Small-molecule inhibition of pyruvate phosphate dikinase targeting the nucleotide binding site

PLoS One. 2017 Jul 10;12(7):e0181139. doi: 10.1371/journal.pone.0181139. eCollection 2017.

Abstract

Pyruvate phosphate dikinase (PPDK) is an essential enzyme of C4 photosynthesis in plants, catalyzing the ATP-driven conversion of pyruvate to phosphoenolpyruvate (PEP). It is further used by some bacteria and unicellular protists in the reverse, ATP-forming direction. Many weed species use C4 photosynthesis in contrast to world's major crops, which are C3 plants. Hence inhibitors of PPDK may be used as C4-specific herbicides. By screening a library of 80 commercially available kinase inhibitors, we identified compounds derived from bisindolylmaleimide (bisindolylmaleimide IV, IC50 = 0.76 ± 0.13 μM) and indirubin (indirubin-3'-monoxime, IC50 = 4.2 ± 0.9 μM) that showed high inhibitory potency towards PPDK and are among the most effective PPDK inhibitors described today. Physiological studies on leaf tissues of a C4 model plant confirmed in vivo inhibition of C4-driven photosynthesis by these substances. Moreover, comparative docking studies of non-inhibitory bisindolylmaleimide derivatives suggest that the selectivity towards PPDK may be increased by addition of functional groups to the core structure.

MeSH terms

  • Binding Sites
  • Enzyme Activation / drug effects
  • Nucleotides / metabolism*
  • Plant Proteins / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Pyruvate, Orthophosphate Dikinase / metabolism*

Substances

  • Nucleotides
  • Plant Proteins
  • Protein Kinase Inhibitors
  • Pyruvate, Orthophosphate Dikinase

Grant support

This work was supported by Heinrich Heine University Düsseldorf (scholarships within the iGRASPseed-Graduate Cluster for AM) (http://igrasp.hhu.de/).