title: A Molecular Dynamics (MD) and Quantum Mechanics/Molecular Mechanics (QM/MM) study on Ornithine Cyclodeaminase (OCD): a tale of two iminiums.
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)=NH(2)+ 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)=NH(2)+ 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-NH(2) group to give the Δ1-pyrroline-2-carboxylate that is subsequently reduced to L-proline.
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada. gauld@uwindsor.ca.
authors.forename: Bogdan F
authors.initials: BF
authors.lastname: Ion
authors.forename: Eric A C
authors.initials: EA
authors.lastname: Bushnell
authors.forename: Phil De
authors.initials: PD
authors.lastname: Luna
authors.forename: James W
authors.initials: JW
authors.lastname: Gauld
mesh_terms: D000642:Ammonia-Lyases / Q000737:chemistry* / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D056004:Molecular Dynamics Simulation; D009243:NAD / Q000737:chemistry / Q000378:metabolism; D009952:Ornithine / Q000737:chemistry / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D016958:Pseudomonas putida / Q000201:enzymology; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D001426:Bacterial Proteins; C467925:aminoproline; D009243:NAD; D011392:Proline; D009952:Ornithine; D000642:Ammonia-Lyases; C021914:ornithine cyclodeaminase