4.7 Article

Cyclin-Dependent Kinase 5 Inhibitor Butyrolactone I Elicits a Partial Agonist Activity of Peroxisome Proliferator-Activated Receptor γ

Journal

BIOMOLECULES
Volume 10, Issue 2, Pages -

Publisher

MDPI
DOI: 10.3390/biom10020275

Keywords

butyrolactone I; PPAR gamma partial agonism; CDK inhibitor; human bone marrow mesenchymal stem cells; polypharmacology

Funding

  1. MRC grant through NRF Korea [NRF-2018R1A5A2024425]
  2. National Research Foundation of Korea (NRF) [2019R1A2C2085749]
  3. National Research Foundation of Korea (NRF) grant [NRF-2019H1A2A1075154]
  4. National Research Foundation (NRF) [2018R1A4A1021703]
  5. Tumor Microenvironment Global Core Research Center through the National Research Foundation of the Ministry of Science and ICT of Korea [2011-0030001]
  6. Brain Korea (BK21) PLUS program
  7. National Research Foundation of Korea [2019H1A2A1075154, 2019R1A2C2085749] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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Adiponectin is an adipocyte-derived cytokine having an insulin-sensitizing activity. During the phenotypic screening of secondary metabolites derived from the marine fungus Aspergillus terreus, a poly cyclin-dependent kinase (CDK) inhibitor butyrolactone I affecting CDK1 and CDK5 was discovered as a potent adiponectin production-enhancing compound in the adipogenesis model of human bone marrow-derived mesenchymal stem cells (hBM-MSCs). CDK5 inhibitors exhibit insulin-sensitizing activities by suppressing the phosphorylation of peroxisome proliferator-activated receptor gamma (PPAR gamma). However, the adiponectin production-enhancing activities of butyrolactone I have not been correlated with the potency of CDK5 inhibitor activities. In a target identification study, butyrolactone I was found to directly bind to PPAR gamma. In the crystal structure of the human PPAR gamma, the ligand-binding domain (LBD) in complex with butyrolactone I interacted with the amino acid residues located in the hydrophobic binding pockets of the PPAR gamma LBD, which is a typical binding mode of the PPAR gamma partial agonists. Therefore, the adiponectin production-enhancing effect of butyrolactone I was mediated by its polypharmacological dual modulator activities as both a CDK5 inhibitor and a PPAR gamma partial agonist.

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