metal ion in Cd(II)1-BcII is distributed between both available binding sites in both the uninhibited and the inhibited enzyme, Cd(II)1-CphA shows only one defined ligand geometry with the thiolate sulfur coordinating to the metal ion in the site composed of 1 Cys, 1 His, and 1 Asp. CphA shows a strong preference for d-captopril, which is also reflected in a very rigid structure of the complex as determined by perturbed angular correlation spectroscopy. For BcII and CphA, which are representatives of the metallo-beta-lactamase subclasses B1 and B2, we find two different inhibitor binding modes.
Heinz
Uwe
U
Department of Biochemistry, University of the Saarland, D-66041 Saarbruecken, Germany.
Bauer
Rogert
R
Wommer
Sandra
S
Meyer-Klaucke
Wolfram
W
Papamichaels
Cyril
C
Bateson
John
J
Adolph
Hans-Werner
HW
D015502:Absorptiometry, Photon; D016980:Aeromonas hydrophila; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D002104:Cadmium / Q000737:chemistry*; D002216:Captopril / Q000378:metabolism; D003035:Cobalt / Q000737:chemistry*; D011485:Protein Binding; D013056:Spectrophotometry, Ultraviolet; D001618:beta-Lactamases / Q000737:chemistry* / Q000378:metabolism*
D000806:Angiotensin-Converting Enzyme Inhibitors; D001426:Bacterial Proteins; D002104:Cadmium; D003035:Cobalt; D002216:Captopril; D001618:beta-Lactamases; C082063:cphA protein, Aeromonas hydrophila