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| | <StructureSection load='6odz' size='340' side='right'caption='[[6odz]], [[Resolution|resolution]] 1.30Å' scene=''> | | <StructureSection load='6odz' size='340' side='right'caption='[[6odz]], [[Resolution|resolution]] 1.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6odz]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ODZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ODZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6odz]] is a 1 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=6ODZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ODZ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=M8J:2-(2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-N-(4-sulfamoylphenyl)acetamide'>M8J</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 1.3Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Carbonate_dehydratase Carbonate dehydratase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.1 4.2.1.1] </span></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=M8J:2-(2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)-N-(4-sulfamoylphenyl)acetamide'>M8J</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <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=6odz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6odz OCA], [http://pdbe.org/6odz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6odz RCSB], [http://www.ebi.ac.uk/pdbsum/6odz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6odz ProSAT]</span></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=6odz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6odz OCA], [https://pdbe.org/6odz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6odz RCSB], [https://www.ebi.ac.uk/pdbsum/6odz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6odz ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/CAH2_HUMAN CAH2_HUMAN]] Defects in CA2 are the cause of osteopetrosis autosomal recessive type 3 (OPTB3) [MIM:[http://omim.org/entry/259730 259730]]; also known as osteopetrosis with renal tubular acidosis, carbonic anhydrase II deficiency syndrome, Guibaud-Vainsel syndrome or marble brain disease. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. The disorder occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Autosomal recessive osteopetrosis is usually associated with normal or elevated amount of non-functional osteoclasts. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation.<ref>PMID:1928091</ref> <ref>PMID:1542674</ref> <ref>PMID:8834238</ref> <ref>PMID:9143915</ref> <ref>PMID:15300855</ref> | + | [https://www.uniprot.org/uniprot/CAH2_HUMAN CAH2_HUMAN] Defects in CA2 are the cause of osteopetrosis autosomal recessive type 3 (OPTB3) [MIM:[https://omim.org/entry/259730 259730]; also known as osteopetrosis with renal tubular acidosis, carbonic anhydrase II deficiency syndrome, Guibaud-Vainsel syndrome or marble brain disease. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. The disorder occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Autosomal recessive osteopetrosis is usually associated with normal or elevated amount of non-functional osteoclasts. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation.<ref>PMID:1928091</ref> <ref>PMID:1542674</ref> <ref>PMID:8834238</ref> <ref>PMID:9143915</ref> <ref>PMID:15300855</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CAH2_HUMAN CAH2_HUMAN]] Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye.<ref>PMID:10550681</ref> <ref>PMID:11831900</ref> | + | [https://www.uniprot.org/uniprot/CAH2_HUMAN CAH2_HUMAN] Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye.<ref>PMID:10550681</ref> <ref>PMID:11831900</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6odz" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6odz" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Carbonic anhydrase 3D structures|Carbonic anhydrase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Carbonate dehydratase]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Peat, T S]] | + | [[Category: Peat TS]] |
| - | [[Category: Carbonic anhydrase inhibitor]]
| + | |
| - | [[Category: Lyase-lyase inhibitor complex]]
| + | |
| - | [[Category: Metalloenzyme]]
| + | |
| - | [[Category: Organoselenium]]
| + | |
| Structural highlights
Disease
CAH2_HUMAN Defects in CA2 are the cause of osteopetrosis autosomal recessive type 3 (OPTB3) [MIM:259730; also known as osteopetrosis with renal tubular acidosis, carbonic anhydrase II deficiency syndrome, Guibaud-Vainsel syndrome or marble brain disease. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. The disorder occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Autosomal recessive osteopetrosis is usually associated with normal or elevated amount of non-functional osteoclasts. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation.[1] [2] [3] [4] [5]
Function
CAH2_HUMAN Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye.[6] [7]
Publication Abstract from PubMed
Carbonic Anhydrases have been recently validated as novel therapeutic targets in neuropathic pain. In this study, we combine the anticonvulsant propriety of spyrohydantoin and the CA inhibitor moiety of benzenesulfonamide to synthesize a novel series of spyrohydantoin bearing sulfonamides with strong activity against hCA II and VII. These isoforms are present in the nervous system and largely expressed both at the central as well as at peripheral level and can be modulated for pain relief. The crystal structures of hCA II in complex with selected compounds 5a-c demonstrate the importance of the tail in the binding modes within the isoform. Finally, in vivo, in an animal model of oxaliplatin induced neuropathy, compounds with organoselenium tails (8b-c) showed potent neuropathic pain attenuating effects. Taken together, these data strongly suggest the translational utility of these inhibitors as novel pain relievers.
Benzensulfonamides bearing spyrohydantoin moieties act as potent inhibitors of human carbonic anhydrases II and VII and show neuropathic pain attenuating effects.,Angeli A, Di Cesare Mannelli L, Ghelardini C, Peat TS, Bartolucci G, Menicatti M, Carta F, Supuran CT Eur J Med Chem. 2019 May 21;177:188-197. doi: 10.1016/j.ejmech.2019.05.058. PMID:31136893[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Venta PJ, Welty RJ, Johnson TM, Sly WS, Tashian RE. Carbonic anhydrase II deficiency syndrome in a Belgian family is caused by a point mutation at an invariant histidine residue (107 His----Tyr): complete structure of the normal human CA II gene. Am J Hum Genet. 1991 Nov;49(5):1082-90. PMID:1928091
- ↑ Roth DE, Venta PJ, Tashian RE, Sly WS. Molecular basis of human carbonic anhydrase II deficiency. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1804-8. PMID:1542674
- ↑ Soda H, Yukizane S, Yoshida I, Koga Y, Aramaki S, Kato H. A point mutation in exon 3 (His 107-->Tyr) in two unrelated Japanese patients with carbonic anhydrase II deficiency with central nervous system involvement. Hum Genet. 1996 Apr;97(4):435-7. PMID:8834238
- ↑ Hu PY, Lim EJ, Ciccolella J, Strisciuglio P, Sly WS. Seven novel mutations in carbonic anhydrase II deficiency syndrome identified by SSCP and direct sequencing analysis. Hum Mutat. 1997;9(5):383-7. PMID:9143915 doi:<383::AID-HUMU1>3.0.CO;2-5 10.1002/(SICI)1098-1004(1997)9:5<383::AID-HUMU1>3.0.CO;2-5
- ↑ Shah GN, Bonapace G, Hu PY, Strisciuglio P, Sly WS. Carbonic anhydrase II deficiency syndrome (osteopetrosis with renal tubular acidosis and brain calcification): novel mutations in CA2 identified by direct sequencing expand the opportunity for genotype-phenotype correlation. Hum Mutat. 2004 Sep;24(3):272. PMID:15300855 doi:10.1002/humu.9266
- ↑ Briganti F, Mangani S, Scozzafava A, Vernaglione G, Supuran CT. Carbonic anhydrase catalyzes cyanamide hydration to urea: is it mimicking the physiological reaction? J Biol Inorg Chem. 1999 Oct;4(5):528-36. PMID:10550681
- ↑ Kim CY, Whittington DA, Chang JS, Liao J, May JA, Christianson DW. Structural aspects of isozyme selectivity in the binding of inhibitors to carbonic anhydrases II and IV. J Med Chem. 2002 Feb 14;45(4):888-93. PMID:11831900
- ↑ Angeli A, Di Cesare Mannelli L, Ghelardini C, Peat TS, Bartolucci G, Menicatti M, Carta F, Supuran CT. Benzensulfonamides bearing spyrohydantoin moieties act as potent inhibitors of human carbonic anhydrases II and VII and show neuropathic pain attenuating effects. Eur J Med Chem. 2019 May 21;177:188-197. doi: 10.1016/j.ejmech.2019.05.058. PMID:31136893 doi:http://dx.doi.org/10.1016/j.ejmech.2019.05.058
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