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Issue 47, 2013
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Penicillin's catalytic mechanism revealed by inelastic neutrons and quantum chemical theory

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Abstract

Penicillin, travels through bodily fluids, targeting and acylatively inactivating enzymes responsible for cell-wall synthesis in gram-positive bacteria. Somehow, it avoids metabolic degradation remaining inactive en route. To resolve this ability to switch from a non-active, to a highly reactive form, we investigated the dynamic structure–activity relationship of penicillin by inelastic neutron spectroscopy, reaction kinetics, NMR and multi-scale theoretical modelling (QM/MM and post-HF ab initio). Results show that by a self-activating physiological pH-dependent two-step proton-mediated process, penicillin changes geometry to activate its irreversibly reactive acylation, facilitated by systemic intramolecular energy management and cooperative vibrations. This dynamic mechanism is confirmed by the first ever reported characterisation of an antibiotic by neutrons, achieved on the TOSCA instrument (ISIS facility, RAL, UK).

Graphical abstract: Penicillin's catalytic mechanism revealed by inelastic neutrons and quantum chemical theory

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Submitted
27 Feb 2013
Accepted
28 May 2013
First published
12 Jun 2013

Phys. Chem. Chem. Phys., 2013,15, 20447-20455
Article type
Paper

Penicillin's catalytic mechanism revealed by inelastic neutrons and quantum chemical theory

Z. Mucsi, G. A. Chass, P. Ábrányi-Balogh, B. Jójárt, D. Fang, A. J. Ramirez-Cuesta, B. Viskolcz and I. G. Csizmadia, Phys. Chem. Chem. Phys., 2013, 15, 20447
DOI: 10.1039/C3CP50868D

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