Inhibition of protein phosphatase-1 and -2A by ellagitannins: structure-inhibitory potency relationships and influences on cellular systems

J Enzyme Inhib Med Chem. 2019 Dec;34(1):500-509. doi: 10.1080/14756366.2018.1557653.

Abstract

Several ellagitannins inhibited the activity of protein phosphatase-1 (PP1) and -2 A (PP2A) catalytic subunits (PP1c and PP2Ac) with preferential suppression of PP1c over PP2Ac. The inhibitory potency for PP1c followed the order of tellimagrandin I > mahtabin A > praecoxin B > 1.2-Di-O-galloyl-4.6-(S)-HHDP-β-D-glucopyranose > pedunculagin with IC50 values ranging from 0.20 µM to 2.47 µM. The interaction of PP1c and tellimagrandin I was assessed by NMR saturation transfer difference, surface plasmon resonance, isothermal titration calorimetry, and microscale thermophoresis based binding techniques. Tellimagrandin I suppressed viability and phosphatase activity of HeLa cells, while mahtabin A was without effect. Conversely, mahtabin A increased the phosphorylation level of SNAP-25Thr138 and suppressed exocytosis of cortical synaptosomes, whereas tellimagrandin I was without influence. Our results establish ellagitannins as partially selective inhibitors of PP1 and indicate that these polyphenols may act distinctly in cellular systems depending on their membrane permeability and/or their actions on cell membranes.

Keywords: Tellimagrandin I; mahtabin A; protein phosphatase-1; protein phosphatase-2A; synaptosomal exocytosis.

MeSH terms

  • Animals
  • Calorimetry / methods*
  • Cell Survival / drug effects
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Exocytosis / drug effects
  • HeLa Cells
  • Humans
  • Hydrolyzable Tannins / chemistry*
  • Hydrolyzable Tannins / pharmacology*
  • Inhibitory Concentration 50
  • Magnetic Resonance Spectroscopy
  • Mice
  • Muscle, Skeletal / enzymology
  • Phosphorylation
  • Protein Phosphatase 1 / antagonists & inhibitors*
  • Protein Phosphatase 2 / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Surface Plasmon Resonance
  • Synaptosomal-Associated Protein 25 / metabolism
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism

Substances

  • Enzyme Inhibitors
  • Hydrolyzable Tannins
  • SNAP25 protein, human
  • Synaptosomal-Associated Protein 25
  • Protein Phosphatase 1
  • Protein Phosphatase 2

Grants and funding

This research was supported by the National Research, Development and Innovation Fund (NKFI) under grant numbers K129104 (to F. E), NN 128368 (to K.E.K), and FK125043 (to BL), and by the EU co-financed by the European Regional Development Fund under the projects GINOP-2.3.2–15-2016–00044, GINOP-2.3.3–15-2016–00020 and EFOP-3.6.2–16-2017–00006.