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Research article

Trypanothione-dependent glyoxalase I in Trypanosoma cruzi

Neil Greig, Susan Wyllie, Tim J. Vickers, Alan H. Fairlamb
Biochemical Journal Dec 01, 2006, 400 (2) 217-223; DOI: 10.1042/BJ20060882
Neil Greig
Division of Biological Chemistry and Molecular Microbiology, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, Scotland, U.K.
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Susan Wyllie
Division of Biological Chemistry and Molecular Microbiology, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, Scotland, U.K.
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Tim J. Vickers
Division of Biological Chemistry and Molecular Microbiology, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, Scotland, U.K.
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Alan H. Fairlamb
Division of Biological Chemistry and Molecular Microbiology, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, Scotland, U.K.
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  • For correspondence: a.h.fairlamb@dundee.ac.uk
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Abstract

The glyoxalase system, comprizing glyoxalase I and glyoxalase II, is a ubiquitous pathway that detoxifies highly reactive aldehydes, such as methylglyoxal, using glutathione as a cofactor. Recent studies of Leishmania major glyoxalase I and Trypanosoma brucei glyoxalase II have revealed a unique dependence upon the trypanosomatid thiol trypanothione as a cofactor. This difference suggests that the trypanothione-dependent glyoxalase system may be an attractive target for rational drug design against the trypanosomatid parasites. Here we describe the cloning, expression and kinetic characterization of glyoxalase I from Trypanosoma cruzi. Like L. major glyoxalase I, recombinant T. cruzi glyoxalase I showed a preference for nickel as its metal cofactor. In contrast with the L. major enzyme, T. cruzi glyoxalase I was far less fast-idious in its choice of metal cofactor efficiently utilizing cobalt, manganese and zinc. T. cruzi glyoxalase I isomerized hemithio-acetal adducts of trypanothione more than 2400 times more efficiently than glutathione adducts, with the methylglyoxal adducts 2–3-fold better substrates than the equivalent phenylglyoxal adducts. However, glutathionylspermidine hemithioacetal adducts were most efficiently isomerized and the glutathionylspermidine-based inhibitor S-4-bromobenzylglutathionylspermidine was found to be a potent linear competitive inhibitor of the T. cruzi enzyme with a Ki of 5.4±0.6 μM. Prediction algorithms, combined with subcellular fractionation, suggest that T. cruzi glyoxalase I localizes not only to the cytosol but also the mitochondria of T. cruzi epimastigotes. The contrasting substrate specificities of human and trypanosomatid glyoxalase enzymes, confirmed in the present study, suggest that the glyoxalase system may be an attractive target for anti-trypanosomal chemotherapy.

  • drug discovery
  • glyoxalase
  • methylglyoxal
  • trypano-thione

Abbreviations: ECL, enhanced chemiluminesence; GLO1, glyoxalase I; TcGLO1, Trypanosoma cruzi GLO1; MALDI–TOF-MS, matrix-assisted laser-desorption ionization–time-of-flight MS; TCEP, tris(2-carboxyethyl)phosphine; T[SH]2, trypanothione, N1,N8-bis(glutathionyl)spermidine

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December 2006

Volume: 400 Issue: 2

Biochemical Journal: 400 (2)
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Trypanothione-dependent glyoxalase I in Trypanosoma cruzi
Neil Greig, Susan Wyllie, Tim J. Vickers, Alan H. Fairlamb
Biochemical Journal Dec 2006, 400 (2) 217-223; DOI: 10.1042/BJ20060882
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Trypanothione-dependent glyoxalase I in Trypanosoma cruzi
Neil Greig, Susan Wyllie, Tim J. Vickers, Alan H. Fairlamb
Biochemical Journal Dec 2006, 400 (2) 217-223; DOI: 10.1042/BJ20060882

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Keywords

drug discovery
glyoxalase
methylglyoxal
trypano-thione

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