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Bioorg Med Chem Lett. 2016 Jan 15;26(2):401-405. doi: 10.1016/j.bmcl.2015.11.104. Epub 2015 Dec 1.

Sulfonamide inhibition studies of the α-carbonic anhydrase from the gammaproteobacterium Thiomicrospira crunogena XCL-2, TcruCA.

Author information

1
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
2
Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Box 100245, Gainesville, FL 32610, USA.
3
Università degli Studi di Firenze, Polo Scientifico, Neurofarba Department and Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.

Abstract

We report a sulfonamide/sulfamate inhibition study of the α-carbonic anhydrase (CA, EC 4.2.1.1) present in the gammaproteobacterium Thiomicrospira crunogena XCL-2, a mesophilic hydrothermal vent-isolate organism, TcruCA. As Thiomicrospira crunogena is one of thousands of marine organisms that uses CA for metabolic regulation, the effect of sulfonamide inhibition has been considered. Sulfonamide-based drugs have been widely used in a variety of antibiotics, and bioelimination of these compounds results in exposure of these compounds to marine life. The enzyme was highly inhibited, with Ki values ranging from 2.5 to 40.7nM by a variety of sulfonamides including acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, benzolamide and benzenesulfonamides incorporating 4-hydroxyalkyl moieties. Less effective inhibitors were topiramate, zonisamide, celecoxib, saccharin and hydrochlorothiazide as well as simple benzenesulfonamides incorporating amino, halogeno, alkyl, aminoalkyl and other moieties in the ortho- or para-positions of the aromatic ring (Kis of 202-933nM). The active site interactions between TcruCA and three clinically-used CA inhibitors, acetazolamide (Diamox®), dorzolamide (Trusopt®), and brinzolamide (Azopt®) are studied using molecular docking to provide insight into the reported Ki values. Comparison between various enzymes belonging to this family may also bring interesting hints in these fascinating phenomena.

KEYWORDS:

CO(2) removal; Carbonic anhydrase; Sulfonamide; Thiomicrospira crunogena

PMID:
26691758
DOI:
10.1016/j.bmcl.2015.11.104
[Indexed for MEDLINE]

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