5bnl: Difference between revisions
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==Deciphering the Mechanism of Carbonic Anhydrase Inhibition with Coumarins and Thiocoumarins== | ==Deciphering the Mechanism of Carbonic Anhydrase Inhibition with Coumarins and Thiocoumarins== | ||
<StructureSection load='5bnl' size='340' side='right' caption='[[5bnl]], [[Resolution|resolution]] 2.00Å' scene=''> | <StructureSection load='5bnl' size='340' side='right'caption='[[5bnl]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5bnl]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BNL OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5bnl]] 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=5BNL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5BNL FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2HC:(2E)-3-(2-HYDROXYPHENYL)ACRYLIC+ACID'>2HC</scene>, <scene name='pdbligand=HG:MERCURY+(II)+ION'>HG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene | </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=2HC:(2E)-3-(2-HYDROXYPHENYL)ACRYLIC+ACID'>2HC</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=5bnl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bnl OCA], [https://pdbe.org/5bnl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5bnl RCSB], [https://www.ebi.ac.uk/pdbsum/5bnl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5bnl ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Disease == | == 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 == | == 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> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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==See Also== | ==See Also== | ||
*[[Carbonic anhydrase|Carbonic anhydrase]] | *[[Carbonic anhydrase 3D structures|Carbonic anhydrase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Maresca | [[Category: Large Structures]] | ||
[[Category: Masereel | [[Category: Maresca A]] | ||
[[Category: Pochet | [[Category: Masereel B]] | ||
[[Category: Scozzafava | [[Category: Pochet L]] | ||
[[Category: Supuran | [[Category: Scozzafava A]] | ||
[[Category: Temperini | [[Category: Supuran CT]] | ||
[[Category: Temperini C]] | |||
Latest revision as of 14:16, 10 January 2024
Deciphering the Mechanism of Carbonic Anhydrase Inhibition with Coumarins and ThiocoumarinsDeciphering the Mechanism of Carbonic Anhydrase Inhibition with Coumarins and Thiocoumarins
Structural highlights
DiseaseCAH2_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] FunctionCAH2_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 PubMedCoumarin derivatives were recently shown to constitute a totally new class of inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), being hydrolyzed within the CA active site to 2-hydroxycinnamic acids. We explore here a new series of variously substituted coumarins and a thiocoumarin for their interaction with 13 mammalian CA isoforms, detecting low nanomolar and isoform selective inhibitors. The mechanism of action of this class of inhibitors is delineated in detail by resolving the X-ray crystal structure of CA II in complex with trans-2-hydroxy-cinnamic acid, the in situ hydrolysis product of simple coumarin. Thiocoumarins also act as efficient CAIs, similarly to coumarins. The versatility of the (thio)coumarin chemistry, the cis-trans isomerization evidenced here, and easy derivatization of the (thio)coumarin rings, coupled with the nanomolar inhibition range of several isozymes, afford isoform-selective CAIs with various biomedical applications, which render these classes of compounds superior to the clinically used sulfonamides. Deciphering the mechanism of carbonic anhydrase inhibition with coumarins and thiocoumarins.,Maresca A, Temperini C, Pochet L, Masereel B, Scozzafava A, Supuran CT J Med Chem. 2010 Jan 14;53(1):335-44. doi: 10.1021/jm901287j. PMID:19911821[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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