Eugene P. Kennedy's pioneering work on oxidative phosphorylation included elucidation of his eponymous pathway for biosynthesis of phospholipids. Specifically, phosphotidylcholine (PC) and phosphotidylethanolamine (PE) are two common phospholipids which are key components of cell membranes. They are produced following the Kennedy pathway: (i) the starting alcohol, namely choline or ethanolamine, is phosphorylated by action of choline kinase or ethanolamine kinase; (ii) phosphocholine or phosphoethanolamine subsequently reacts with cytidine triphosphate (CTP); (iii) CTP-choline or CTP-ethanolamine then reacts with a diacylglycerol to form the corresponding final phosphoglyceride. Inhibition of biosynthesis of phospholipids has been found to be promising in development of anti-malarials. It is possible that this pathway is also druggable in the parasite Cryptosporidium parvum.
Most of the reported work on biosynthesis of human or parasite phospholipids concentrated on producing and testing inhibitors to choline kinase. In fact, choline kinase has garnered more research efforts in general, possibly because it was thought at one point to be the single catalyst responsible for phosphorylating both choline and ethanolamine. Because phosphotidylcholine can be generated in vivo by an alternative means to the Kennedy pathway - namely by methylation of phosphotidylethanolamine, blocking the synthesis of PE may turn out to be more effective.
We have previously obtained the structures of human choline kinase α (PDB ID: 2I7Q), human choline kinase β (PDB ID: 2IG7), Plasmodium vivax ethanolamine kinase - the first structure of EK (PDB ID: 2QG7) and choline kinase from P. knowlesi (PDB ID: 3C5I) and P. falciparum (PDB ID: 3FI8; http://www.thesgc.org/structures/details?pdbid=3FI8). Here we present the structure of choline kinase from Cryptosporidium parvum, a parasite with responsible for cryptosporiodiosis.
