Human Arginase II:  Crystal Structure and Physiological Role in Male and Female Sexual Arousal^,

Abstract

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.

Crystal structure of human arginase I at 1.29-Å resolution and exploration of inhibition in the immune response

“…Some differences are evident in the binding of BEC to the active sites of human arginases I and II. The ␣-carboxylate and ␣-amino groups of BEC are anchored to the active site of human arginase I by three direct and four water-mediated hydrogen bonds, whereas these interactions consist of two direct and five water-mediated hydrogen bonds in the human arginase II complex (21). By inference, then, water-mediated hydrogen bonds make the majority of interactions with the ␣-carboxylate and ␣-amino group of the substrate L-arginine.…”

Recent Advances in Understanding Endothelial Dysfunction in Atherosclerosis

“…155 The primary function of arginase I is thought to be involved in ammonia detoxification, whereas that of arginase II, in biosynthesis of polyamines and the amino acids, ornithine, proline and glutamate, 156 plays a primary role of regulation of endothelial NO production. 47,157 Interestingly, expression and activity of arginase II were found to be increased in human diabetic corpus cavernosum and inhibition of the enzyme enhances NO-dependent relaxation of corpus cavernosum smooth muscle 158,159 suggesting a potential role of arginase II in negative regulation of NO production in diabetic erectile dysfunction. Most recently, an increase in arginase II expression or activity has been implicated in endothelial dysfunction associated with pulmonary hypertension, 160 aging, 161,162 ischemia-reperfusion-induced endothelial dysfunction, 163 aortic coarctation hypertension, 164 salt-induced hypertension 165 and atherosclerosis.…”

Endothelial arginase: A new target in atherosclerosis

“…In human endothelial cells, arginase II seems to be the predominant isoenzyme [13••,39]. The expression and activity of arginase II were found to be increased in human diabetic corpus cavernosum, and inhibition of the enzyme enhances NO-dependent relaxation of corpus cavernosum smooth muscle [40,41], suggesting a potential role for arginase II in negative regulation of NO production in diabetic erectile dysfunction. Similarly, arginase activity was also found to be higher in the aortas of type 1 and type 2 diabetic animal models (Yang and Ming, Unpublished results).…”