Human arginase II: crystal structure and physiological role in male and female sexual arousal

Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea. The X-ray crystal structure of a fully active, truncated form of human Arginase II complexed with a boronic acid transition state analogue inhibitor has been determined at 2.7 A resolution. This structure is consistent with the hydrolysis of l-arginine through a metal-activated hydroxide mechanism. Given that human Arginase II appears to play a role in regulating l-arginine bioavailability to NO Synthase in human penile corpus cavernosum smooth muscle, the inhibition of human Arginase II is a potential new strategy for the treatment of erectile dysfunction [Kim, N. N., COX, J. D., Baggio, R. F., Emig, F. A., Mistry, S., Harper, S. L., Speicher, D. W., Morris, S. M., Ash, D. E., Traish, A. M., and Christianson, D. W. (2001) Biochemistry 40, 2678-2688]. Since NO Synthase is found in human clitoral corpus cavernosum and vagina, we hypothesized that human Arginase II is similarly present in these tissues and functions to regulate l-arginine bioavailability to NO Synthase. Accordingly, hemodynamic studies conducted with a boronic acid Arginase Inhibitor in vivo are summarized, suggesting that the extrahepatic Arginase plays a role in both male and female sexual arousal. Therefore, Arginase II is a potential target for the treatment of male and female sexual arousal disorders.