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Quantum mechanics/molecular mechanics studies on the mechanism of action of cofactor pyridoxal 5'-phosphate in ornithine 4,5-aminomutase

Quantum mechanics/molecular mechanics studies on the mechanism of action of cofactor pyridoxal 5'-phosphate in ornithine 4,5-aminomutase

Pang, Jiayun, Scrutton, Nigel S. and Sutcliffe, Michael J. (2014) Quantum mechanics/molecular mechanics studies on the mechanism of action of cofactor pyridoxal 5'-phosphate in ornithine 4,5-aminomutase. Chemistry - A European Journal, 20 (36). pp. 11390-11401. ISSN 0947-6539 (Print), 1521-3765 (Online) (doi:10.1002/chem.201402759)

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Abstract

A computational study was performed on the experimentally elusive cyclisation step in the cofactor pyridoxal 5′-phosphate (PLP)-dependent D-ornithine 4,5-aminomutase (OAM)-catalysed reaction. Calculations using both model systems and a combined quantum mechanics/molecular mechanics approach suggest that regulation of the cyclic radical intermediate is achieved through the synergy of the intrinsic catalytic power of cofactor PLP and the active site of the enzyme. The captodative effect of PLP is balanced by an enzyme active site that controls the deprotonation of both the pyridine nitrogen atom (N1) and the Schiff-base nitrogen atom (N2). Furthermore, electrostatic interactions between the terminal carboxylate and amino groups of the substrate and Arg297 and Glu81 impose substantial “strain” energy on the orientation of the cyclic intermediate to control its trajectory. In addition the “strain” energy, which appears to be sensitive to both the number of carbon atoms in the substrate/analogue and the position of the radical intermediates, may play a key role in controlling the transition of the enzyme from the closed to the open state. Our results provide new insights into several aspects of the radical mechanism in aminomutase catalysis and broaden our understanding of cofactor PLP-dependent reactions.

Item Type: Article
Additional Information: [1] The Author's Accepted Manuscript is attached to this GALA record. This is the accepted version of the following article: Pang, J., Scrutton, N. S. and Sutcliffe, M. J. (2014), Quantum Mechanics/Molecular Mechanics Studies on the Mechanism of Action of Cofactor Pyridoxal 5′-Phosphate in Ornithine 4,5-Aminomutase. Chem. Eur. J., 20: 11390–11401. doi: 10.1002/chem.201402759, which has been published in final form at http://dx.doi.org/10.1002/chem.201402759. [2] Chemistry—A European Journal is published on behalf of ChemPubSoc Europe, a group of 16 national chemical societies from within Europe, and supported by the Asian Chemical Editorial Societies. The ChemPubSoc Europe family comprises: Angewandte Chemie, Chemistry—A European Journal, European Journal of Organic Chemistry, European Journal of Inorganic Chemistry, ChemPhysChem, ChemBioChem, ChemMedChem, ChemCatChem, ChemSusChem, ChemPlusChem, ChemElectroChem, and ChemistryOpen.
Uncontrolled Keywords: density functional calculations, enzyme catalysis, enzyme models, molecular mechanics, radical reactions
Subjects: Q Science > Q Science (General)
Q Science > QC Physics
Q Science > QD Chemistry
Faculty / Department / Research Group: Faculty of Engineering & Science
Faculty of Engineering & Science > Department of Pharmaceutical, Chemical & Environmental Sciences
Related URLs:
Last Modified: 11 Apr 2017 08:47
Selected for GREAT 2016: GREAT a
Selected for GREAT 2017: None
Selected for GREAT 2018: None
URI: http://gala.gre.ac.uk/id/eprint/12115

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