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The | ==Synthesis, carbonic anhydrase inhibition and protein X-ray structure of the unusual natural product primary sulfonamide Psammaplin C== | ||
<StructureSection load='5a6h' size='340' side='right' caption='[[5a6h]], [[Resolution|resolution]] 1.57Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5a6h]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5A6H OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5A6H FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=OE2:PSAMMAPLIN+C'>OE2</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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='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=5a6h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5a6h OCA], [http://pdbe.org/5a6h PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5a6h RCSB], [http://www.ebi.ac.uk/pdbsum/5a6h PDBsum]</span></td></tr> | |||
</table> | |||
== 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> | |||
== 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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Psammaplin C is one of only two described natural product primary sulfonamides. Here we report the synthesis of psammaplin C and evaluate the inhibition profile against therapeutically relevant carbonic anhydrase (CA) zinc metalloenzymes. The compound exhibited unprecedented inhibition of an important cancer-associated isozyme, hCA XII, with a Ki of 0.79 nM. The compound also displayed good isoform selectivity for hCA XII over other CAs. We present the first reported protein X-ray crystal structures of psammaplin C in complex with human CAs. We engineered the easily crystallized hCA II enzyme to mimic both the hCA IX and hCA XII binding sites and then utilized protein X-ray crystallography to determine the binding pose of psammaplin C within the hCA II, hCA IX, and hCA XII mimic active sites, all to high resolution. This is the first time a natural product primary sulfonamide inhibitor has been assessed for inhibition and binding to CAs. | |||
An Unusual Natural Product Primary Sulfonamide: Synthesis, Carbonic Anhydrase Inhibition, and Protein X-ray Structures of Psammaplin C.,Mujumdar P, Teruya K, Tonissen KF, Vullo D, Supuran CT, Peat TS, Poulsen SA J Med Chem. 2016 May 23. PMID:27172398<ref>PMID:27172398</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5a6h" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Carbonate dehydratase]] | |||
[[Category: Mujumdar, P]] | |||
[[Category: Peat, T S]] | |||
[[Category: Poulsen, S]] | [[Category: Poulsen, S]] | ||
[[Category: | [[Category: Supuran, C T]] | ||
[[Category: | [[Category: Carbonic anhydrase inhibitor]] | ||
[[Category: | [[Category: Lyase]] | ||
[[Category: Natural product]] | |||
Revision as of 01:52, 2 June 2016
Synthesis, carbonic anhydrase inhibition and protein X-ray structure of the unusual natural product primary sulfonamide Psammaplin CSynthesis, carbonic anhydrase inhibition and protein X-ray structure of the unusual natural product primary sulfonamide Psammaplin C
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 PubMedPsammaplin C is one of only two described natural product primary sulfonamides. Here we report the synthesis of psammaplin C and evaluate the inhibition profile against therapeutically relevant carbonic anhydrase (CA) zinc metalloenzymes. The compound exhibited unprecedented inhibition of an important cancer-associated isozyme, hCA XII, with a Ki of 0.79 nM. The compound also displayed good isoform selectivity for hCA XII over other CAs. We present the first reported protein X-ray crystal structures of psammaplin C in complex with human CAs. We engineered the easily crystallized hCA II enzyme to mimic both the hCA IX and hCA XII binding sites and then utilized protein X-ray crystallography to determine the binding pose of psammaplin C within the hCA II, hCA IX, and hCA XII mimic active sites, all to high resolution. This is the first time a natural product primary sulfonamide inhibitor has been assessed for inhibition and binding to CAs. An Unusual Natural Product Primary Sulfonamide: Synthesis, Carbonic Anhydrase Inhibition, and Protein X-ray Structures of Psammaplin C.,Mujumdar P, Teruya K, Tonissen KF, Vullo D, Supuran CT, Peat TS, Poulsen SA J Med Chem. 2016 May 23. PMID:27172398[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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