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Synchrotron Radiation Provides a Plausible Explanation for the Generation of a Free Radical Adduct of Thioxolone in Mutant Carbonic Anhydrase II.

Sippel KH, Genis C, Govindasamy L, Agbandje-McKenna M, Kiddle JJ, Tripp BC, McKenna R
J Phys Chem Lett 1 2898-2902 (2010)
Cited: 7 times
EuropePMC logo PMID: 20976122

Abstract

Thioxolone acts as a prodrug in the presence of carbonic anhydrase II (CA II), whereby the molecule is cleaved by thioester hydrolysis to the carbonic anhydrase inhibitor, 4-mercaptobenzene-1,3-diol (TH0). Thioxolone was soaked into the proton transfer mutant H64A of CA II in an effort to capture a reaction intermediate via X-ray crystallography. Structure determination of the 1.2 Å resolution data revealed the TH0 had been modified to a 4,4'-disulfanediyldibenzene-1,3-diol, a product of crystallization conditions, and a zinc ligated 2,4-dihydroxybenzenesulfenic acid, most likely induced by radiation damage. Neither ligand was likely a result of an enzymatic mechanism.

Articles - 4fik mentioned but not cited (5)

  1. Dioxygen, an unexpected carbonic anhydrase ligand. Ferraroni M, Gaspari R, Scozzafava A, Cavalli A, Supuran CT. J Enzyme Inhib Med Chem 33 999-1005 (2018)
  2. Benchmark Sets for Binding Hot Spot Identification in Fragment-Based Ligand Discovery. Wakefield AE, Yueh C, Beglov D, Castilho MS, Kozakov D, Keserű GM, Whitty A, Vajda S. J Chem Inf Model 60 6612-6623 (2020)
  3. Development of Praziquantel sulphonamide derivatives as antischistosomal drugs. Angeli A, Ferraroni M, Carta F, Häberli C, Keiser J, Costantino G, Supuran CT. J Enzyme Inhib Med Chem 37 1479-1494 (2022)
  4. Diversely N-substituted benzenesulfonamides dissimilarly bind to human carbonic anhydrases: crystallographic investigations of N-nitrosulfonamides. Angeli A, Ferraroni M, Bonardi A, Supuran CT, Nocentini A. J Enzyme Inhib Med Chem 38 2178430 (2023)
  5. First-in-Class Dual Hybrid Carbonic Anhydrase Inhibitors and Transient Receptor Potential Vanilloid 1 Agonists Revert Oxaliplatin-Induced Neuropathy. Angeli A, Micheli L, Carta F, Ferraroni M, Pirali T, Fernandez Carvajal A, Ferrer Montiel A, Di Cesare Mannelli L, Ghelardini C, Supuran CT. J Med Chem 66 1616-1633 (2023)


Reviews citing this publication (1)

  1. Thermodynamic, kinetic, and structural parameterization of human carbonic anhydrase interactions toward enhanced inhibitor design. Linkuvienė V, Zubrienė A, Manakova E, Petrauskas V, Baranauskienė L, Zakšauskas A, Smirnov A, Gražulis S, Ladbury JE, Matulis D. Q Rev Biophys 51 e10 (2018)

Articles citing this publication (1)

  1. Structural and kinetic effects on changes in the CO(2) binding pocket of human carbonic anhydrase II. West D, Kim CU, Tu C, Robbins AH, Gruner SM, Silverman DN, McKenna R. Biochemistry 51 9156-9163 (2012)


Related citations provided by authors (1)

  1. Inhibition of Carbonic Anhydrase II by Thioxolone: A Mechanistic and Structural Study. Barrese AA, Genis C, Fisher SZ, Orwenyo JN, Kumara MT, Dutta SK, Phillips E, Kiddle JJ, Tu C, Silverman DN, Govindasamy L, Agbandje-McKenna M, McKenna R, Tripp BC Biochemistry 47 3174- (2008)

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