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

Pyruvate phosphate dikinase (PPDK) is an essential enzyme of C(4) 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 C(4) photosynthesis in contrast to world’s major crops, which are C(3) plants. Hence inhibitors of PPDK may be used as C(4)-specific herbicides. By screening a library of 80 commercially available kinase inhibitors, we identified compounds derived from bisindolylmaleimide (bisindolylmaleimide IV, IC(50) = 0.76 ± 0.13 μM) and indirubin (indirubin-3’-monoxime, IC(50) = 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 C(4) model plant confirmed in vivo inhibition of C(4)-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.