Pyruvate kinase from plasmodium falciparum: Structural and kinetic insights into the allosteric mechanism

Wenhe Zhong, Kuohan Li, Qixu Cai, Jingjing Guo, Meng Yuan, Yee Hwa Wong, Malcolm D. Walkinshaw, Linda A. Fothergill-gilmore, Paul A.m. Michels, Peter C. Dedon, Julien Lescar

Research output: Contribution to journalArticlepeer-review

Abstract

During its intra-erythrocytic growth phase, the malaria parasite Plasmodium falciparum relies heavily on glycolysis for its energy requirements. Pyruvate kinase (PYK) is essential for regulating glycolytic flux and for ATP production, yet the allosteric mechanism of P. falciparum PYK (PfPYK) remains poorly understood. Here we report the first crystal structure of PfPYK in complex with substrate analogues oxalate and the ATP product. Comparisons of PfPYK structures in the active R-state and inactive T-state reveal a ‘rock-and-lock’ allosteric mechanism regulated by rigid-body rotations of each subunit in the tetramer. Kinetic data and structural analysis indicate glucose 6-phosphate is an activator by increasing the apparent maximal velocity of the enzyme. Intriguingly, the trypanosome drug suramin inhibits PfPYK, which points to glycolysis as a set of potential therapeutic targets against malaria.
Original languageEnglish
Pages (from-to)370-376
JournalBiochemical and Biophysical Research Communications
Volume532
Issue number3
Early online date30 Aug 2020
DOIs
Publication statusPublished - 12 Nov 2020

Keywords

  • allostery
  • kinetics
  • kinases
  • crystal structures

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