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

作者：Ion Bogdan F; Bushnell Eric A C; De Luna Phil; Gauld James W^*

来源：International Journal of Molecular Sciences, 2012, 13(10): 12994-13011.

DOI：10.3390/ijms131012994

• OCD
• L-proline
• crystallin
• oxidative deamination
• iminium

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%26apos;s C-alpha-H group to the NAD(+) cofactor with concomitant formation of a C-alpha=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-alpha=NH2+ intermediate to form the corresponding carbonyl. Instead, the reaction proceeds via a non-hydrolytic mechanism involving direct nucleophilic attack of the delta-amine at the C-alpha-position. This is then followed by cleavage and loss of the alpha-NH2 group to give the Delta(1)-pyrroline-2-carboxylate that is subsequently reduced to L-proline.

• 出版日期2012-10