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Inhibition of Urease by Disulfiram, an FDA-Approved Thiol Reagent Used in Humans

2016; Multidisciplinary Digital Publishing Institute; Volume: 21; Issue: 12 Linguagem: Inglês

10.3390/molecules21121628

1433-1373

Ángel G. Díaz‐Sánchez, Emilio ́Álvarez-Parrilla, Alejandro Martínez‐Martínez, Luis Guadalupe Aguirre-Reyes, Jesica Orozpe-Olvera, Miguel Ramos-Soto, José A. Núñez‐Gastélum, Bonifacio Alvarado‐Tenorio, Laura A. de la Rosa,

Phytase and its Applications

Urease 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.