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Int. J. Mol. Sci. 2012, 13(10), 12994-13011; doi:10.3390/ijms131012994
Article

A Molecular Dynamics (MD) and Quantum Mechanics/Molecular Mechanics (QM/MM) Study on Ornithine Cyclodeaminase (OCD): A Tale of Two Iminiums

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Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada
* Author to whom correspondence should be addressed.
Received: 10 September 2012 / Revised: 27 September 2012 / Accepted: 27 September 2012 / Published: 11 October 2012
(This article belongs to the Special Issue Enzyme Optimization and Immobilization)
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Abstract

Ornithine cyclodeaminase (OCD) is an NAD+-dependent deaminase that is found in bacterial species such as Pseudomonas putida. Importantly, it catalyzes the direct conversion of the amino acid L-ornithine to L-proline. Using molecular dynamics (MD) and a hybrid quantum mechanics/molecular mechanics (QM/MM) method in the ONIOM formalism, the catalytic mechanism of OCD has been examined. The rate limiting step is calculated to be the initial step in the overall mechanism: hydride transfer from the L-ornithine’s Cα–H group to the NAD+ cofactor with concomitant formation of a Cα=NH2+ Schiff base with a barrier of 90.6 kJ mol−1. Importantly, no water is observed within the active site during the MD simulations suitably positioned to hydrolyze the Cα=NH2+ intermediate to form the corresponding carbonyl. Instead, the reaction proceeds via a non-hydrolytic mechanism involving direct nucleophilic attack of the δ-amine at the Cα-position. This is then followed by cleavage and loss of the α-NH2 group to give the Δ1-pyrroline-2-carboxylate that is subsequently reduced to L-proline.
Keywords: OCD; L-proline; crystallin; oxidative deamination; iminium OCD; L-proline; crystallin; oxidative deamination; iminium
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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Ion, B.F.; Bushnell, E.A.C.; Luna, P.D.; Gauld, J.W. A Molecular Dynamics (MD) and Quantum Mechanics/Molecular Mechanics (QM/MM) Study on Ornithine Cyclodeaminase (OCD): A Tale of Two Iminiums. Int. J. Mol. Sci. 2012, 13, 12994-13011.

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