Inhibitor Coordination Interactions in the Binuclear Manganese Cluster of Arginase,

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Abstract
Arginase is a manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. The structure and stability of the binuclear manganese cluster are critical for catalytic activity as it activates the catalytic nucleophile, metal-bridging hydroxide ion, and stabilizes the tetrahedral intermediate and its flanking states. Here, we report X-ray structures of a series of inhibitors bound to the active site of arginase, and each inhibitor exploits a different mode of coordination with the Mn2+2 cluster. Specifically, we have studied the binding of fluoride ion (F-; an uncompetitive inhibitor) and l-arginine, l-valine, dinor-Nω-hydroxy-l-arginine, descarboxy-nor-Nω-hydroxy-l-arginine, and dehydro-2(S)-amino-6-boronohexanoic acid. Some inhibitors, such as fluoride ion, dinor-Nω-hydroxy-l-arginine, and dehydro-2(S)-amino-6-boronohexanoic acid, cause the net addition of one ligand to the Mn2+2 cluster. Other inhibitors, such as descarboxy-nor-Nω-hydroxy-l-arginine, simply displace the metal-bridging hydroxide ion of the native enzyme and do not cause any net change in the metal coordination polyhedra. The highest affinity inhibitors displace the metal-bridging hydroxide ion (and sometimes occupy a Mn2+A site found vacant in the native enzyme) and maintain a conserved array of hydrogen bonds with their α-amino and -carboxylate groups.

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