Artículo
Benznidazole (Bz), the drug used for treatment of Chagas' disease (caused by the protozoan Trypanosoma cruzi), is activated by a parasitic NADH-dependent type I nitroreductase (NTR I). However, several studies have shown that other enzymes are involved. The aim of this study was to evaluate whether the aldo-keto reductase from T. cruzi (TcAKR), a NADPH-dependent oxido-reductase previously described by our group, uses Bz as the substrate. We demonstrated that both recombinant and native TcAKR enzymes reduce Bz by using NADPH, but not NADH, as a cofactor. TcAKR-overexpressing epimastigotes showed higher NADPH-dependent Bz reductase activity and a 50% inhibitory concentration (IC50) value for Bz 1.8-fold higher than that of the controls, suggesting that TcAKR is involved in Bz detoxification instead of activation. To understand the role of TcAKR in Bz metabolism, we studied TcAKR expression and NADPH/NADH-dependent Bz reductase activities in two T. cruzi strains with differential susceptibility to Bz: CL Brener and Nicaragua. Taking into account the results obtained with TcAKR-overexpressing epimastigotes, we expected the more resistant strain, Nicaragua, to have higher TcAKR levels than CL Brener. However, the results were the opposite. CL Brener showed 2-fold higher TcAKR expression and 5.7-fold higher NADPH-Bz reduction than the Nicaragua strain. In addition, NADH-dependent Bz reductase activity, characteristic of NTR I, was also higher in CL Brener than in Nicaragua. We conclude that although TcAKR uses Bz as the substrate, TcAKR activity is not a determinant of Bz resistance in wild-type strains and may be overcome by other enzymes involved in Bz activation, such as NADPH- and NADH-dependent reductases. Benznidazole (Bz), the drug used for treatment of Chagas' disease (caused by the protozoan Trypanosoma cruzi), is activated by a parasitic NADH-dependent type I nitroreductase (NTR I). However, several studies have shown that other enzymes are involved. The aim of this study was to evaluate whether the aldo-keto reductase from T. cruzi (TcAKR), a NADPH-dependent oxido-reductase previously described by our group, uses Bz as the substrate. We demonstrated that both recombinant and native TcAKR enzymes reduce Bz by using NADPH, but not NADH, as a cofactor. TcAKR-overexpressing epimastigotes showed higher NADPH-dependent Bz reductase activity and a 50% inhibitory concentration (IC50) value for Bz 1.8-fold higher than that of the controls, suggesting that TcAKR is involved in Bz detoxification instead of activation. To understand the role of TcAKR in Bz metabolism, we studied TcAKR expression and NADPH/NADH-dependent Bz reductase activities in two T. cruzi strains with differential susceptibility to Bz: CL Brener and Nicaragua. Taking into account the results obtained with TcAKR-overexpressing epimastigotes, we expected the more resistant strain, Nicaragua, to have higher TcAKR levels than CL Brener. However, the results were the opposite. CL Brener showed 2-fold higher TcAKR expression and 5.7-fold higher NADPH-Bz reduction than the Nicaragua strain. In addition, NADH-dependent Bz reductase activity, characteristic of NTR I, was also higher in CL Brener than in Nicaragua. We conclude that although TcAKR uses Bz as the substrate, TcAKR activity is not a determinant of Bz resistance in wild-type strains and may be overcome by other enzymes involved in Bz activation, such as NADPH- and NADH-dependent reductases. Benznidazole (Bz), the drug used for treatment of Chagas' disease (caused by the protozoan Trypanosoma cruzi), is activated by a parasitic NADH-dependent type I nitroreductase (NTR I). However, several studies have shown that other enzymes are involved. The aim of this study was to evaluate whether the aldo-keto reductase from T. cruzi (TcAKR), a NADPH-dependent oxido-reductase previously described by our group, uses Bz as the substrate. We demonstrated that both recombinant and native TcAKR enzymes reduce Bz by using NADPH, but not NADH, as a cofactor. TcAKR-overexpressing epimastigotes showed higher NADPH-dependent Bz reductase activity and a 50% inhibitory concentration (IC50) value for Bz 1.8-fold higher than that of the controls, suggesting that TcAKR is involved in Bz detoxification instead of activation. To understand the role of TcAKR in Bz metabolism, we studied TcAKR expression and NADPH/NADH-dependent Bz reductase activities in two T. cruzi strains with differential susceptibility to Bz: CL Brener and Nicaragua. Taking into account the results obtained with TcAKR-overexpressing epimastigotes, we expected the more resistant strain, Nicaragua, to have higher TcAKR levels than CL Brener. However, the results were the opposite. CL Brener showed 2-fold higher TcAKR expression and 5.7-fold higher NADPH-Bz reduction than the Nicaragua strain. In addition, NADH-dependent Bz reductase activity, characteristic of NTR I, was also higher in CL Brener than in Nicaragua. We conclude that although TcAKR uses Bz as the substrate, TcAKR activity is not a determinant of Bz resistance in wild-type strains and may be overcome by other enzymes involved in Bz activation, such as NADPH- and NADH-dependent reductases. Benznidazole (Bz), the drug used for treatment of Chagas' disease (caused by the protozoan Trypanosoma cruzi), is activated by a parasitic NADH-dependent type I nitroreductase (NTR I). However, several studies have shown that other enzymes are involved. The aim of this study was to evaluate whether the aldo-keto reductase from T. cruzi (TcAKR), a NADPH-dependent oxido-reductase previously described by our group, uses Bz as the substrate. We demonstrated that both recombinant and native TcAKR enzymes reduce Bz by using NADPH, but not NADH, as a cofactor. TcAKR-overexpressing epimastigotes showed higher NADPH-dependent Bz reductase activity and a 50% inhibitory concentration (IC50) value for Bz 1.8-fold higher than that of the controls, suggesting that TcAKR is involved in Bz detoxification instead of activation. To understand the role of TcAKR in Bz metabolism, we studied TcAKR expression and NADPH/NADH-dependent Bz reductase activities in two T. cruzi strains with differential susceptibility to Bz: CL Brener and Nicaragua. Taking into account the results obtained with TcAKR-overexpressing epimastigotes, we expected the more resistant strain, Nicaragua, to have higher TcAKR levels than CL Brener. However, the results were the opposite. CL Brener showed 2-fold higher TcAKR expression and 5.7-fold higher NADPH-Bz reduction than the Nicaragua strain. In addition, NADH-dependent Bz reductase activity, characteristic of NTR I, was also higher in CL Brener than in Nicaragua. We conclude that although TcAKR uses Bz as the substrate, TcAKR activity is not a determinant of Bz resistance in wild-type strains and may be overcome by other enzymes involved in Bz activation, such as NADPH- and NADH-dependent reductases. Benznidazole (Bz), the drug used for treatment of Chagas' disease (caused by the protozoan Trypanosoma cruzi), is activated by a parasitic NADH-dependent type I nitroreductase (NTR I). However, several studies have shown that other enzymes are involved. The aim of this study was to evaluate whether the aldo-keto reductase from T. cruzi (TcAKR), a NADPH-dependent oxido-reductase previously described by our group, uses Bz as the substrate. We demonstrated that both recombinant and native TcAKR enzymes reduce Bz by using NADPH, but not NADH, as a cofactor. TcAKR-overexpressing epimastigotes showed higher NADPH-dependent Bz reductase activity and a 50% inhibitory concentration (IC50) value for Bz 1.8-fold higher than that of the controls, suggesting that TcAKR is involved in Bz detoxification instead of activation. To understand the role of TcAKR in Bz metabolism, we studied TcAKR expression and NADPH/NADH-dependent Bz reductase activities in two T. cruzi strains with differential susceptibility to Bz: CL Brener and Nicaragua. Taking into account the results obtained with TcAKR-overexpressing epimastigotes, we expected the more resistant strain, Nicaragua, to have higher TcAKR levels than CL Brener. However, the results were the opposite. CL Brener showed 2-fold higher TcAKR expression and 5.7-fold higher NADPH-Bz reduction than the Nicaragua strain. In addition, NADH-dependent Bz reductase activity, characteristic of NTR I, was also higher in CL Brener than in Nicaragua. We conclude that although TcAKR uses Bz as the substrate, TcAKR activity is not a determinant of Bz resistance in wild-type strains and may be overcome by other enzymes involved in Bz activation, such as NADPH- and NADH-dependent reductases.
Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism
Título:
Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism;
Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism;
Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism;
Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism
Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism;
Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism;
Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism
Garavaglia, Patricia Andrea; Garavaglia, Patricia Andrea; Garavaglia, Patricia Andrea; Garavaglia, Patricia Andrea; Garavaglia, Patricia Andrea; Laverriere, Marc
; Laverriere, Marc
; Laverriere, Marc
; Laverriere, Marc
; Laverriere, Marc
; Cannata, Joaquin Juan Bautista
; Cannata, Joaquin Juan Bautista
; Cannata, Joaquin Juan Bautista
; Cannata, Joaquin Juan Bautista
; Cannata, Joaquin Juan Bautista
; Garcia, Gabriela Andrea
; Garcia, Gabriela Andrea
; Garcia, Gabriela Andrea
; Garcia, Gabriela Andrea
; Garcia, Gabriela Andrea
Fecha de publicación:
05/2016
05/2016
05/2016
05/2016
05/2016
05/2016
05/2016
05/2016
05/2016
Editorial:
American Society for Microbiology
American Society for Microbiology
American Society for Microbiology
American Society for Microbiology
American Society for Microbiology
American Society for Microbiology
American Society for Microbiology
American Society for Microbiology
American Society for Microbiology
Revista:
Antimicrobial Agents and Chemotherapy
Antimicrobial Agents and Chemotherapy
Antimicrobial Agents and Chemotherapy
Antimicrobial Agents and Chemotherapy
Antimicrobial Agents and Chemotherapy
Antimicrobial Agents and Chemotherapy
Antimicrobial Agents and Chemotherapy
Antimicrobial Agents and Chemotherapy
Antimicrobial Agents and Chemotherapy
ISSN:
0066-4804
0066-4804
0066-4804
0066-4804
0066-4804
0066-4804
0066-4804
0066-4804
0066-4804
Idioma:
Inglés
Inglés
Inglés
Inglés
Inglés
Inglés
Inglés
Inglés
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
Archivos asociados
Licencia
Identificadores
Colecciones
Articulos(SEDE CENTRAL)
Articulos de SEDE CENTRAL
Articulos de SEDE CENTRAL
Citación
Garavaglia, Patricia Andrea; Laverriere, Marc; Cannata, Joaquin Juan Bautista; Garcia, Gabriela Andrea; Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 60; 5; 5-2016; 2664-2670
Garavaglia, Patricia Andrea; Laverriere, Marc; Cannata, Joaquin Juan Bautista; Garcia, Gabriela Andrea; Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 60; 5; 5-2016; 2664-2670
Garavaglia, Patricia Andrea; Laverriere, Marc; Cannata, Joaquin Juan Bautista; Garcia, Gabriela Andrea; Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 60; 5; 5-2016; 2664-2670
Garavaglia, Patricia Andrea; Laverriere, Marc; Cannata, Joaquin Juan Bautista; Garcia, Gabriela Andrea; Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 60; 5; 5-2016; 2664-2670
Garavaglia, Patricia Andrea; Laverriere, Marc; Cannata, Joaquin Juan Bautista; Garcia, Gabriela Andrea; Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 60; 5; 5-2016; 2664-2670
Garavaglia, Patricia Andrea; Laverriere, Marc; Cannata, Joaquin Juan Bautista; Garcia, Gabriela Andrea; Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 60; 5; 5-2016; 2664-2670
Garavaglia, Patricia Andrea; Laverriere, Marc; Cannata, Joaquin Juan Bautista; Garcia, Gabriela Andrea; Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 60; 5; 5-2016; 2664-2670
Garavaglia, Patricia Andrea; Laverriere, Marc; Cannata, Joaquin Juan Bautista; Garcia, Gabriela Andrea; Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 60; 5; 5-2016; 2664-2670
Garavaglia, Patricia Andrea; Laverriere, Marc; Cannata, Joaquin Juan Bautista; Garcia, Gabriela Andrea; Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 60; 5; 5-2016; 2664-2670
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