This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.
Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.
Sandbox Reserved 322
From Proteopedia
| Line 8: | Line 8: | ||
---- | ---- | ||
Arginase is a 105 kD homotrimeric metallo-protein that 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 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 that 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 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>. | ||
| + | |||
The two types of arginases 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 ureohydrolase superfamily, which also includes agmatinase, histone de-acetylase and acetylpolyamine amidohydrolase<ref name="a"/>. | The two types of arginases 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 ureohydrolase superfamily, which also includes agmatinase, histone de-acetylase and acetylpolyamine amidohydrolase<ref name="a"/>. | ||
==='''Structure and Function'''=== | ==='''Structure and Function'''=== | ||
---- | ---- | ||
| - | 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 1. 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"/>. 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>. | + | 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 1. 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"/>. |
| + | |||
| + | 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 β-sheet, and the metal binding sites is located on the edge of the β-sheet4. The metal ion that is more deeply situated in the active-site cleft is designated Mn2+A while the other metal ion is designated Mn2+B. Mn2+A is coordinated by His 101, Asp124, Asp 128, Asp 232 and a solvent molecule, with a square pyramidal geometry4. The solvent molecule bridges both metal ions and also donates a hydrogen bond to Asp 1284. Mn2+B is coordinated by His 126, Asp 124, Asp 232, Asp 234 and the bridging solvent molecule in a distorted octahedral fashion4. All metal ligands except for Asp 128 make hydrogen-bond interactions with other protein residues, and these interactions contribute to the stability of the metal binding site4. | One site of the active-site cleft is partially defined by the central 8-stranded β-sheet, and the metal binding sites is located on the edge of the β-sheet4. The metal ion that is more deeply situated in the active-site cleft is designated Mn2+A while the other metal ion is designated Mn2+B. Mn2+A is coordinated by His 101, Asp124, Asp 128, Asp 232 and a solvent molecule, with a square pyramidal geometry4. The solvent molecule bridges both metal ions and also donates a hydrogen bond to Asp 1284. Mn2+B is coordinated by His 126, Asp 124, Asp 232, Asp 234 and the bridging solvent molecule in a distorted octahedral fashion4. All metal ligands except for Asp 128 make hydrogen-bond interactions with other protein residues, and these interactions contribute to the stability of the metal binding site4. | ||
| + | |||
There are three different types of bridging metal ligands that facilitate the observed spin coupling between Mn2+A and Mn2+B4. For the first ligand, the carboxylate side chain of Asp 124 is a syn-syn bidentate bridging ligand, with Oδ1 coordinated to Mn2+A and Oδ2 coordinated to Mn2+B4. For the second ligand, the carboxylate side chain of Asp 232 is a monodentate briging ligand, with Oδ1 coordinated to both Mn2+A and Mn2+B with anti- and syn-coordination stereochemistry, respectively4. And finally the third ligand, is the solvent molecule bridges both manganese ion symmetrically4. Overall the two manganese metal role in aginase is to maintain proper function of the enzyme2. 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 urea3. | There are three different types of bridging metal ligands that facilitate the observed spin coupling between Mn2+A and Mn2+B4. For the first ligand, the carboxylate side chain of Asp 124 is a syn-syn bidentate bridging ligand, with Oδ1 coordinated to Mn2+A and Oδ2 coordinated to Mn2+B4. For the second ligand, the carboxylate side chain of Asp 232 is a monodentate briging ligand, with Oδ1 coordinated to both Mn2+A and Mn2+B with anti- and syn-coordination stereochemistry, respectively4. And finally the third ligand, is the solvent molecule bridges both manganese ion symmetrically4. Overall the two manganese metal role in aginase is to maintain proper function of the enzyme2. 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 urea3. | ||
Revision as of 04:53, 2 April 2011
| This Sandbox is Reserved from January 10, 2010, through April 10, 2011 for use in BCMB 307-Proteins course taught by Andrea Gorrell at the University of Northern British Columbia, Prince George, BC, Canada. |
To get started:
More help: Help:Editing |
| |||||||
| 3mmr, resolution 2.14Å () | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , | ||||||
| Gene: | PFI0320w (Plasmodium falciparum 3D7) | ||||||
| Activity: | Arginase, with EC number 3.5.3.1 | ||||||
| |||||||
| Resources: | FirstGlance, OCA, RCSB, PDBsum | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Contents |
Arginase
Introduction
Arginase is a 105 kD homotrimeric metallo-protein that catalysis the hydrolysis of arginine to ornithine and urea by means of a binuclear spin-coupled Mn2+ cluster in the active site[1]. Many organisms contain the enzyme arginase, for example Homo sapiens and Plasmodium falciparum, a parasite that causes cerebral malaria[2]. In humans there are two forms of arginases that have evolved with differing tissue distributions and sub-cellular locations in mammals[3].
The two types of arginases found in mammalian, are arginase I (hAI) and arginases II (hAII)[3]. Arginase I is found predominantly in the liver, where it catalyzes the final cytosolic step of the urea cycle[3]. 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[3]. 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[1]. In addition the arginase fold is part of the ureohydrolase superfamily, which also includes agmatinase, histone de-acetylase and acetylpolyamine amidohydrolase[1].
Structure and Function
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 1. 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[3]. Additionally Plasmodium falciparum arginase is comparable to human arginase, due to the fact that it is 27% identical with human aginase I and II[2].
Overall arginase is a homotrimeric metallo-enzyme with a binuclear manganese cluster in each monomer as shown in the PDB identifier 3mmr[3]. The overall fold of the arginase monomer belongs to the α/β protein class with a globular structure[4]. One site of the active-site cleft is partially defined by the central 8-stranded β-sheet, and the metal binding sites is located on the edge of the β-sheet4. The metal ion that is more deeply situated in the active-site cleft is designated Mn2+A while the other metal ion is designated Mn2+B. Mn2+A is coordinated by His 101, Asp124, Asp 128, Asp 232 and a solvent molecule, with a square pyramidal geometry4. The solvent molecule bridges both metal ions and also donates a hydrogen bond to Asp 1284. Mn2+B is coordinated by His 126, Asp 124, Asp 232, Asp 234 and the bridging solvent molecule in a distorted octahedral fashion4. All metal ligands except for Asp 128 make hydrogen-bond interactions with other protein residues, and these interactions contribute to the stability of the metal binding site4.
There are three different types of bridging metal ligands that facilitate the observed spin coupling between Mn2+A and Mn2+B4. For the first ligand, the carboxylate side chain of Asp 124 is a syn-syn bidentate bridging ligand, with Oδ1 coordinated to Mn2+A and Oδ2 coordinated to Mn2+B4. For the second ligand, the carboxylate side chain of Asp 232 is a monodentate briging ligand, with Oδ1 coordinated to both Mn2+A and Mn2+B with anti- and syn-coordination stereochemistry, respectively4. And finally the third ligand, is the solvent molecule bridges both manganese ion symmetrically4. Overall the two manganese metal role in aginase is to maintain proper function of the enzyme2. 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 urea3.
Reference
- ↑ 1.0 1.1 1.2 Wells GA, Muller IB, Wrenger C, Louw AI. The activity of Plasmodium falciparum arginase is mediated by a novel inter-monomer salt-bridge between Glu295-Arg404. FEBS J. 2009 Jul;276(13):3517-30. Epub 2009 May 18. PMID:19456858 doi:10.1111/j.1742-4658.2009.07073.x
- ↑ 2.0 2.1 Dowling DP, Ilies M, Olszewski KL, Portugal S, Mota MM, Llinas M, Christianson DW. Crystal Structure of Arginase from Plasmodium falciparum and Implications for l-Arginine Depletion in Malarial Infection . Biochemistry. 2010 Jun 9. PMID:20527960 doi:10.1021/bi100390z
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Christianson DW. Arginase: structure, mechanism, and physiological role in male and female sexual arousal. Acc Chem Res. 2005 Mar;38(3):191-201. PMID:15766238 doi:10.1021/ar040183k
- ↑ Kanyo ZF, Scolnick LR, Ash DE, Christianson DW. Structure of a unique binuclear manganese cluster in arginase. Nature. 1996 Oct 10;383(6600):554-7. PMID:8849731 doi:10.1038/383554a0
- ↑ Wells GA, Muller IB, Wrenger C, Louw AI. The activity of Plasmodium falciparum arginase is mediated by a novel inter-monomer salt-bridge between Glu295-Arg404. FEBS J. 2009 Jul;276(13):3517-30. Epub 2009 May 18. PMID:19456858 doi:10.1111/j.1742-4658.2009.07073.x
- ↑ Dowling DP, Ilies M, Olszewski KL, Portugal S, Mota MM, Llinas M, Christianson DW. Crystal Structure of Arginase from Plasmodium falciparum and Implications for l-Arginine Depletion in Malarial Infection . Biochemistry. 2010 Jun 9. PMID:20527960 doi:10.1021/bi100390z
- ↑ Christianson DW. Arginase: structure, mechanism, and physiological role in male and female sexual arousal. Acc Chem Res. 2005 Mar;38(3):191-201. PMID:15766238 doi:10.1021/ar040183k
- ↑ Kanyo ZF, Scolnick LR, Ash DE, Christianson DW. Structure of a unique binuclear manganese cluster in arginase. Nature. 1996 Oct 10;383(6600):554-7. PMID:8849731 doi:10.1038/383554a0
