Drug target validation of the trypanothione pathway enzymes through metabolic modelling
Por:
Olin-Sandoval V., González-Chávez Z., Berzunza-Cruz M., Martínez I., Jasso-Chávez R., Becker I., Espinoza B., Moreno-Sánchez R., Saavedra E.
Publicada:
1 may 2012
Resumen:
A kinetic model of trypanothione [T(SH)2] metabolism in Trypanosoma cruzi was constructed based on enzyme kinetic parameters determined under near-physiological conditions (including glutathione synthetase), and the enzyme activities, metabolite concentrations and fluxes determined in the parasite under control and oxidizing conditions. The pathway structure is characterized by a T(SH)2 synthetic module of low flux and low catalytic capacity, and another more catalytically efficient T(SH)2-dependent antioxidant/regenerating module. The model allowed quantification of the contribution of each enzyme to the control of T(SH)2 synthesis and concentration (flux control and concentration control coefficients, respectively). The main control of flux was exerted by ?-glutamylcysteine synthetase (?ECS) and trypanothione synthetase (TryS) (control coefficients of 0.580.7 and 0.490.58, respectively), followed by spermidine transport (0.24); negligible flux controls by trypantothione reductase (Tr
Filiaciones:
Olin-Sandoval V.:
Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No. 1 Col. Sección XVI, Tlalpan, Mé xico Distrito Federal 14080, Mexico
González-Chávez Z.:
Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No. 1 Col. Sección XVI, Tlalpan, Mé xico Distrito Federal 14080, Mexico
Berzunza-Cruz M.:
Univ Nacl Autonoma Mexico, Fac Med, Dept Expt Med, Mexico City 04510, DF, Mexico
Martínez I.:
Univ Nacl Autonoma Mexico, Dept Inmunol, Inst Invest Biomed, Mexico City 04510, DF, Mexico
Jasso-Chávez R.:
Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No. 1 Col. Sección XVI, Tlalpan, Mé xico Distrito Federal 14080, Mexico
Becker I.:
Univ Nacl Autonoma Mexico, Fac Med, Dept Expt Med, Mexico City 04510, DF, Mexico
Espinoza B.:
Univ Nacl Autonoma Mexico, Dept Inmunol, Inst Invest Biomed, Mexico City 04510, DF, Mexico
Moreno-Sánchez R.:
Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No. 1 Col. Sección XVI, Tlalpan, Mé xico Distrito Federal 14080, Mexico
Saavedra E.:
Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano No. 1 Col. Sección XVI, Tlalpan, Mé xico Distrito Federal 14080, Mexico
Bronze
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