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