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 microM) requires 2,3-unsaturation and polyhydroxylation involving at least two of the three flavonoid rings. 3-Hydroxyflavone (IC50 value 4 microM), 3,5,7,2',4'-pentahydroxyflavone (IC50 = 10 microM) and 5,7,4'-trihydroxyflavone (IC50 = 7 microM) 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 microM), also inhibit cAK. Flavonoids and related compounds are in general much better inhibitors of cAK than of avian Ca(2+)-calmodulin-dependent myosin light chain kinase or of plant Ca(2+)-dependent protein kinase. Tricetin (IC50 = 1 microM) inhibits cAK in a fashion that is non-competitive with respect to both peptide substrate and ATP (Ki value 0.7 microM). When histone III-S is used as a substrate, inhibition of cAK requires much higher flavonoid concentrations.
Jinsart
W
W
Department of Chemistry, La Trobe University, Bundoora, Victoria, Australia.
Ternai
B
B
Polya
G M
GM
D000595:Amino Acid Sequence; D000818:Animals; D005419:Flavonoids / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008969:Molecular Sequence Data; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship
D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases