Elsevier

Biochemical Pharmacology

Volume 38, Issue 10, 15 May 1989, Pages 1617-1624
Biochemical Pharmacology

Protein kinase C inhibition by plant flavonoids: Kinetic mechanisms and structure-activity relationships

https://doi.org/10.1016/0006-2952(89)90309-2Get rights and content

Abstract

Protein kinase C (PKC) from rat brain was inhibited by plant flavonoids in a concentrationdependent manner depending on flavonoid structure. Of the fifteen flavonoids studied, fisetin, quercetin and luteolin were the most potent, while hesperetin, taxifolin and rutin were among the least potent. The flavonol fisetin was almost 100% inhibitory at a concentration of 100 μM. The extent of inhibition was the same whether diacylglycerol or 12-O-tetradecanoylphorbol-13-acetate was used as enzyme activator. Inhibition was independent of Ca2+, phospholipid, and enzyme activator, as shown by inhibition of protamine phosphorylation in the absence of the regulatory components. Fisetin was a competitive inhibitor with respect to ATP binding and noncompetitive with respect to protein substrate. The X-ray crystal structure analysis of hesperetin monohydrate showed that the molecule is essentially planar despite the sofa conformation of the γ-pyran ring and the 27° twist of the 2-phenyl ring. Comparison of this inactive flavanone with those of the active flavones showed that, although hesperetin can adopt a planar profile similar to those of fisetin and quercetin, the 4'-methoxy substituent blocks an essential structural feature required for inhibitory activity. Analysis of these structure-activity data revealed a model of the minimal essential features required for PKC inhibition by flavonoids: a coplanar flavone structure with free hydroxyl substituents at the 3', 4' and 7-positions.

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This study was funded by research grants from the Department of Citrus, State of Florida (E. M. Jr.), and from Tsumura Juntendo, Inc. (V. C.).

Present address: National Institute of Environmental Health Science, Laboratory of Pulmonary Pathobiology, Research Triangle Park, NC 27709.

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