Arginase-boronic acid complex highlights a physiological role in erectile function

The crystal structure of the complex between the binuclear manganese metall oenzyme arginase and the boronic acid analog of L-arginine, 2(S)-amino-6-bo ronohexanoic acid (ABH), has been determined at 1.7 Angstrom resolution fro m a crystal perfectly twinned by hemihedry, ABH binds as the tetrahedral bo ronate anion, with one hydroxyl oxygen symmetrically bridging the binuclear manganese duster and a second hydroxyl oxygen coordinating to Mn-A(2+). Th is binding mode mimics the transition state of a metal-activated hydroxide mechanism. This transition state structure differs from that occurring in N O biosynthesis, thereby explaining why ABH does not inhibit NO synthase. We also show that arginase activity is present in the penis. Accordingly, the tight binding and specificity of ABH allows us to probe the physiological role of arginase in modulating the NO-dependent smooth muscle relaxation re quired for erection, Strikingly, ABH causes significant enhancement of nona drenergic, noncholinergic nerve-mediated relaxation of penile corpus cavern osum smooth muscle, suggesting that arginase inhibition sustains L-arginine concentrations for NO synthase activity. Therefore, human penile arginase is a potential target for therapeutic intervention in the treatment of erec tile dysfunction.