title: Inhibition of Urease by Disulfiram, an FDA-Approved Thiol Reagent Used in Humans.
abstract: 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 inCitrullus 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.
authors.affiliation: Departamento de Ciencias Químico-Biológicas, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua 32310, Mexico. angel.diaz@uacj.mx.
authors.forename: Ángel Gabriel
authors.initials: ÁG
authors.lastname: Díaz-Sánchez
authors.affiliation: Departamento de Ciencias Químico-Biológicas, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua 32310, Mexico. ealvarez@uacj.mx.
authors.forename: Emilio
authors.initials: E
authors.lastname: Alvarez-Parrilla
authors.affiliation: Departamento de Ciencias Químico-Biológicas, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua 32310, Mexico. alejandro.martinez@uacj.mx.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Martínez-Martínez
authors.affiliation: Departamento de Ciencias Químico-Biológicas, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua 32310, Mexico. laraguirre30@gmail.com.
authors.forename: Luis
authors.initials: L
authors.lastname: Aguirre-Reyes
authors.affiliation: Departamento de Ciencias Químico-Biológicas, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua 32310, Mexico. al113457@alumnos.uacj.mx.
authors.forename: Jesica Aline
authors.initials: JA
authors.lastname: Orozpe-Olvera
authors.affiliation: Departamento de Ciencias Químico-Biológicas, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua 32310, Mexico. al113429@alumnos.uacj.mx.
authors.forename: Miguel Armando
authors.initials: MA
authors.lastname: Ramos-Soto
authors.affiliation: Departamento de Ciencias Químico-Biológicas, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua 32310, Mexico. jose.nunez@uacj.mx.
authors.forename: José Alberto
authors.initials: JA
authors.lastname: Núñez-Gastélum
authors.affiliation: Departamento de Ciencias Químico-Biológicas, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua 32310, Mexico. bonifacio.alvarado@uacj.mx.
authors.forename: Bonifacio
authors.initials: B
authors.lastname: Alvarado-Tenorio
authors.affiliation: Departamento de Ciencias Químico-Biológicas, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua 32310, Mexico. ldelaros@uacj.mx.
authors.forename: Laura Alejandra
authors.initials: LA
authors.lastname: de la Rosa
mesh_terms: D004221:Disulfiram / Q000494:pharmacology*; D017277:Drug Approval / Q000331:legislation & jurisprudence; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D013439:Sulfhydryl Reagents / Q000494:pharmacology*; D014481:United States; D014486:United States Food and Drug Administration; D014510:Urease / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D013439:Sulfhydryl Reagents; D014510:Urease; D004221:Disulfiram
keywords: disulfiram; inhibition; urease