The crystal structure of the Plasmodium falciparum PdxK provides an experimental model for pro-drug activation

Abstract

Pyridoxine/pyridoxal kinase (PdxK), belongs to the ribokinase family and is involved in the vitamin B6 salvage pathway by phosphorylating 5-pyridoxal (PL) into an active form. In the human malaria parasite, Plasmodium falciparum, Pf PdxK functions to salvage vitamin B6 from both itself and its host. Here, we report the crystal structure of Pf PdxK from P. falciparum in complex with a non-hydrolyzable ATP analog (AMP-PNP) and PL. As expected, the fold is retained and both AMP-PNP and PL occupy the same binding sites when compared to the human ortholog. However, our model allows us to identify a FIxxIIxL motif at the C terminus of the disordered repeat motif (XNXH)m that is implicated in binding the WD40 domain and may provide temporal control of Pf PdxK through an interaction with a E3 ligase complex. Furthermore, molecular docking approaches based on our model allow us to explain differential Pf PdxK phosphorylation and activation of a novel class of potent antimalarials (PT3, PT5 and PHME), providing a basis for further development of these compounds. Finally, the structure of Pf PdxK provides a high-quality model for a better understanding of vitamin B6 synthesis and salvage in the parasite.