Journal
BIOCHEMISTRY
Volume 42, Issue 28, Pages 8445-8451Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi034340j
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Funding
- NIDDK NIH HHS [R01 DK056846, DK56846, DK02696] Funding Source: Medline
- NIGMS NIH HHS [GM67788, GM49758, R01 GM067788] Funding Source: Medline
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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 Angstrom 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.
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