Importance of UDP-glucose biosynthesis for the protozoan parasite Leishmania major

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Is UDP-Glucose (UDP-Glc) biosynthesis essential for the growth of Leishmania parasites? Recently, we demonstrated that deletion of Leishmania major UDP-glucose pyrophosphorylase (UGP) did not result in UDP-Glc deficient parasites and described an unusual UDP-sugar pyrophosphorylase (USP) likely compensating for its loss. Our attempts to generate a mutant deficient in both enzymes were unsuccessful suggesting that UDP-Glc is essential for Leishmania parasites. Using a recently developed system, we wish to generate a mutant in which the level of UDP-Glc can be tuned and reduced to negligible level to unequivocally demonstrate the essentiality of this nucleotide sugar for parasite viability and study its roles. UDP-Glc is likely involved in the biosynthesis of the lipophosphoglycan anchor and is crucial for glycocalix formation. More importantly, it is, as in every eukaryote, required in the endoplasmic reticulum (ER) for the calreticulin cycle that ensures proper protein folding. The importance of this ER quality control is currently unknown in Leishmania but the UDP-Glc transporter HUT1L and thus delivery of UDP-glucose to the ER seems essential. This project will thus particularly address the role of UDP-Glc in the ER and its link to cellular viability. We hope to provide important information about the ER quality control in Leishmania that could be translated to other organisms. Moreover, the knowledge gained with this project might help defining how to tackle Leishmania parasites, which are the second parasitic killer in the world.