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| - Ornithine Cyclodeaminase: Structure, Mechanism of Action, and Implications forthe μ-Crystallin Family,
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| - Ornithine cyclodeaminase catalyzes the conversion of l-ornithine to l-proline by an NAD+-dependent hydride transfer reaction that culminates in ammonia elimination. Phylogenetic comparisonsof amino acid sequences revealed that the enzyme belongs to the μ-crystallin protein family whose three-dimensional fold has not been reported. Here we describe the crystal structure of ornithine cyclodeaminasein complex with NADH, refined to 1.80 Å resolution. The enzyme consists of a homodimeric fold whosesubunits comprise two functional regions: (i) a novel substrate-binding domain whose antiparallel β-strandsform a 14-stranded barrel at the oligomeric interface and (ii) a canonical Rossmann fold that interactswith a single dinucleotide positioned for re hydride transfer. The adenosyl moiety of the cofactor residesin a solvent-exposed crevice on the protein surface and makes contact with a “domain-swapped”-likecoil−helix module originating from the dyad-related molecule. Diffraction data were also collected to1.60 Å resolution on crystals grown in the presence of l-ornithine. The structure revealed that the substratecarboxyl group interacts with the side chains of Arg45, Lys69, and Arg112. In addition, the ammonialeaving group hydrogen bonds to the side chain of Asp228 and the site of hydride transfer is 3.8 Å fromC4 of the nicotinamide. The absence of an appropriately positioned water suggested that a previouslyproposed mechanism that calls for hydrolytic elimination of the imino intermediate must be reconsidered.A more parsimonious description of the chemical mechanism is proposed and discussed in relation to thestructure and function of μ-crystallins.
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