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The protozoan parasite <i>Plasmodium falciparum</i> 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 <i>Plasmodium</i> is the production of ATP via glycolysis. Due to the parasite’s strong dependence on this pathway and the significant structural differences of its glycolytic enzymes compared to its human counterpart, glycolysis is considered a potential drug target. In this study, we provide the first three-dimensional protein structure of <i>P. falciparum</i> hexokinase (<i>Pf</i>HK) containing novel information about the mechanisms of <i>Pf</i>HK. We identified for the first time a <i>Plasmodium</i>-specific insertion that lines the active site. Moreover, we propose that this insertion plays a role in 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 <i>Pf</i>HK is targeted and affected by oxidative posttranslational modifications (oxPTMs). Both S-glutathionylation and S-nitrosation revealed an inhibitory effect on the enzymatic activity of <i>Pf</i>HK.