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structure, mechanism, and physiological role in male and female sexual arousal.
D.W. Christianson, Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104-6323, USA, Acc Chem Res. 2005 Mar;38(3):191-201. 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. |
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