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

• Published in: Biomolecules (Basel, Switzerland) Switzerland), 2020-02, Vol.10 (2), p.275
• Main Authors: Ahn, Sungjin, Jang, Dong Man, Park, Sung Chul, An, Seungchan, Shin, Jongheon, Han, Byung Woo, Noh, Minsoo
• Format: Article
• Language: English
• Subjects: 4-Butyrolactone - analogs & derivatives; 4-Butyrolactone - chemistry; 4-Butyrolactone - pharmacology; Adipogenesis - drug effects; Adiponectin - biosynthesis; Binding Sites - physiology; Bone Marrow Cells; butyrolactone i; cdk inhibitor; Cells, Cultured; Crystallography, X-Ray; Cyclin-Dependent Kinase 5 - antagonists & inhibitors; Cyclin-Dependent Kinase 5 - chemistry; human bone marrow mesenchymal stem cells; Humans; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Phosphorylation - drug effects; polypharmacology; PPAR gamma - agonists; PPAR gamma - chemistry; pparγ partial agonism; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Structure, Tertiary
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom10020275

Adiponectin is an adipocyte-derived cytokine having an insulin-sensitizing activity. During the phenotypic screening of secondary metabolites derived from the marine fungus , 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 γ (PPARγ). 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 PPARγ. In the crystal structure of the human PPARγ, the ligand-binding domain (LBD) in complex with butyrolactone I interacted with the amino acid residues located in the hydrophobic binding pockets of the PPARγ LBD, which is a typical binding mode of the PPARγ 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 PPARγ partial agonist.