Anion inhibitors of the β-carbonic anhydrase from the pathogenic bacterium responsible of tularemia, Francisella tularensis. Issue 17 (1st September 2017)

• Record Type: Journal Article
• Authors: Del Prete, Sonia; Vullo, Daniela; Osman, Sameh M.; AlOthman, Zeid; Donald, William A.; Winum, Jean-Yves; Supuran, Claudiu T.; Capasso, Clemente
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 17(2017)
• Page Start: 4800
• Page End: 4804
• Publication Date: 2017-09-01
• Subjects: Carbonic anhydrase -- β-Class -- CA inhibitors -- Anions -- Francisella tularensis -- Tularemia; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.07.033
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: A β-class carbonic anhydrase (CA, EC 4.2.1.1) from the pathogenic bacterium Francisella tularensis (FtuβCA) was cloned and purified, and the anion inhibition profile was investigated. Based on the measured kinetic parameters for the enzyme catalyzed CO2 hydration reaction (kcat of 9.8 × 10 5 s −1 and a kcat /KM of 8.9 × 10 7 M −1 s −1 ), FtuβCA is a highly effective enzyme. The activity of FtuβCA was not inhibited by a range of anions that do not typically coordinate Zn(II) effectively, including perchlorate, tetrafluoroborate, and hexafluorophosphate. Surprisingly, some anions which generally complex well with many cations, including Zn(II), also did not effectively inhibit FtuβCA, e.g., fluoride, cyanide, azide, nitrite, bisulphite, sulfate, tellurate, perrhenate, perrhuthenate, and peroxydisulfate. However, the most effective inhibitors were in the range of 90–94 µM (sulfamide, sulfamic acid, phenylarsonic and phenylboronic acid). N, N -Diethyldithiocarbamate (K I of 0.31 mM) was a moderately potent inhibitor. As Francisella tularensis is the causative agent of tularemia, the discovery of compounds that can interfere with the life cycle of this pathogen may result in novel opportunities to fight antibiotic drug resistance.