4.7 Article

Non-psychotropic cannabinoids as inhibitors of TET1 protein

Journal

BIOORGANIC CHEMISTRY
Volume 124, Issue -, Pages -

Publisher

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2022.105793

Keywords

Cannabinoids; TET1 protein; Iron chelation; DNA methylation; Epigenetic

Funding

  1. Charles University in Prague [SVV260521, UNCE 204064, Progress Q26-38/LF1, Q27/LF1]
  2. Ministry of Education, Youth and Sports [LM2018133]
  3. Ministry of Industry and Trade of Czech Republic [FV40120]
  4. Technology Agency of the Czech Republic [TN01000013, FW02020128]
  5. Ministry of Health of the Czech Republic [NU21-08-00407, NU22-D-136, NU22-08-00160]
  6. Operational Programme Research, Development and Education, within the project: Center for Tumor Ecology-Research of the Cancer Microenvironment Supporting Cancer Growth and Spread [CZ.02.1.01/0.0/0.0/16_019/0000785]
  7. National Institute for Cancer Research - European Union - Next Generation EU [LX22NPO5102]
  8. National Institute for Neurological Research - European Union - Next Generation EU [LX22NPO5107]

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Predicting and studying the effects of non-psychotropic cannabinoids on DNA methylation is crucial for assessing the safety of these products. Researchers found that these cannabinoids can interfere with TET enzymes, affecting methylation patterns, possibly through chelating ferrous ions.
Non-psychotropic cannabinoids (e.g., cannabidiol, cannabinol and cannabigerol) are contained in numerous alimentary and medicinal products. Therefore, predicting and studying their possible side effects, such as changes in DNA methylation, is an important task for assessing the safety of these products. Interference with TET enzymes by chelating ferrous ions can contribute to the altered methylation pattern. All tested cannabinoids displayed a strong affinity for Fe(II) ions. Cannabidiol and cannabinol exhibited potent inhibitory activities (IC50 = 4.8 and 6.27 mu M, respectively) towards the TET1 protein, whereas cannabigerol had no effect on the enzyme activity. An in silico molecular docking study revealed marked binding potential within the catalytic cavity for CBD/CBN, but some affinity was also found for CBG, thus the total lack of activity remains unexplained. These results imply that cannabinoids could affect the activity of the TET1 protein not only due to their affinity for Fe(II) but also due to other types of interactions (e.g., hydrophobic interactions and hydrogen bonding).

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