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J. Biol. Chem., Vol. 275, Issue 26, 20012-20019, June 30, 2000

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Mechanism of Inactivation of Ornithine Transcarbamoylase by N-(N'-Sulfodiaminophosphinyl)-L-ornithine, a True Transition State Analogue?
CRYSTAL STRUCTURE AND IMPLICATIONS FOR CATALYTIC MECHANISM^*

David B. Langley, Matthew D. Templeton^§, Barry A. Fields, Robin E. Mitchell^§, and Charles A. Collyer^¶

From the  Department of Biochemistry, The University of Sydney, Sydney 2006, Australia and the ^§ Horticultural and Food Research Institute of New Zealand, Mt Albert Research Centre, Auckland 1003, New Zealand

The crystal structure is reported at 1.8 Å resolution of Escherichia coli ornithine transcarbamoylase in complex with the active derivative of phaseolotoxin from Pseudomonas syringae pv. phaseolicola, N-(N'-sulfodiaminophosphinyl)-L-ornithine. Electron density reveals that the complex is not a covalent adduct as previously thought. Kinetic data confirm that N-(N'-sulfodiaminophosphinyl)-L-ornithine exhibits reversible inhibition with a half-life in the order of ~22 h and a dissociation constant of K_D = 1.6 × 10¹² M at 37 °C and pH 8.0. Observed hydrogen bonding about the chiral tetrahedral phosphorus of the inhibitor is consistent only with the presence of the R enantiomer. A strong interaction is also observed between Arg⁵⁷ N and the P-N-S bridging nitrogen indicating that imino tautomers of N-(N'-sulfodiaminophosphinyl)-L-ornithine are present in the bound state. An imino tautomer of N-(N'-sulfodiaminophosphinyl)-L-ornithine is structurally analogous to the proposed reaction transition state. Hence, we propose that N-(N'-sulfodiaminophosphinyl)-L-ornithine, with its three unique N-P bonds, represents a true transition state analogue for ornithine transcarbamoylases, consistent with the tight binding kinetics observed.

The atomic coordinates and the structure factors (code 1DUV) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

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