Wendler, Alexandra, Irsch, Thorsten, Rabbani, Naila, Thornalley, Paul J. and Krauth-Siegel, R. Luise. (2009) Glyoxalase II does not support methylglyoxal detoxification but serves as a general trypanothione thioesterase in African trypanosomes. Molecular and Biochemical Parasitology, Vol.163 (No.1). pp. 19-27. ISSN 0166-6851

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Abstract

Glyoxalase I and II form a ubiquitous glutathione-dependent pathway for the detoxification of reactive and mutagenic ketoaldehydes. Methylglyoxal produced as spontaneous by-product of glycolysis is probably the main physiological substrate. Consequently, African trypanosomes with their exorbitant glucose turnover were expected to have a most efficient detoxification system. Trypanosoma brucei possesses a trypanothione [bis(glutathionyl)spermidine]-dependent glyoxalase II but lacks a glyoxalase I gene. Methylglyoxal reductase as well as dehydrogenase activities are negligible. However, the concentrations of methylglyoxal and advanced glycation end products in the parasites are similar to those in different mammalian cells and the mechanism of methylglyoxal elimination remains elusive. Glyoxalase II is an abundant protein. Overexpression of the gene as well as RNA interference in bloodstream and procyclic cells did not result in a growth phenotype. Deletion of both alleles in procyclic parasites revealed that the enzyme is not essential at least under culture conditions. Recombinant glyoxalase II hydrolyzed the trypanothione-thioesters of methylglyoxal, glyoxal and 4,5-dioxovalerate, substrates of the classical glyoxalase system, with high efficiency. The absence of a glyoxalase I, however, renders these thioesters unlikely as physiological substrates. Here we show that trypanothione-thioesters can be generated from the respective coenzyme A derivative by transesterification. S-Acetyl- and S-prop ionyl trypanothione obtained by this spontaneous reaction proved to be excellent substrates of T brucei glyoxalase II. This offers a function for the parasite glyoxalase II as general trypanothione thioesterase independent of ketoaldehyde detoxification. Crown Copyright (C) 2008 Published by Elsevier B.V. All rights reserved.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry Q Science > QL Zoology
Divisions:	Faculty of Medicine > Warwick Medical School > Clinical Sciences Research Institute (CSRI) Faculty of Medicine > Warwick Medical School > Metabolic and Vascular Health Faculty of Medicine > Warwick Medical School
Journal or Publication Title:	Molecular and Biochemical Parasitology
Publisher:	Elsevier Science BV
ISSN:	0166-6851
Date:	January 2009
Volume:	Vol.163
Number:	No.1
Number of Pages:	9
Page Range:	pp. 19-27
Identification Number:	10.1016/j.molbiopara.2008.09.005
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Deutsche Forschungsgemeinschaft (DFG)
Grant number:	Kr 1242/4-1-2
URI:	http://wrap.warwick.ac.uk/id/eprint/28751

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