1994
DOI: 10.1139/v94-131
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Ab initio molecular orbital calculations on the neutral hydrolysis and methanolysis of azetidinones, including catalysis by water. Relationship to the mechanism of action of β-lactam antibiotics

Abstract: The docking of penicillins to a computer model of the active site of the penicillin-binding protein of Streptornyces R61 produces structures that exhibit a four-centred interaction between the 0 -H of a serine residue and the (0)C-N of the p-lactam ring. If such a structure is a stationary point on the reaction coordinate for the acylation of the serine OH by the p-lactam carbonyl group, the acylation mechanism would appear to consist of 0-C and H-N bond formation, concerted with the cleavage of the C-N bond. … Show more

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Cited by 30 publications
(32 citation statements)
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“…This arrangement of the reacting groups suggests that the "reactivity" step of Scheme 1, which produces the acyl-enzyme, involves C=O bond formation and proton transfer to nitrogen, concerted with the $fission of the p-1ac:am bon:. As we report elsewhere (8), ab initio MP216-3 1 G 1/3-21 G calculations (9) of the neutral hydrolysis and alcoholysis of N-methylazetidinone (4) and penam (5) confirm that a concerted mechanism, with proton transfer to nitrogen, exists, and is 5-10 kcaY mol energetically more favorable than addition to the carbonyl group, with proton transfer to oxygen. In addition, attack on 5 from the convex face is more favourable than attack from the concave face.…”
Section: I1supporting
confidence: 65%
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“…This arrangement of the reacting groups suggests that the "reactivity" step of Scheme 1, which produces the acyl-enzyme, involves C=O bond formation and proton transfer to nitrogen, concerted with the $fission of the p-1ac:am bon:. As we report elsewhere (8), ab initio MP216-3 1 G 1/3-21 G calculations (9) of the neutral hydrolysis and alcoholysis of N-methylazetidinone (4) and penam (5) confirm that a concerted mechanism, with proton transfer to nitrogen, exists, and is 5-10 kcaY mol energetically more favorable than addition to the carbonyl group, with proton transfer to oxygen. In addition, attack on 5 from the convex face is more favourable than attack from the concave face.…”
Section: I1supporting
confidence: 65%
“…The methanolysis of 4 exhibits significant catalysis by one water molecule (8). In this case, based on 3-21G calculations, the reaction proceeds via a ternary complex (Fig.…”
Section: I1mentioning
confidence: 98%
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“…A large number of kinetic studies regarding penicillin and cephalosporin degradation in acidic medium are found in the literature [17][18][19]; however, at present, there are still important doubts concerning the reaction pathway [20][21][22].…”
Section: Introductionmentioning
confidence: 99%
“…Examination of the geometry of the interaction between the serine 0 -H and the p-lactam N-C(0) in these complexes led to the suggestion that Step 2 may involve protonation of the p-lactam nitrogen concerted with C7-0 bond formation. Support has now been obtained for the existence and, indeed, energetic preference for this mechanism (8) in the gas phase, and also in the presence of a catalytic water molecule (9).…”
mentioning
confidence: 80%