Glycosomal localization of dihydroxyacetone phosphate acyltransferase LmDAT is important for lipophosphoglycan biosynthesis

Protozoan parasites of the genus Leishmania are the causative agents of several human and animal diseases collectively called leishmaniases. The parasite cycles between an insect vector the sand fly, and mammalian host's macrophages. Cell‐surface components protect the parasite from the host immune system and constitute virulence factors. Ether glycerolipids are a significant part of the parasite's membranes and ether glycerolipid based macromolecules are also important virulence factors. Thus, enzymes involved in synthesis of ether lipids in Leshmania may represent a drug target for control of the disease. In L. major, a glycosomal dihydroxyacetonephosphate acyltransferase, Lm DAT, initiates the ether lipid biosynthetic pathway. We demonstrated that an active Lm DAT is critical for normal growth and survival of the parasite during stationary phase. Deletion of the N‐terminal amino acid residues of the enzyme reveals that this domain may be important for proper folding of the enzyme and hence for its activity. Abrogation of its C‐terminal glycosomal targeting sequence leads to its extraglycosomal localization. However, this mislocalization does not affect its enzymatic activity but alters the synthesis of the ether‐lipid based virulence factor, lipophosphopglycan, demonstrating that glycosomal subcellular localization is critical for the production of ether‐lipids. This work was funded by American Heart Association.