2osm
From Proteopedia
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'''Inhibition of Carbonic Anhydrase II by Thioxolone: A Mechanistic and Structural Study''' | '''Inhibition of Carbonic Anhydrase II by Thioxolone: A Mechanistic and Structural Study''' | ||
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[[Category: Tripp, B C.]] | [[Category: Tripp, B C.]] | ||
[[Category: 2-hydroxythiophenol]] | [[Category: 2-hydroxythiophenol]] | ||
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Revision as of 08:34, 4 May 2008
Inhibition of Carbonic Anhydrase II by Thioxolone: A Mechanistic and Structural Study
Overview
This paper examines the functional mechanism of thioxolone, a compound recently identified as a weak inhibitor of human carbonic anhydrase II by Iyer et al. (2006) J. Biomol. Screening 11, 782-791 . Thioxolone lacks sulfonamide, sulfamate, or hydroxamate functional groups that are typically found in therapeutic carbonic anhydrase (CA) inhibitors, such as acetazolamide. Analytical chemistry and biochemical methods were used to investigate the fate of thioxolone upon binding to CA II, including Michaelis-Menten kinetics of 4-nitrophenyl acetate esterase cleavage, liquid chromatography-mass spectrometry (LC-MS), oxygen-18 isotope exchange studies, and X-ray crystallography. Thioxolone is proposed to be a prodrug inhibitor that is cleaved via a CA II zinc-hydroxide mechanism known to catalyze the hydrolysis of esters. When thioxolone binds in the active site of CA II, it is cleaved and forms 4-mercaptobenzene-1,3-diol via the intermediate S-(2,4-thiophenyl)hydrogen thiocarbonate. The esterase cleavage product binds to the zinc active site via the thiol group and is therefore the active CA inhibitor, while the intermediate is located at the rim of the active-site cavity. The time-dependence of this inhibition reaction was investigated in detail. Because this type of prodrug inhibitor mechanism depends on cleavage of ester bonds, this class of inhibitors may have advantages over sulfonamides in determining isozyme specificity. A preliminary structure-activity relationship study with a series of structural analogues of thioxolone yielded similar estimates of inhibition constants for most compounds, although two compounds with bromine groups at the C1 carbon of thioxolone were not inhibitory, suggesting a possible steric effect.
About this Structure
2OSM is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Inhibition of Carbonic Anhydrase II by Thioxolone: A Mechanistic and Structural Study., Barrese AA 3rd, 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. 2008 Mar 11;47(10):3174-3184. Epub 2008 Feb 12. PMID:18266323 Page seeded by OCA on Sun May 4 11:34:28 2008
