Methylglyoxal metabolism in trypanosomes and leishmania

    Research output: Contribution to journalReview articlepeer-review

    26 Citations (Scopus)

    Abstract

    Methylglyoxal is a toxic by-product of glycolysis and other metabolic pathways. In mammalian cells, the principal route for detoxification of this reactive metabolite is via the glutathione-dependent glyoxalase pathway forming D-lactate, involving lactoylglutathione lyase (GLO1; EC 4.4.1.5) and hydroxyacylglutathione hydrolase (GLO2; EC 3.2.1.6). In contrast, the equivalent enzymes in the trypanosomatid parasites Trypanosoma cruzi and Leishmania spp. show >200-fold selectivity for glutathionylspermidine and trypanothione over glutathione and are therefore sensu stricto lactoylglutathionylspermidine lyases (EC 4.4.1.-) and hydroxyacylglutathionylspermidine hydrolases (EC 3.2.1.-). The unique substrate specificity of the parasite glyoxalase enzymes can be directly attributed to their unusual active site architecture. The African trypanosome differs from these parasites in that it lacks GLO1 and converts methylglyoxal to l-lactate rather than D-lactate. Since Trypanosoma brucei is the most sensitive of the trypanosomatids to methylglyoxal toxicity, the absence of a complete and functional glyoxalase pathway in these parasites is perplexing. Alternative routes of methylglyoxal detoxification in T. brucei are discussed along with the potential of exploiting trypanosomatid glyoxalase enzymes as targets for anti-parasitic chemotherapy. (C) 2011 Elsevier Ltd. All rights reserved.

    Original languageEnglish
    Pages (from-to)271-277
    Number of pages7
    JournalSeminars in Cell & Developmental Biology
    Volume22
    Issue number3
    DOIs
    Publication statusPublished - May 2011

    Keywords

    • Trypanosoma
    • Leishmania
    • Methylglyoxal
    • Glyoxalase
    • Trypanothione
    • Drug discovery
    • DEPENDENT GLYOXALASE-I
    • BLOOD-STREAM FORMS
    • AFRICAN TRYPANOSOMES
    • D-LACTATE
    • PARASITIC PROTOZOA
    • ALDOSE REDUCTASE
    • THIOL-METABOLISM
    • POTENTIAL TARGET
    • BRUCEI-BRUCEI
    • HUMAN ENZYME

    Cite this