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Kinetic and Molecular‐Modelling Study of the Interaction between Staphylococcus aureus PC1 Enzyme and Imipenem
Author(s) -
Vilanova Bartolomé,
Coll Miguel,
Frau Juan,
Muñoz Francisco,
Donoso Josefa
Publication year - 2001
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/1522-2675(20011114)84:11<3366::aid-hlca3366>3.0.co;2-t
Subject(s) - imipenem , chemistry , benzylpenicillin , substrate (aquarium) , enzyme , carbapenem , stereochemistry , ring (chemistry) , hydrolysis , staphylococcus aureus , antibiotics , bacteria , biochemistry , organic chemistry , penicillin , antibiotic resistance , oceanography , geology , biology , genetics
The interactions between imipenem ( 3 ), a clinically significant carbapenem antibiotic, and Staphylococcus aureus PC1 enzyme, were studied in detail. Imipenem behaves as a slow substrate that reacts by a branched pathway, which suggests the formation of a second acyl‐enzyme intermediate. The individual microscopic rate constants for the process were determined. The results were analysed in the light of molecular‐modelling considerations. Based on the analysis, the Ser‐70(O γ ) group in the Michaelis‐Menten complex formed between 3 and PC1 is very distant from the carbonyl group of the β ‐lactam ring of 3 , which is consistent with the decreased value of k 2 ( Model 2 , see Scheme 2 ) for imipenem relative to an appropriate substrate such as benzylpenicillin ( 2 ). The deacylation is the rate‐determining step of the turnover process. This can be ascribed to the fact that in the deacylation of the second acyl‐enzyme, the H 2 O molecule lying closest to the ester group, Wat81, is in an unfavorable orientation to hydrolyse the intermediate.