Target of rapamycin (TOR) kinases in Leishmania: Insights from comparative analyses with Trypanosomatids

The Target of Rapamycin (TOR) kinase family is a central regulator of eukaryotic cell growth and metabolism. Unlike most eukaryotes that possess one or two TOR genes, Leishmania species encode four distinct paralogs, suggesting lineage-specific expansion and functional diversification. In this study, we performed a comprehensive phylogenetic and domain analysis of TOR paralogs across multiple Leishmania species, with Trypanosoma brucei serving as a comparative reference. TOR1 and TOR2 were found to be highly conserved, possessing canonical FAT, FRB, and PI3Kc domains, consistent with their roles in the essential TORC1 and TORC2 complexes. TOR3 and TOR4 displayed significant sequence divergence and altered domain structures, particularly in visceral and mucocutaneous species. TOR3 lacks the FRB domain but retains kinase activity and is implicated in arginine sensing and acidocalcisome biogenesis. TOR4 shows the highest divergence, including truncated domains and species-specific clustering, suggesting a role in parasite adaptation or stage differentiation. Functional annotations further support this, as TOR1 and TOR2 are enriched in kinase functions, while TOR3 and TOR4 are associated with hypothetical or uncharacterized proteins. The conserved PI3Kc domain across all paralogs offers a target for drug development. These findings enhance our understanding of TOR evolution and its therapeutic potential in leishmaniasis.