Glyoxalase Enzymes in Trypanosomatids

• Type: Chapter or Part of a Book
• Date: 2013

Authors

silva, ms (Author) Other; ferreira, aen (Author) Other; gomes, r (Author) Other; tomás, am (Author) FCUP; freire, ap (Author) Other; cordeiro, c (Author) Other

Book

Title: Trypanosomatid Diseases: Molecular Routes to Drug Discovery

Indexing

ISI Web of Knowledge

Scopus - 1 Citation

Other information

Authenticus ID: P-008-BF7

DOI: 10.1002/9783527670383.ch8

Abstract (EN): The glyoxalase pathway catalyzes the formation of d-lactate from methylglyoxal - a non-enzymatic glycolytic byproduct with toxic effects. This pathway comprises two enzymes, glyoxalase I and glyoxalase II, and usually uses glutathione as catalytic cofactor. In trypanosomatids, this system makes no exception in respect of the functional replacement of glutathione by trypanothione. Structural analysis of both glyoxalase enzymes revealed key amino acids for glutathione binding, explaining why glyoxalase I is a more promiscuous enzyme. Glyoxalase II shows absolute specificity towards trypanothione. Changing two residues at the active site enables the enzyme to also use the glutathione as substrate. Although it was tempting to propose that the inhibition of this pathway might impair the parasite's viability, due to methylglyoxal accumulation and potential toxic effects, several studies indicate that the glyoxalases are unlike targets for this purpose. Indeed, there are alternative catabolic routes for methylglyoxal in both Leishmania and Trypanosoma, and the system is not complete in T. brucei, where only glyoxalase II was found. Sensitivity analysis using a complete model of the methylglyoxal metabolism in L. infantum revealed that inhibition of both the glyoxalase pathway and aldose reductase by 90% only causes a negligible increase of the steady-state concentration of methylglyoxal. The activities of these enzymes change during the life cycle of L. infantum and T. brucei, but the robustness and regulation of the metabolism of these parasites keeps the intracellular concentration of methylglyoxal way below toxic values. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14