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

Author(s)

Gao, Kai ^[1] ; Wang, Wenjia ^[1] ; Kronenberger, Thales ^{[2, 3]} ; Wrenger, Carsten ^[2] ; Groves, Matthew R. ^[1]

Affiliation

^[1] Univ Groningen, Groningen Res Inst Pharm, Drug Design XB20, NL-9700 AD Groningen - Netherlands

^[2] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Unit Drug Discovery, BR-05508000 Sao Paulo, SP - Brazil

^[3] Univ Hosp Tubingen, Dept Med Oncol & Pneumol, Internal Med 8, D-72076 Tubingen - Germany

• Document type: Journal article
• Source: CRYSTALS; v. 9, n. 10 OCT 2019.
• Web of Science Citations: 0

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. (AU)

• FAPESP's process: 17/03966-4 - Targeting lipoic acid salvage and biosynthesis pathways in MRSA
• Grantee: Carsten Wrenger
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/03644-9 - Targeting alternative ligand-binding sites in nuclear receptors using computational and experimental screening
• Grantee: Thales Kronenberger
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 15/26722-8 - Drug discovery against human infectious diseases
• Grantee: Carsten Wrenger
• Support Opportunities: Research Projects - Thematic Grants