Arginase: structure, mechanism, and physiological role in male and female sexual arousal.
Mammalian arginases I and II require an intact binuclear manganese cluster for the hydrolysis of L-arginine to generate L-ornithine and urea. Although arginase isozymes differ in terms of their tissue distribution, cellular localization, and metabolic function, each employs a metal-activated hydroxide mechanism for catalysis. To date, the best arginase inhibitors are those bearing N-hydroxyguanidinium or boronic acid "warheads" that can bridge the binuclear manganese cluster. Strikingly, the trigonal planar boronic acids undergo nucleophilic attack by hydroxide ion to form tetrahedral boronate anions that mimic the tetrahedral intermediate and its flanking transition states in the arginase mechanism. Given their affinity and specificity for arginase, boronic acid inhibitors are especially useful for probing the role of arginase in living systems. Arginase can regulate L-arginine bioavailability to nitric oxide synthase by depleting the substrate pool for NO biosynthesis, so arginase inhibition can enhance the substrate pool for NO biosynthesis. Accordingly, arginase inhibition can enhance NO-dependent physiological processes, such as the smooth muscle relaxation required for sexual arousal: administration of arginase inhibitors in vitro and in vivo enhances erectile function and engorgement in the male and female genitalia. Therefore, arginase is a potential therapeutic target for the treatment of sexual arousal disorders in men and women.
Christianson
David W
DW
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104-6323, USA.
D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D010410:Penile Erection / Q000502:physiology*; D010413:Penis / Q000033:anatomy & histology / Q000378:metabolism; D020836:Protein Structure, Quaternary; D051381:Rats; D043762:Reproductive Behavior / Q000502:physiology*; D013379:Substrate Specificity
D007527:Isoenzymes; D006655:Histone Deacetylases; D001119:Arginase