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| - | [[Image:2ez7.gif|left|200px]]<br /><applet load="2ez7" size="350" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="2ez7, resolution 2.0Å" /> | |
| - | '''Carbonic anhydrase activators. Activation of isozymes I, II, IV, VA, VII and XIV with L- and D-histidine and crystallographic analysis of their adducts with isoform II: engineering proton transfer processes within the active site of an enzyme'''<br /> | |
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| - | ==Overview== | + | ==Carbonic anhydrase activators. Activation of isozymes I, II, IV, VA, VII and XIV with L- and D-histidine and crystallographic analysis of their adducts with isoform II: engineering proton transfer processes within the active site of an enzyme== |
| - | Activation of six human carbonic anhydrases (CA, EC 4.2.1.1), that is, hCA I, II, IV, VA, VII, and XIV, with l- and d-histidine was investigated through kinetics and by X-ray crystallography. l-His was a potent activator of isozymes I, VA, VII, and XIV, and a weaker activator of hCA II and IV. d-His showed good hCA I, VA, and VII activation properties, being a moderate activator of hCA XIV and a weak activator of hCA II and IV. The structures as determined by X-ray crystallography of the hCA II-l-His/d-His adducts showed the activators to be anchored at the entrance of the active site, contributing to extended networks of hydrogen bonds with amino acid residues/water molecules present in the cavity, explaining their different potency and interaction patterns with various isozymes. The residues involved in l-His recognition were His64, Asn67, Gln92, whereas three water molecules connected the activator to the zinc-bound hydroxide. Only the imidazole moiety of l-His interacted with these amino acids. For the d-His adduct, the residues involved in recognition of the activator were Trp5, His64, and Pro201, whereas two water molecules connected the zinc-bound water to the activator. Only the COOH and NH(2) moieties of d-His participated in hydrogen bonds with these residues. This is the first study showing different binding modes of stereoisomeric activators within the hCA II active site, with consequences for overall proton-transfer processes (rate-determining for the catalytic cycle). The study also points out differences of activation efficiency between various isozymes with structurally related activators, convenient for designing alternative proton-transfer pathways, useful both for a better understanding of the catalytic mechanism and for obtaining pharmacologically useful derivatives, for example, for the management of Alzheimer's disease. | + | <StructureSection load='2ez7' size='340' side='right'caption='[[2ez7]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[2ez7]] 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=2EZ7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2EZ7 FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DHI:D-HISTIDINE'>DHI</scene>, <scene name='pdbligand=HG:MERCURY+(II)+ION'>HG</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'>[https://proteopedia.org/fgij/fg.htm?mol=2ez7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ez7 OCA], [https://pdbe.org/2ez7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ez7 RCSB], [https://www.ebi.ac.uk/pdbsum/2ez7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ez7 ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Disease == |
| | + | [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 == |
| | + | [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> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ez/2ez7_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2ez7 ConSurf]. |
| | + | <div style="clear:both"></div> |
| | | | |
| - | ==Disease== | + | ==See Also== |
| - | Known disease associated with this structure: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=611492 611492]]
| + | *[[Carbonic anhydrase 3D structures|Carbonic anhydrase 3D structures]] |
| - | | + | == References == |
| - | ==About this Structure== | + | <references/> |
| - | 2EZ7 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=HG:'>HG</scene>, <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=DHI:'>DHI</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2EZ7 OCA].
| + | __TOC__ |
| - | | + | </StructureSection> |
| - | ==Reference==
| + | |
| - | Carbonic anhydrase activators. Activation of isozymes I, II, IV, VA, VII, and XIV with l- and d-histidine and crystallographic analysis of their adducts with isoform II: engineering proton-transfer processes within the active site of an enzyme., Temperini C, Scozzafava A, Vullo D, Supuran CT, Chemistry. 2006 Sep 18;12(27):7057-66. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16807956 16807956]
| + | |
| - | [[Category: Carbonate dehydratase]]
| + | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Single protein]] | + | [[Category: Large Structures]] |
| - | [[Category: Scozzafava, A.]] | + | [[Category: Scozzafava A]] |
| - | [[Category: Supuran, C T.]] | + | [[Category: Supuran CT]] |
| - | [[Category: Temperini, C.]] | + | [[Category: Temperini C]] |
| - | [[Category: Vullo, D.]] | + | [[Category: Vullo D]] |
| - | [[Category: DHI]]
| + | |
| - | [[Category: HG]]
| + | |
| - | [[Category: ZN]]
| + | |
| - | [[Category: activators]]
| + | |
| - | [[Category: carbonic anhydrase ii]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:16:00 2008''
| + | |
| 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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
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
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