Abstract
A newly described β-carbonic anhydrase (CA, EC 4.2.1.1) from the pathogenic protozoan Entamoeba histolytica, EhiCA, was recently shown to possess a significant catalytic activity for the physiologic CO2 hydration reaction (kcat of 6.7 × 105 s−1 and a kcat/Km of 8.9 × 107 M−1 s−1). A panel of sulfonamides and one sulfamate, some of which are clinically used drugs, were investigated for their inhibitory properties against EhiCA. The best inhibitors detected in the study were 4-hydroxymethyl/ethyl-benzenesulfonamide (KIs of 36–89 nM), whereas some sulfanilyl-sulfonamides showed activities in the range of 285–331 nM. Acetazolamide, methazolamide, ethoxzolamide, and dichlorophenamide were less effective inhibitors (KIs of 509–845 nM) compared to other sulfonamides investigated here. As β-CAs are not present in vertebrates, the present study may be useful for detecting lead compounds for the design of more effective inhibitors with potential to develop anti-infectives with alternative mechanisms of action.
Highlights
The pathogenic protozoan Entamoeba histolytica is the leading cause of diarrhea globally, producing a disease called amebiasis
Like most enzymes belonging to the CA superfamily, EhiCA was inhibited by acetazolamide (AZA, 5-acetamido-1,3,4-thiadiazole-2-sulfonamide), a standard, clinically used sulfonamide CA inhibitor [1,2,3]
EhiCA shows a catalytic activity similar to that of mtCA 2 and hCA I, being a highly effective catalyst for the hydration of CO2, whereas its inhibition by acetazolamide is similar to the behavior of mtCA 1, which has a low affinity for this inhibitor, with a KI of 480 nM, comparable to that of EhiCA, of 509 nM (Table 1)
Summary
The pathogenic protozoan Entamoeba histolytica is the leading cause of diarrhea globally, producing a disease called amebiasis. We have investigated the role of the metalloenzymes, carbonic anhydrases (CAs, EC 4.2.1.1), in various pathogenic organisms belonging to the bacteria, fungal or protozoan domains [11,12,13]. These enzymes effectively catalyze the reaction between CO2 and water, with the formation of bicarbonate (HCO3−) and protons (H+), being among the very fast catalysts known in nature [14,15,16,17,18,19,20]. We report an investigation of the catalytic activity and the sulfonamide/sulfamate inhibition profile of the recombinant enzyme belonging to the β-class, identified in the genome of the pathogenic protozoan E. histolytica, denominated EhiCA
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