title: Methylglyoxal metabolism in trypanosomes and leishmania.
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.
authors.affiliation: Division of Biological Chemistry and Drug Discovery, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee, Angus, Scotland, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Wyllie
authors.forename: Alan H
authors.initials: AH
authors.lastname: Fairlamb
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000737:chemistry / Q000378:metabolism; D007891:Leishmania / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D011765:Pyruvaldehyde / Q000737:chemistry / Q000378:metabolism*; D013869:Thiolester Hydrolases / Q000737:chemistry / Q000378:metabolism; D014345:Trypanosoma / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D000099301:Hydroxyacylglutathione Hydrolase
chemical_list: D000981:Antiprotozoal Agents; D007791:Lactoylglutathione Lyase; D011765:Pyruvaldehyde; D013869:Thiolester Hydrolases; D000099301:Hydroxyacylglutathione Hydrolase