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.
Highlights
L-proline (Pro) is one of the naturally occurring 20 genetically encoded amino acids and is unique amongst them in being the only one with a secondary α-amine
In certain pathogenic bacteria, it has been suggested that proline metabolism plays a role in enabling the pathogen to survive under harsh conditions [9,10,11]
The Molecular Operating Environment (MOE) [53] program was used for model preparation and the molecular dynamics (MD) simulations
Summary
L-proline (Pro) is one of the naturally occurring 20 genetically encoded amino acids and is unique amongst them in being the only one with a secondary α-amine. The interconversion between proline and Δ1-pyrroline-5-carboxylate (P5C), an intermediate in its biosynthesis and catabolism, is believed to be involved in cell apoptosis [1,14,15,16,17,18]. This cycle provides a redox shuttle between the cytosol and mitochondria, controlling the formation of reactive oxygen species [14,19,20]. It is important to understand the functions of the enzymes that metabolize proline
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