Sandbox Reserved 322: Difference between revisions
Brian Huang (talk | contribs) No edit summary |
Brian Huang (talk | contribs) No edit summary |
||
| Line 13: | Line 13: | ||
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"/>. | 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'''=== | ==='''Structure and Function'''=== | ||
---- | ---- | ||
| Line 21: | Line 21: | ||
Overall arginase is a homotrimeric metallo-enzyme with a binuclear manganese <scene name='Sandbox_Reserved_322/Mn/5'>MN</scene> cluster in each monomer as shown in the PDB identifier 3mmr<ref name="c"/>. The overall fold of the arginase monomer belongs to the α/β protein class with a globular structure<ref name="d">PMID: 8849731 </ref>. | Overall arginase is a homotrimeric metallo-enzyme with a binuclear manganese <scene name='Sandbox_Reserved_322/Mn/5'>MN</scene> cluster in each monomer as shown in the PDB identifier 3mmr<ref name="c"/>. The overall fold of the arginase monomer belongs to the α/β protein class with a globular structure<ref name="d">PMID: 8849731 </ref>. | ||
One site of the active-site cleft is partially defined by the central 8-stranded <scene name='Sandbox_Reserved_322/8-stranded_beta-sheet/1'>β-sheet</scene>, and the <scene name='Sandbox_Reserved_322/Metal_binding_sites/1'>metal binding sites</scene> is located on the edge of the β-sheet<ref name="d"/>. The metal ion that is more deeply situated in the active-site cleft is designated <scene name='Sandbox_Reserved_322/Mn2a/1'>Mn2+A</scene> while the other metal ion is designated | One site of the active-site cleft is partially defined by the central 8-stranded <scene name='Sandbox_Reserved_322/8-stranded_beta-sheet/1'>β-sheet</scene>, and the <scene name='Sandbox_Reserved_322/Metal_binding_sites/1'>metal binding sites</scene> is located on the edge of the β-sheet<ref name="d"/>. The metal ion that is more deeply situated in the active-site cleft is designated <scene name='Sandbox_Reserved_322/Mn2a/1'>Mn2+A</scene> while the other metal ion is designated <scene name='Sandbox_Reserved_322/Mn_b/1'>Mn2+B</scene>. In ''Plasmodium falciparum'' arginase Mn<sup>2+</sup><sub>A</sub> is coordinated by <scene name='Sandbox_Reserved_322/Mna/1'>His 193, Asp 216, Asp 220, Asp 323</scene> and a solvent molecule, with a square pyramidal geometry<ref name="b"/><ref name="d"/>. The solvent molecule bridges both metal ions and also donates a hydrogen bond to Asp 220<ref name="b"/><ref name="d"/>. Mn<sup>2+</sup><sub>B</sub> is coordinated by <scene name='Sandbox_Reserved_322/Mnb/1'>His 218, Asp 216, Asp 323, Asp 325</scene> and the bridging solvent molecule in a distorted octahedral fashion<ref name="d"/>. All metal ligands except for Asp 220 make hydrogen-bond interactions with other protein residues, and these interactions contribute to the stability of the metal binding site<ref name="b"/><ref name="d"/>. | ||
There are three different types of bridging metal ligands that facilitate the observed spin coupling between Mn<sup>2+</sup><sub>A</sub> and Mn<sup>2+</sup><sub>B</sub><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 Mn<sup>2+</sup><sub>A</sub> and Oδ2 coordinated to Mn<sup>2+</sup><sub>B</sub><ref name="d"/>. For the second ligand, the carboxylate side chain of Asp 323 is a monodentate bridging ligand, with Oδ1 coordinated to both Mn<sup>2+</sup><sub>A</sub> and Mn<sup>2+</sup><sub>B</sub> 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 Mn<sup>2+</sup> 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"/>. | There are three different types of bridging metal ligands that facilitate the observed spin coupling between Mn<sup>2+</sup><sub>A</sub> and Mn<sup>2+</sup><sub>B</sub><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 Mn<sup>2+</sup><sub>A</sub> and Oδ2 coordinated to Mn<sup>2+</sup><sub>B</sub><ref name="d"/>. For the second ligand, the carboxylate side chain of Asp 323 is a monodentate bridging ligand, with Oδ1 coordinated to both Mn<sup>2+</sup><sub>A</sub> and Mn<sup>2+</sup><sub>B</sub> 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 Mn<sup>2+</sup> 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"/>. | ||