INHIBITION OF RAT-LIVER CYCLIC AMP-DEPENDENT PROTEIN-KINASE BY FLAVONOIDS

Rat liver cyclic AMP-dependent protein kinase catalytic subunit (cAK), assayed using the synthetic peptide substrate, LRRASLG, is inhibited by a range of plant-derived flavonoids. In general, maximal inhibitory effectiveness (IC50 values 1 to 2-mu-M) requires 2,3-unsaturation and polyhydroxylation involving at least two of the three flavonoid rings. 3-Hydroxyflavone (IC50 value 4-mu-M), 3,5,7,2',4'-pentahydroxyflavone (IC50 = 10-mu-m) and 5,7,4'-trihydroxyflavone (IC50 = 7-mu-M) represent somewhat less active variations from this pattern. Flavonoid O-methylation or O-glycosylation greatly decreases inhibitory effectiveness, as does 2,3-saturation. Various flavonoid-related compounds, notably gossypol (IC50 = 10-mu-M), also inhibit cAK. Flavonoids and related compounds are in general much better inhibitors of cAK than of avian Ca2+-calmodulin-dependent myosin light chain kinase or of plant Ca2+-dependent protein kinase. Tricetin (IC50 = 1-mu-M) inhibits cAK in a fashion that is non-competitive with respect to both peptide substrate and ATP (K(i) value 0.7-mu-M). When histone III-S is used as a substrate, inhibition of cAK requires much higher flavonoid concentrations.