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| <StructureSection load='3thh' size='340' side='right'caption='[[3thh]], [[Resolution|resolution]] 1.85Å' scene=''> | | <StructureSection load='3thh' size='340' side='right'caption='[[3thh]], [[Resolution|resolution]] 1.85Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[3thh]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3THH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3THH FirstGlance]. <br> | | <table><tr><td colspan='2'>[[3thh]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3THH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3THH FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ABH:2(S)-AMINO-6-BORONOHEXANOIC+ACID'>ABH</scene>, <scene name='pdbligand=CO:COBALT+(II)+ION'>CO</scene></td></tr> | | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.85Å</td></tr> |
| <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3thj|3thj]], [[3the|3the]], [[3th7|3th7]], [[3tf3|3tf3]], [[2aeb|2aeb]], [[2pha|2pha]]</td></tr>
| | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ABH:2(S)-AMINO-6-BORONOHEXANOIC+ACID'>ABH</scene>, <scene name='pdbligand=CO:COBALT+(II)+ION'>CO</scene></td></tr> |
| <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ARG1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3thh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3thh OCA], [https://pdbe.org/3thh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3thh RCSB], [https://www.ebi.ac.uk/pdbsum/3thh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3thh ProSAT]</span></td></tr> |
| <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Arginase Arginase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.3.1 3.5.3.1] </span></td></tr>
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| <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3thh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3thh OCA], [http://pdbe.org/3thh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3thh RCSB], [http://www.ebi.ac.uk/pdbsum/3thh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3thh ProSAT]</span></td></tr> | |
| </table> | | </table> |
| == Disease == | | == Disease == |
| [[http://www.uniprot.org/uniprot/ARGI1_HUMAN ARGI1_HUMAN]] Defects in ARG1 are the cause of argininemia (ARGIN) [MIM:[http://omim.org/entry/207800 207800]]; also known as hyperargininemia. Argininemia is a rare autosomal recessive disorder of the urea cycle. Arginine is elevated in the blood and cerebrospinal fluid, and periodic hyperammonemia occurs. Clinical manifestations include developmental delay, seizures, mental retardation, hypotonia, ataxia, progressive spastic quadriplegia.<ref>PMID:1463019</ref> <ref>PMID:7649538</ref> | | [https://www.uniprot.org/uniprot/ARGI1_HUMAN ARGI1_HUMAN] Defects in ARG1 are the cause of argininemia (ARGIN) [MIM:[https://omim.org/entry/207800 207800]; also known as hyperargininemia. Argininemia is a rare autosomal recessive disorder of the urea cycle. Arginine is elevated in the blood and cerebrospinal fluid, and periodic hyperammonemia occurs. Clinical manifestations include developmental delay, seizures, mental retardation, hypotonia, ataxia, progressive spastic quadriplegia.<ref>PMID:1463019</ref> <ref>PMID:7649538</ref> |
| <div style="background-color:#fffaf0;">
| | == Function == |
| == Publication Abstract from PubMed == | | [https://www.uniprot.org/uniprot/ARGI1_HUMAN ARGI1_HUMAN] |
| The binuclear manganese metalloenzyme human arginase I (HAI) is a potential protein drug for cancer chemotherapy, in that it is capable of depleting extracellular l-Arg levels in the microenvironment of tumor cells that require this nutrient to thrive. Substitution of the native Mn(2+)(2) cluster with a Co(2+)(2) cluster in the active site yields an enzyme with enhanced catalytic activity at physiological pH ( approximately 7.4) that could serve as an improved protein drug for l-Arg depletion therapy [Stone, E. M., Glazer, E. S., Chantranupong, L., Cherukuri, P., Breece, R. M., Tierney, D. L., Curley, S. A., Iverson, B. L., and Georgiou, G. (2010) ACS Chem. Biol. 5, 333-342]. A different catalytic mechanism is proposed for Co(2+)(2)-HAI compared with that of Mn(2+)(2)-HAI, including an unusual Nepsilon-Co(2+) coordination mode, to rationalize the lower K(M) value of l-Arg and the lower K(i) value of l-Orn. However, we now report that no unusual metal coordination modes are observed in the cobalt-reconstituted enzyme. The X-ray crystal structures of unliganded Co(2+)(2)-HAI determined at 2.10 A resolution (pH 7.0) and 1.97 A resolution (pH 8.5), as well as the structures of Co(2+)(2)-HAI complexed with the reactive substrate analogue 2(S)-amino-6-boronohexanoic acid (ABH, pH 7.0) and the catalytic product l-Orn (pH 7.0) determined at 1.85 and 1.50 A resolution, respectively, are essentially identical to the corresponding structures of Mn(2+)(2)-HAI. Therefore, in the absence of significant structural differences between Co(2+)(2)-HAI and Mn(2+)(2)-HAI, we suggest that a higher concentration of metal-bridging hydroxide ion at physiological pH for Co(2+)(2)-HAI, a consequence of the lower pK(a) of a Co(2+)-bound water molecule compared with a Mn(2+)-bound water molecule, strengthens electrostatic interactions with cationic amino acids and accounts for enhanced affinity as reflected in the lower K(M) value of l-Arg and the lower K(i) value of l-Orn.
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| Crystal structures of complexes with cobalt-reconstituted human arginase I.,D'Antonio EL, Christianson DW Biochemistry. 2011 Sep 20;50(37):8018-27. Epub 2011 Aug 26. PMID:21870783<ref>PMID:21870783</ref>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 3thh" style="background-color:#fffaf0;"></div>
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| ==See Also== | | ==See Also== |
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Arginase]] | | [[Category: Homo sapiens]] |
| [[Category: Human]]
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| [[Category: Large Structures]] | | [[Category: Large Structures]] |
| [[Category: Antonio, E L.D]] | | [[Category: Christianson DW]] |
| [[Category: Christianson, D W]] | | [[Category: D'Antonio EL]] |
| [[Category: Arginase fold]]
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| [[Category: Hydrolase]]
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