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- Title
Quantitative assessment of the glyoxalase pathway inLeishmania infantumas a therapeutic target by modelling and computer simulation.
- Authors
Silva, Marta Sousa; Ferreira, António E. N.; Tomás, Ana Maria; Cordeiro, Carlos; Freire, Ana Ponces
- Abstract
The glyoxalase pathway ofLeishmania infantumwas kinetically characterized as a trypanothione-dependent system. Using time course analysis based on parameter fitting with a genetic algorithm, kinetic parameters were estimated for both enzymes, with trypanothione derived substrates. AKm of 0.253 mmand aVof 0.21 µmol·min−1·mg−1for glyoxalase I, and aKm of 0.098 mmand aVof 0.18 µmol·min−1·mg−1 for glyoxalase II, were obtained. Modelling and computer simulation were used for evaluating the relevance of the glyoxalase pathway as a potential therapeutic target by revealing the importance of critical parameters of this pathway inLeishmania infantum. A sensitivity analysis of the pathway was performed using experimentally validated kinetic models and experimentally determined metabolite concentrations and kinetic parameters. The measurement of metabolites inL. infantuminvolved the identification and quantification of methylglyoxal and intracellular thiols. Methylglyoxal formation inL. infantumis nonenzymatic. The sensitivity analysis revealed that the most critical parameters for controlling the intracellular concentration of methylglyoxal are its formation rate and the concentration of trypanothione. Glyoxalase I and II activities play only a minor role in maintaining a low intracellular methylglyoxal concentration. The importance of the glyoxalase pathway as a therapeutic target is very small, compared to the much greater effects caused by decreasing trypanothione concentration or increasing methylglyoxal concentration.
- Subjects
GLYOXALASE; LEISHMANIA; COMPUTER simulation; ALGORITHMS; ENZYMES; PROTEINS
- Publication
FEBS Journal, 2005, Vol 272, Issue 10, p2388
- ISSN
1742-464X
- Publication type
Article
- DOI
10.1111/j.1742-4658.2005.04632.x