Purification and Identification of Natural Inhibitors of Protein Arginine Methyltransferases from Plants

Mol Cell Biol. 2022 Apr 21;42(4):e0052321. doi: 10.1128/mcb.00523-21. Epub 2022 Mar 21.


Protein arginine methyltransferase (PRMT) enzymes catalyze posttranslational modifications of target proteins and are often upregulated in human cancers. In this study, we purified two chemical compounds from seeds of Foeniculum vulgare based on their ability to inhibit the enzymatic activity of PRMT5. These two compounds were identified as Pheophorbide a (PPBa) and Pheophorbide b (PPBb), two breakdown products of chlorophyll. PPBa and PPBb inhibited the enzymatic activity of both Type I and Type II PRMTs with IC50 values at sub micromole concentrations, inhibited the arginine methylation of histones in cells, and suppressed proliferation of prostate cancer cells. Molecular docking results predicted that PPBa binds to an allosteric site in the PRMT5 structure with a high affinity (ΔG = -9.0 kcal/mol) via hydrogen bond, ionic, and π-π stacking interactions with amino acid residues in PRMT5. Another group of natural compounds referred to as protoporphyrins and sharing structural similarity with pheophorbide also inhibited the PRMT enzymatic activity. This study is the first report on the PRMT-inhibitory activity of the tetrapyrrole macrocycles and provides useful information regarding the application of these compounds as natural therapeutic reagents for cancer prevention and treatment.

Keywords: natural compounds; pheophorbide; protein arginine methyltransferase inhibitors; protoporphyrin; tetrapyrrole macrocycle.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Arginine / metabolism
  • Histones* / metabolism
  • Humans
  • Male
  • Methylation
  • Molecular Docking Simulation
  • Protein-Arginine N-Methyltransferases* / metabolism


  • Histones
  • Arginine
  • PRMT5 protein, human
  • Protein-Arginine N-Methyltransferases