Inhibition of Urease by Disulfiram, an FDA-Approved Thiol Reagent Used in Humans
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, a...
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| Format: | Article |
| Language: | English |
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MDPI AG
2016-11-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/21/12/1628 |
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| author | Ángel Gabriel Díaz-Sánchez Emilio Alvarez-Parrilla Alejandro Martínez-Martínez Luis Aguirre-Reyes Jesica Aline Orozpe-Olvera Miguel Armando Ramos-Soto José Alberto Núñez-Gastélum Bonifacio Alvarado-Tenorio Laura Alejandra de la Rosa |
| author_facet | Ángel Gabriel Díaz-Sánchez Emilio Alvarez-Parrilla Alejandro Martínez-Martínez Luis Aguirre-Reyes Jesica Aline Orozpe-Olvera Miguel Armando Ramos-Soto José Alberto Núñez-Gastélum Bonifacio Alvarado-Tenorio Laura Alejandra de la Rosa |
| author_sort | Ángel Gabriel Díaz-Sánchez |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-16T14:03:41Z |
| format | Article |
| id | doaj.art-6556b9e9b826435db1c73614f7804515 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-16T14:03:41Z |
| publishDate | 2016-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-6556b9e9b826435db1c73614f78045152022-12-21T22:28:58ZengMDPI AGMolecules1420-30492016-11-012112162810.3390/molecules21121628molecules21121628Inhibition of Urease by Disulfiram, an FDA-Approved Thiol Reagent Used in HumansÁngel Gabriel Díaz-Sánchez0Emilio Alvarez-Parrilla1Alejandro Martínez-Martínez2Luis Aguirre-Reyes3Jesica Aline Orozpe-Olvera4Miguel Armando Ramos-Soto5José Alberto Núñez-Gastélum6Bonifacio Alvarado-Tenorio7Laura Alejandra de la Rosa8Departamento de Ciencias Químico-Biológicas, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua 32310, MexicoDepartamento de Ciencias Químico-Biológicas, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua 32310, MexicoDepartamento de Ciencias Químico-Biológicas, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua 32310, MexicoDepartamento de Ciencias Químico-Biológicas, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua 32310, MexicoDepartamento de Ciencias Químico-Biológicas, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua 32310, MexicoDepartamento de Ciencias Químico-Biológicas, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua 32310, MexicoDepartamento de Ciencias Químico-Biológicas, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua 32310, MexicoDepartamento de Ciencias Químico-Biológicas, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua 32310, MexicoDepartamento de Ciencias Químico-Biológicas, Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Ciudad Juárez, Chihuahua 32310, MexicoUrease 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.http://www.mdpi.com/1420-3049/21/12/1628ureaseinhibitiondisulfiram |
| spellingShingle | Ángel Gabriel Díaz-Sánchez Emilio Alvarez-Parrilla Alejandro Martínez-Martínez Luis Aguirre-Reyes Jesica Aline Orozpe-Olvera Miguel Armando Ramos-Soto José Alberto Núñez-Gastélum Bonifacio Alvarado-Tenorio Laura Alejandra de la Rosa Inhibition of Urease by Disulfiram, an FDA-Approved Thiol Reagent Used in Humans Molecules urease inhibition disulfiram |
| title | Inhibition of Urease by Disulfiram, an FDA-Approved Thiol Reagent Used in Humans |
| title_full | Inhibition of Urease by Disulfiram, an FDA-Approved Thiol Reagent Used in Humans |
| title_fullStr | Inhibition of Urease by Disulfiram, an FDA-Approved Thiol Reagent Used in Humans |
| title_full_unstemmed | Inhibition of Urease by Disulfiram, an FDA-Approved Thiol Reagent Used in Humans |
| title_short | Inhibition of Urease by Disulfiram, an FDA-Approved Thiol Reagent Used in Humans |
| title_sort | inhibition of urease by disulfiram an fda approved thiol reagent used in humans |
| topic | urease inhibition disulfiram |
| url | http://www.mdpi.com/1420-3049/21/12/1628 |
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