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==Carbonic anhydrase II mutant (I91C) dually binding an IrCp* complex to generate an artificial transfer hydrogenase (ATHase)== | ==Carbonic anhydrase II mutant (I91C) dually binding an IrCp* complex to generate an artificial transfer hydrogenase (ATHase)== | ||
<StructureSection load='7onv' size='340' side='right'caption='[[7onv]]' scene=''> | <StructureSection load='7onv' size='340' side='right'caption='[[7onv]], [[Resolution|resolution]] 1.04Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7ONV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ONV FirstGlance]. <br> | <table><tr><td colspan='2'>[[7onv]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7ONV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ONV FirstGlance]. <br> | ||
</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=7onv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7onv OCA], [https://pdbe.org/7onv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7onv RCSB], [https://www.ebi.ac.uk/pdbsum/7onv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7onv ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=O:OXYGEN+ATOM'>O</scene>, <scene name='pdbligand=VKZ:4-[2-(4-azanyl-9-chloranyl-2,3,4,5,6-pentamethyl-7-oxidanylidene-spiro[1$l^{4},8-diaza-9$l^{8}-iridabicyclo[4.3.0]nona-1,3,5-triene-9,1-1$l^{8}-iridapentacyclo[2.2.0.0^{1,3}.0^{1,5}.0^{2,6}]hexane]-8-yl)ethyl]benzenesulfonamide'>VKZ</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'>[https://en.wikipedia.org/wiki/Carbonate_dehydratase Carbonate dehydratase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=7onv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7onv OCA], [https://pdbe.org/7onv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7onv RCSB], [https://www.ebi.ac.uk/pdbsum/7onv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7onv ProSAT]</span></td></tr> | |||
</table> | </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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Artificial metalloenzymes result from anchoring a metal cofactor within a host protein. Such hybrid catalysts combine the selectivity and specificity of enzymes with the versatility of (abiotic) transition metals to catalyze new-to-nature reactions in an evolvable scaffold. With the aim of improving the localization of an arylsulfonamide-bearing iridium-pianostool catalyst within human carbonic anhydrase II (hCAII) for the enantioselective reduction of prochiral imines, we introduced a covalent linkage between the host and the guest. Herein, we show that a judiciously positioned cysteine residue reacts with a p-nitropicolinamide ligand bound to iridium to afford an additional sulfonamide covalent linkage. Three rounds of directed evolution, performed on the dually anchored cofactor, led to improved activity and selectivity for the enantioselective reduction of harmaline (up to 97% ee (R) and >350 turnovers on a preparative scale). To evaluate the substrate scope, the best hits of each generation were tested with eight substrates. X-ray analysis, carried out at various stages of the evolutionary trajectory, was used to scrutinize (i) the nature of the covalent linkage between the cofactor and the host as well as (ii) the remodeling of the substrate-binding pocket. | |||
A Dual Anchoring Strategy for the Directed Evolution of Improved Artificial Transfer Hydrogenases Based on Carbonic Anhydrase.,Stein A, Chen D, Igareta NV, Cotelle Y, Rebelein JG, Ward TR ACS Cent Sci. 2021 Nov 24;7(11):1874-1884. doi: 10.1021/acscentsci.1c00825. Epub , 2021 Nov 11. PMID:34849402<ref>PMID:34849402</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7onv" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Carbonate dehydratase]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Cotelle Y]] | [[Category: Cotelle, Y]] | ||
[[Category: Dongping C]] | [[Category: Dongping, C]] | ||
[[Category: Rebelein | [[Category: Rebelein, J G]] | ||
[[Category: Stein A]] | [[Category: Stein, A]] | ||
[[Category: Ward | [[Category: Ward, T R]] | ||
[[Category: Artificial metalloenzyme]] | |||
[[Category: Artificial transfer hydrogenase]] | |||
[[Category: Metal binding protein]] | |||
[[Category: Oxidoreductase]] | |||
Revision as of 20:00, 15 December 2021
Carbonic anhydrase II mutant (I91C) dually binding an IrCp* complex to generate an artificial transfer hydrogenase (ATHase)Carbonic anhydrase II mutant (I91C) dually binding an IrCp* complex to generate an artificial transfer hydrogenase (ATHase)
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 PubMedArtificial metalloenzymes result from anchoring a metal cofactor within a host protein. Such hybrid catalysts combine the selectivity and specificity of enzymes with the versatility of (abiotic) transition metals to catalyze new-to-nature reactions in an evolvable scaffold. With the aim of improving the localization of an arylsulfonamide-bearing iridium-pianostool catalyst within human carbonic anhydrase II (hCAII) for the enantioselective reduction of prochiral imines, we introduced a covalent linkage between the host and the guest. Herein, we show that a judiciously positioned cysteine residue reacts with a p-nitropicolinamide ligand bound to iridium to afford an additional sulfonamide covalent linkage. Three rounds of directed evolution, performed on the dually anchored cofactor, led to improved activity and selectivity for the enantioselective reduction of harmaline (up to 97% ee (R) and >350 turnovers on a preparative scale). To evaluate the substrate scope, the best hits of each generation were tested with eight substrates. X-ray analysis, carried out at various stages of the evolutionary trajectory, was used to scrutinize (i) the nature of the covalent linkage between the cofactor and the host as well as (ii) the remodeling of the substrate-binding pocket. A Dual Anchoring Strategy for the Directed Evolution of Improved Artificial Transfer Hydrogenases Based on Carbonic Anhydrase.,Stein A, Chen D, Igareta NV, Cotelle Y, Rebelein JG, Ward TR ACS Cent Sci. 2021 Nov 24;7(11):1874-1884. doi: 10.1021/acscentsci.1c00825. Epub , 2021 Nov 11. PMID:34849402[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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