The Crystal Structure of the Plasmodium falciparum PdxK Provides an Experimental Model for Pro-Drug Activation

Kai Gao, Wenjia Wang, Thales Kronenberger, Carsten Wrenger, Matthew R. Groves*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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, PfPdxK functions to salvage vitamin B6 from both itself and its host. Here, we report the crystal structure of PfPdxK 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 PfPdxK through an interaction with a E3 ligase complex. Furthermore, molecular docking approaches based on our model allow us to explain differential PfPdxK 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 PfPdxK provides a high-quality model for a better understanding of vitamin B6 synthesis and salvage in the parasite.

Original languageEnglish
Article number534
Number of pages11
JournalCrystals
Volume9
Issue number10
DOIs
Publication statusPublished - 17-Oct-2019

Keywords

  • PfPdxK
  • motif
  • PT3
  • PT5
  • PHME
  • PYRIDOXAL KINASE
  • BIOSYNTHESIS
  • GENE
  • IDENTIFICATION
  • SEQUENCE
  • ENCODES
  • PATHWAY
  • COMPLEX
  • DOMAIN

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