Sandbox Reserved 322: Difference between revisions

The two types of arginase is found in mammalian, are arginase I (hAI) and arginases II (hAII)<ref name="c"/>. Arginase I is found predominantly in the liver, where it catalyzes the final cytosolic step of the urea cycle<ref name="c"/>. Arginases II is a mitochondrial enzyme that does not appear to function in the urea cycle and is more widely disturbed in numerous tissues, for example kidney, brains, skeletal muscle, mammary gland and penile corpus cavernosum<ref name="c"/>. Recent studies show that ''Plasmodium falciparum'' arginase (PFA) plays a role in systemic depletion of arginine levels, which in turn has been associated with human cerebral malaria pathogenesis<ref name="a"/>. In addition the arginase fold is part of the [http://en.wikipedia.org/wiki/Ureohydrolase ''ureohydrolase''] superfamily, which also includes agmatinase, histone de-acetylase and acetylpolyamine amidohydrolase<ref name="a"/>.

==='''Structure and Function'''===

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There are three different types of bridging metal ligands that facilitate the observed spin coupling between Mn²⁺_A and Mn²⁺_B<ref name="d"/>. For the first ligand, the carboxylate side chain of Asp 216 is a syn-syn bidentate bridging ligand, with Oδ1 coordinated to Mn²⁺_A and Oδ2 coordinated to Mn²⁺_B<ref name="d"/>. For the second ligand, the carboxylate side chain of Asp 323 is a monodentate bridging ligand, with Oδ1 coordinated to both Mn²⁺_A and Mn²⁺_B with anti- and syn-coordination stereo-chemistry, respectively<ref name="b"/><ref name="d"/>. And finally the third ligand, is the solvent molecule bridges both manganese ion symmetrically<ref name="d"/>. Also the Mn²⁺ ions coordinate with water, orienting and stabilizing the molecule and allowing water to act as a nucleophile and attack L-arginine, hydrolyzing it into orinithine and urea<ref name="c"/>. Overall the two manganese metal ion in arginase maintain the proper function of the enzyme<ref name="b"/>.

==='''Mechanism'''===

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In general arginase is known to convert L-arginine into urea and L-ornithine, via hydrolysis, the proposed mechanism is adopted from Kanyo and colleagues as shown in figure 3<ref name="d"/>. In the first step of the hydrolytic mechanism, Asp 220 stabilizes the metal-bridging hydroxide ion with a hydrogen bond during a nucleophilic attack at the guanidinium carbon of arginine<ref name="b"/><ref name="d"/>. The resulting tetrahedral intermediate fall apart once a proton is transferred to the amino group of ornithine, and the proton transfer is mediated by Asp 220<ref name="b"/><ref name="d"/>. It is proposed that His 233 shuttles a proton from bulk solvent to the ε-amino group of ornithine, before the product dissociation, as well a water molecule displaces urea<ref name="b"/><ref name="d"/>. In addition, the metal coordination facilitates the ionization of this water molecule to regenerate a nucleophilic hydroxide ion<ref name="d"/>. During this process a proton transfer occurs to the bulk solvent and is mediated by shuttle-group His 233<ref name="b"/><ref name="d"/>.

==='''Arginase and the Physiology of Sexual Arousal'''===

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Female sexual arousal disorder is defined as an inability to achieve or maintain sufficient sexual excitement, including clitoral erection and genital engorgement, and it is a physiologically analogous to male erectile dysfunction, which is defined as a  deficiency in genital blood circulation which compromises the hemodynamic of erectons<ref name="c"/>. Nitric oxide (NO) is the principle mediator of erectile functions and governs nonadrenergic, noncholinergic neurotransmission in penile corpus cavernosum smooth muscle<ref name="c"/>. NO cause’s rapid relaxation of smooth muscle tissue and thereby facilitates the engorgement of the corpus cavernosum<ref name="c"/>. Thus, NO synthase is a critical enzyme in the physiology of sexual arousal<ref name="c"/>. Also, human arginase II is a critical enzyme in the physiology of sexual arousal, due to the fact it coexpressed with NO synthase in smooth muscle tissue<ref name="c"/>. Given that hAII and NO synthase compete for the same substrate L-arginine, arginase appears to attenuate NO synthase activity and NO-dependent smooth muscle relaxation by depleting the substrate pool of L-arginine that would be available to NO synthase<ref name="c"/>. In addition arginase is inhibited by the boronic acid inhibitor (<scene name='Sandbox_Reserved_322/Abh/1'>ABH</scene>), which maintains L-arginine concentrations, which in turn enhances NO synthase activity and NO-dependent smooth muscle relaxation in tissue<ref name="c"/>. Thus over expression of human arginase II contributes to erectile dysfunction, and human penile arginase is a potential target for the treatment of male sexual dysfunction<ref name="c"/>.

==='''Reference'''===

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