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• Ion, B
• Bushnell, E
• Luna, P
• Gauld, J
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• Ion, B
• Bushnell, E
• Luna, P
• Gauld, J
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• Ion, B
• Bushnell, E
• Luna, P
• Gauld, J

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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

Bogdan F. Ion, Eric A. C. Bushnell, Phil De Luna and James W. Gauld*

Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada

* Author to whom correspondence should be addressed.

Received: 10 September 2012; in revised form: 27 September 2012 / Accepted: 27 September 2012 / Published: 11 October 2012

(This article belongs to the Special Issue Enzyme Optimization and Immobilization)

Download PDF Full-Text [4638 KB, uploaded 11 October 2012 11:12 CEST]

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 C_α–H group to the NAD⁺ cofactor with concomitant formation of a C_α=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 C_α=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 C_α-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

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