Inhibition of Urease by Disulfiram, an FDA-Approved Thiol Reagent Used in Humans
AbstractUrease is a nickel-dependent amidohydrolase that catalyses the decomposition of urea into carbamate and ammonia, a reaction that constitutes an important source of nitrogen for bacteria, fungi and plants. It is recognized as a potential antimicrobial target with an impact on medicine, agriculture, and the environment. The list of possible urease inhibitors is continuously increasing, with a special interest in those that interact with and block the flexible active site flap. We show that disulfiram inhibits urease in Citrullus vulgaris (CVU), following a non-competitive mechanism, and may be one of this kind of inhibitors. Disulfiram is a well-known thiol reagent that has been approved by the FDA for treatment of chronic alcoholism. We also found that other thiol reactive compounds (l-captopril and Bithionol) and quercetin inhibits CVU. These inhibitors protect the enzyme against its full inactivation by the thiol-specific reagent Aldrithiol (2,2′-dipyridyl disulphide, DPS), suggesting that the three drugs bind to the same subsite. Enzyme kinetics, competing inhibition experiments, auto-fluorescence binding experiments, and docking suggest that the disulfiram reactive site is Cys592, which has been proposed as a “hinge” located in the flexible active site flap. This study presents the basis for the use of disulfiram as one potential inhibitor to control urease activity. View Full-Text
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Díaz-Sánchez, Á.G.; Alvarez-Parrilla, E.; Martínez-Martínez, A.; Aguirre-Reyes, L.; Orozpe-Olvera, J.A.; Ramos-Soto, M.A.; Núñez-Gastélum, J.A.; Alvarado-Tenorio, B.; de la Rosa, L.A. Inhibition of Urease by Disulfiram, an FDA-Approved Thiol Reagent Used in Humans. Molecules 2016, 21, 1628.
Díaz-Sánchez ÁG, Alvarez-Parrilla E, Martínez-Martínez A, Aguirre-Reyes L, Orozpe-Olvera JA, Ramos-Soto MA, Núñez-Gastélum JA, Alvarado-Tenorio B, de la Rosa LA. Inhibition of Urease by Disulfiram, an FDA-Approved Thiol Reagent Used in Humans. Molecules. 2016; 21(12):1628.Chicago/Turabian Style
Díaz-Sánchez, Ángel G.; Alvarez-Parrilla, Emilio; Martínez-Martínez, Alejandro; Aguirre-Reyes, Luis; Orozpe-Olvera, Jesica A.; Ramos-Soto, Miguel A.; Núñez-Gastélum, José A.; Alvarado-Tenorio, Bonifacio; de la Rosa, Laura A. 2016. "Inhibition of Urease by Disulfiram, an FDA-Approved Thiol Reagent Used in Humans." Molecules 21, no. 12: 1628.
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