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.
Cama
Evis
E
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, USA.
Colleluori
Diana M
DM
Emig
Frances A
FA
Shin
Hyunshun
H
Kim
Soo Woong
SW
Kim
Noel N
NN
Traish
Abdulmaged M
AM
Ash
David E
DE
Christianson
David W
DW
D000595:Amino Acid Sequence; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D001143:Arousal / Q000502:physiology*; D001483:Base Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray / Q000379:methods; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D014644:Genetic Variation; D006439:Hemodynamics / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes; D008297:Male; D008958:Models, Molecular; D016133:Polymerase Chain Reaction; D017433:Protein Structure, Secondary; D011817:Rabbits; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D017384:Sequence Deletion; D019529:Sexuality / Q000502:physiology*
D017931:DNA Primers; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011994:Recombinant Proteins; C477631:ARG2 protein, human; D001119:Arginase