title: Effect of Glucuronidation on the Potential of Kaempferol to Inhibit Serine/Threonine Protein Kinases.
abstract: To study the effect of metabolic conjugation of flavonoids on the potential to inhibit protein kinase activity, the inhibitory effects of the dietary flavonol kaempferol and its major plasma conjugate kaempferol-3-O-glucuronide on protein kinases were studied. To this end, the inhibition of the phosphorylation activity of recombinant protein kinase A (PKA) and of cell lysate from the hepatocellular carcinoma cell line HepG2 on 141 putative serine/threonine phosphorylation sites derived from human proteins was assessed. Glucuronidation reduced the inhibitory potency of kaempferol on the phosphorylation activity of PKA and HepG2 lysate on average about 16 and 3.5 times, respectively, but did not appear to affect the target selectivity for kinases present in the lysate. The data demonstrate that, upon glucuronidation, kaempferol retains part of its intrinsic kinase inhibition potential, which implies that K3G does not necessarily need to be deconjugated to the aglycone for a potential inhibitory effect on protein kinases.
authors.affiliation: Division of Toxicology, Wageningen University , Postbus 8000, 6700EA, Wageningen, The Netherlands.
authors.forename: Karsten
authors.initials: K
authors.lastname: Beekmann
authors.affiliation: Division of Toxicology, Wageningen University , Postbus 8000, 6700EA, Wageningen, The Netherlands.
authors.forename: Laura H J
authors.initials: LH
authors.lastname: de Haan
authors.affiliation: Nestlé Research Center, Nestec Ltd., Vers-chez-les-Blanc, Case Postale 44, 1000 Lausanne 26, Switzerland.
authors.forename: Lucas
authors.initials: L
authors.lastname: Actis-Goretta
authors.affiliation: Division of Toxicology, Wageningen University , Postbus 8000, 6700EA, Wageningen, The Netherlands.|Nestlé Research Center, Nestec Ltd., Vers-chez-les-Blanc, Case Postale 44, 1000 Lausanne 26, Switzerland.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van Bladeren
authors.affiliation: Division of Toxicology, Wageningen University , Postbus 8000, 6700EA, Wageningen, The Netherlands.
authors.forename: Ivonne M C M
authors.initials: IM
authors.lastname: Rietjens
mesh_terms: D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry*; D020723:Glucuronic Acid / Q000737:chemistry; D006801:Humans; D044949:Kaempferols / Q000737:chemistry*; D007700:Kinetics; D015394:Molecular Structure; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D044949:Kaempferols; D020723:Glucuronic Acid; D017346:Protein Serine-Threonine Kinases
keywords: conjugation; flavonoid; glucuronidation; serine/threonine protein kinases; substrate microarray