Leishmaniases are (re)emerging neglected tropical diseases caused by Leishmania sps, members of the kinetoplastid family of protozoan parasites. Chemotherapy treatment is difficult to administer, expensive and progressively ineffective due to emergence of drug resistance. The need for new and effective leishmanicidal agents is urgent and identification of novel drug targets is a strong challenge for biomedical research. One class of molecular targets are phosphatases.
Analysis of the phosphatome of the three kinetoplastids (Brenchley et al. 2007) showed that these parasites posses orthologues to many of the phosphatases reported in other eukaryotes, including humans. However, it turns out that several of the kinetoplastid phosphatases have novel domain architectures and unusual combinations of accessory domains which suggest distinct functional roles awaiting further experimental exploration. An interesting difference with other eukaryotic phosphatomes is the large number of atypical protein phosphatases (more than one third of the total phosphatase complement) most of which belong to the dual-specificity phosphatase (DSP) family and show considerable divergence from classic DSPs in both the domain organization and sequence features in their catalytic domain.
We have initiated our study on the Leishmania aDPs (4 in total) by focusing initially on the two MptpB orhologues from L. donovani. They both belong to a new family of phosphoinositide phosphatases designated as atypical lipid phosphatases (ALPs) recently described (Beresford et al. 2010) in bacteria and lower eukaryotes. Phosphoinositide phosphatases from bacterial pathogens modulating PI metabolism in the host constitute attractive targets for chemotherapy, aspect poorly explored yet for intracellular protozoan parasites.
Another interesting family of parasitic phopshatases are the histidine acid phosphatases. We study a histidine acid membrane bound ecto-phosphatase (LdMAcP, GenBank: AF149839.1) from L. donovani, a molecule that is relatively conserved within the Trypanosomatidae family of protozoan parasites (Sacharian et al. 2003) and could be an enzyme important for the interaction of the parasite with its host organisms (invertebrate or vertebrate). Parasite surface factors could mediate Leishmania virulence by modifying host defence mechanisms or acting in nutrient uptake. Our overall objective is the identification of distinct molecular and functional characteristics of this enzyme that will be valuable in designing selective inhibitors with potential therapeutic value.
Brenchley R, Tariq H, McElhinney H, Szoor B, Huxley-Jones J, Stevens R, Matthews K, Tabernero L. (2007). The TriTryp phosphatome: analysis of the protein phosphatase catalytic domains. BMC Genomics, 8:434
Beresford NJ, Saville C, Bennett HJ, Roberts IS, Tabernero L. (2010). A new family of phosphoinositide phosphatases in microorganisms: identification and biochemical analysis. BMC Genomics, 11:457
Shakarian AM, Joshi MB, Yamage M, Ellis SL, Debrabant A, Dwyer DM. (2003). Members of a unique histidine acid phosphatase family are conserved amongst a group of primitive eukaryotic human pathogens. Mol Cell Biochem. 245:31
Speaker: H. Boleti
Dep. of Microbiology & Light Microscopy Unit, Hellenic Pasteur Institute
Time: Wednesday, 2 April 2014, 13:00