Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Structural Analysis of Plasmodium falciparum Hexokinase Provides Novel Information about Catalysis Due to a Plasmodium-Specific Insertion

Melissa Dillenberger
ORCID logo ,
Anke-Dorothee Werner
,
Ann-Sophie Velten
,
Stefan Rahlfs
,
Katja Becker
,
Karin Fritz-Wolf
* ORCID logo
Version 1 : Received: 1 August 2023 / Approved: 2 August 2023 / Online: 2 August 2023 (07:17:43 CEST)

A peer-reviewed article of this Preprint also exists.

Dillenberger, M.; Werner, A.-D.; Velten, A.-S.; Rahlfs, S.; Becker, K.; Fritz-Wolf, K. Structural Analysis of Plasmodium falciparum Hexokinase Provides Novel Information about Catalysis due to a Plasmodium-Specific Insertion. Int. J. Mol. Sci. 2023, 24, 12739. Dillenberger, M.; Werner, A.-D.; Velten, A.-S.; Rahlfs, S.; Becker, K.; Fritz-Wolf, K. Structural Analysis of Plasmodium falciparum Hexokinase Provides Novel Information about Catalysis due to a Plasmodium-Specific Insertion. Int. J. Mol. Sci. 2023, 24, 12739.

Abstract

The protozoan parasite Plasmodium falciparum is the causative pathogen of the most severe form of malaria, for which novel strategies for treatment are urgently required. The primary energy supply for intraerythrocytic stages of Plasmodium is the production of ATP via glycolysis. Due to the parasite’s strong dependence on this pathway and significant structural differences of its glycolytic enzymes compared to their human counterpart, glycolysis is considered as a potential drug target. In this study, we provide the first three-dimensional protein structure of P. falciparum hexokinase (PfHK), containing novel information about the mechanisms of PfHK. We identified for the first time a Plasmodium-specific insertion which lines the active site. Moreover, we propose that this insertion plays a role upon ATP binding. Residues of the insertion further seem to affect the tetrameric interface and therefore suggest a special way of communication among the different monomers. In addition, we confirmed that PfHK is targeted and affected by oxidative posttranslational modifications (oxPTMs). Both Sglutathionylation and Snitrosation revealed an inhibitory effect on the enzymatic activity of PfHK.

Keywords

crystal structure; glycolysis; hexokinase; malaria; posttranslational modification; redox regulation

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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