The crystal structure of the complex between the binuclear manganese metalloenzyme
arginase and the boronic acid analog of L-arginine, 2(S)-amino-6-boronohexanoic
acid (ABH), has been determined at 1.7 Å resolution from a crystal perfectly
twinned by hemihedry. ABH binds as the tetrahedral boronate anion, with one
hydroxyl oxygen symmetrically bridging the binuclear manganese cluster and
a second hydroxyl oxygen coordinating to Mn2+A.
This binding mode mimics the transition state of a metal-activated hydroxide
mechanism. This transition state structure differs from that occurring in
NO 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 required
for erection. Strikingly, ABH causes significant enhancement of nonadrenergic,
noncholinergic nerve-mediated relaxation of penile corpus cavernosum 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 erectile dysfunction.
