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Background  Glyoxalase I is a metalloenzyme of the glyoxalase pathway that plays a central role in eliminating the toxic metabolite methyglyoxal. The protozoan parasite  Leishmania donovani  possesses a unique trypanothione dependent glyoxalase system.    Principal Findings  Analysis of the  L. donovani GLOI  sequence predicted a mitochondrial targeting sequence, suggesting that the enzyme is likely to be targeted to the mitochondria. In order to determine definitively the intracellular localization of GLOI in  L. donovani , a full-length  GLOI  gene was fused to green fluorescent protein (GFP) gene to generate a chimeric construct. Confocal microscopy of  L. donovani  promastigotes carrying this chimeric construct and immunofluorescence microscopy using anti-GLOI antibodies demonstrated that GLOI is localized in the kinetoplast of the parasite apart from the cytosol. To study the physiological role of  GLOI  in  Leishmania,  we first created promastigote mutants heterozygous for  GLOI  by targeted gene replacement using either hygromycin or neomycin phosphotransferases as selectable markers. Heterozygous mutants of  L. donovani  display a slower growth rate, have lower glyoxalase I activity and have reduced ability to detoxify methylglyoxal in comparison to the wild-type parasites. Complementation of the heterozygous mutant with an episomal  GLOI  construct showed the restoration of heterozygous mutant phenotype nearly fully to that of the wild-type. Null mutants were obtained only after  GLOI  was expressed from an episome in heterozygous mutants.    Conclusions  We for the first time report localization of GLOI in  L. donovani  in the kinetoplast. To study the physiological role of GLOI in  Leishmania , we have generated GLOI attenuated strains by targeted gene replacement and report that GLOI is likely to be an important gene since  GLOI  mutants in  L. donovani  showed altered phenotype. The present data supports that the GLOI plays an essential role in the survival of this pathogenic organism and that inhibition of the enzyme potentiates the toxicity of methylglyoxal.

Glyoxalase I Gene Deletion Mutants of Leishmania donovani Exhibit Reduced Methylglyoxal Detoxification