Sandbox Reserved 322: Difference between revisions
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==='''Introduction'''=== | ==='''Introduction'''=== | ||
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[[Image:Arginases_homotrimer.jpg|thumb| | [[Image:Arginases_homotrimer.jpg|thumb|right|300px|Figure 1: Liver arginase illustrating that the general homotrimeric strucutre of arginase<ref name="Homotrimer">accessed April 3,2011: http://en.wikipedia.org/wiki/Arginase.</ref>.]] | ||
Arginase is a 105 kD homotrimeric metallo-protein, as shown in figure 1, and catalysis the hydrolysis of arginine to ornithine and urea by means of a binuclear spin-coupled Mn<sup>2+</sup> cluster in the active site<ref name="a">PMID: 19456858 </ref>. Many organisms contain the enzyme arginase, for example ''Homo sapiens'' and [http://en.wikipedia.org/wiki/Plasmodium_falciparum ''Plasmodium falciparum''], a parasite that causes cerebral malaria<ref name="b">PMID: 20527960 </ref>. In humans there are two forms of arginases that have evolved with differing tissue distributions and sub-cellular locations in mammals<ref name="c">PMID: 15766238 </ref>. | Arginase is a 105 kD homotrimeric metallo-protein, as shown in figure 1, and catalysis the hydrolysis of arginine to ornithine and urea by means of a binuclear spin-coupled Mn<sup>2+</sup> cluster in the active site<ref name="a">PMID: 19456858 </ref>. Many organisms contain the enzyme arginase, for example ''Homo sapiens'' and [http://en.wikipedia.org/wiki/Plasmodium_falciparum ''Plasmodium falciparum''], a parasite that causes cerebral malaria<ref name="b">PMID: 20527960 </ref>. In humans there are two forms of arginases that have evolved with differing tissue distributions and sub-cellular locations in mammals<ref name="c">PMID: 15766238 </ref>. | ||
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==='''Structure and Function'''=== | ==='''Structure and Function'''=== | ||
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[[Image:Arginine. | [[Image:Arginine.png|thumb|right|300px|Figure 2: General reaction of arginase hydrolyzing L-arginine to urea and L-ornithine adopted from Christianson<ref name="c"/>.]] | ||
In general arginase is a homotrimeric enzyme, which is present in the fifth and final step of the urea cycle for mammals. In humans, hAI converts L-arginine into L-orinithine and urea as shown in figure 2. Human arginase II plays a role in L-arginine homeostasis, by regulating L-arginine concentrations from cellular biosynthetic reactions such as nitric oxide (NO) biosynthesis<ref name="c"/>. Additionally ''Plasmodium falciparum'' arginase is comparable to human arginase, due to the fact that it is 27% identical with human aginase I and II<ref name="b"/>. | In general arginase is a homotrimeric enzyme, which is present in the fifth and final step of the urea cycle for mammals. In humans, hAI converts L-arginine into L-orinithine and urea as shown in figure 2. Human arginase II plays a role in L-arginine homeostasis, by regulating L-arginine concentrations from cellular biosynthetic reactions such as nitric oxide (NO) biosynthesis<ref name="c"/>. Additionally ''Plasmodium falciparum'' arginase is comparable to human arginase, due to the fact that it is 27% identical with human aginase I and II<ref name="b"/>. | ||
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==='''Mechanism'''=== | ==='''Mechanism'''=== | ||
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[[Image: | [[Image:Arginase_mechanism_(2).png|thumb|right|300px|Figure 3: Proposed mechanism of arginase hydrolyzing L-arginine to urea and L-ornithine adopted from Kanyo and colleagues<ref name="d"/>.]] | ||
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"/>. | 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"/>. | ||
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==='''Arginase and the Physiology of Sexual Arousal'''=== | ==='''Arginase and the Physiology of Sexual Arousal'''=== | ||
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[[Image:Arginine_catabloism_by_arginase_and_NO_synthase. | [[Image:Arginine_catabloism_by_arginase_and_NO_synthase.png|thumb|left|300px|Figure 4: Chemical reaction of arginine, illustrating how arginase and NO synthase compete for arginine<ref name="c"/>.]] | ||
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 as shown in figure 4, 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"/>. | 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 as shown in figure 4, 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"/>. | ||