Mutation of Phe91 to Asn in human carbonic anhydrase I unexpectedly enhanced both catalytic activity and affinity for sulfonamide inhibitors.
Article Details
- CitationCopy to clipboard
Kockar F, Maresca A, Aydin M, Isik S, Turkoglu S, Sinan S, Arslan O, Guler OO, Turan Y, Supuran CT
Mutation of Phe91 to Asn in human carbonic anhydrase I unexpectedly enhanced both catalytic activity and affinity for sulfonamide inhibitors.
Bioorg Med Chem. 2010 Aug 1;18(15):5498-503. doi: 10.1016/j.bmc.2010.06.056. Epub 2010 Jun 22.
- PubMed ID
- 20624682 [ View in PubMed]
- Abstract
Site-directed mutagenesis has been used to change one amino acid residue considered non essential (Phe91Asn) to catalysis in carbonic anhydrase (CA, EC 4.2.1.1) isozyme I (hCA I), but which is near the substrate binding pocket of the enzyme. This change led to a steady increase of 16% of the catalytic activity of the mutant hCA I over the wild type enzyme, which is a gain of 50% catalytic efficiency if one compares hCA I and hCA II as catalysts for CO(2) hydration. This effect may be due to the bigger hydrophobic pocket in the mutant enzyme compared to the wild type one, which probably leads to the reorganization of the solvent molecules present in the cavity and to a diverse proton transfer pathway in the mutant over the non mutated enzyme. To our surprise, the mutant CA I was not only a better catalyst for the physiologic reaction, but in many cases also showed higher affinity (2.6-15.9 times) for sulfonamide/sulfamate inhibitors compared to the wild type enzyme. As the residue in position 91 is highly variable among the 13 catalytically active CA isoforms, this study may shed a better understanding of catalysis/inhibition by this superfamily of enzymes.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) 4-(2-AMINOETHYL)BENZENESULFONAMIDE Carbonic anhydrase 2 Ki (nM) 160 N/A N/A Details Acetazolamide Carbonic anhydrase 1 Ki (nM) 250 N/A N/A Details Acetazolamide Carbonic anhydrase 2 Ki (nM) 12 N/A N/A Details Celecoxib Carbonic anhydrase 2 Ki (nM) 21 N/A N/A Details Ethoxzolamide Carbonic anhydrase 1 Ki (nM) 25 N/A N/A Details Ethoxzolamide Carbonic anhydrase 2 Ki (nM) 8 N/A N/A Details Topiramate Carbonic anhydrase 1 Ki (nM) 250 N/A N/A Details Topiramate Carbonic anhydrase 2 Ki (nM) 10 N/A N/A Details Zonisamide Carbonic anhydrase 1 Ki (nM) 56 N/A N/A Details Zonisamide Carbonic anhydrase 2 Ki (nM) 35 N/A N/A Details