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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2016-11, Vol.21 (12), p.1628-1628
• Main Authors: Díaz-Sánchez, Ángel Gabriel, Alvarez-Parrilla, Emilio, Martínez-Martínez, Alejandro, Aguirre-Reyes, Luis, Orozpe-Olvera, Jesica Aline, Ramos-Soto, Miguel Armando, Núñez-Gastélum, José Alberto, Alvarado-Tenorio, Bonifacio, de la Rosa, Laura Alejandra
• Format: Article
• Language: English
• Subjects: Citrullus vulgaris; disulfiram; Disulfiram - pharmacology; Drug Approval - legislation & jurisprudence; Enzyme Inhibitors - pharmacology; inhibition; Kinetics; Sulfhydryl Reagents - pharmacology; United States; United States Food and Drug Administration; urease; Urease - antagonists & inhibitors
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules21121628

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 (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.