Inhibition of phenylalanine hydroxylase, a pterin-requiring monooxygenase, by oudenone and its derivatives.
Phenylalanine hydroxylase was shown to be inhibited by oudenone and its derivatives in vitro. At a concentration of 2.3 x 10(-3) M, oudenone inhibited phenylalanine hydroxylase by 50%, and some of the oudenone derivatives showed more potent inhibition. The kinetic data have shown that the inhibition by oudenone is competitive with a tetrahydropterin cofactor (6,7-dimethyltetrahydropterin, DMPH4) and noncompetitive with phenylalanine and oxygen. Among 12 oudenone derivatives, there was no parallel structure-activity relationship between the inhibitory effect for phenylalanine hydroxylase and that for tyrosine hydroxylase. A derivative of oudenone, [compound No. 142; 2-(3,4-dihydroxyphenyl)-1-oxopropyl)cyclohexan-1,3-dione] showed the most potent inhibition among the oudenone derivatives. It inhibited phenylalanine hydroxylase by 50% at a concentration of 1.8 x 10(-5) M. This inhibition was a mixed type with either a tetrahydropterin cofactor, DMPH4, or with the substrate phenylalanine, which was different from the inhibition by oudenone. However, the same noncompetitive inhibition was shown toward oxygen.
D003517:Cyclopentanes / Q000494:pharmacology*; D005663:Furans / Q000494:pharmacology*; D007700:Kinetics; D010651:Phenylalanine Hydroxylase / Q000037:antagonists & inhibitors*; D011621:Pteridines / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D003517:Cyclopentanes; D005663:Furans; D011621:Pteridines; C002780:oudenone; C005063:2-amino-4-hydroxy-6,7-dimethyl-5,6,7,8-tetrahydropteridine; D010651:Phenylalanine Hydroxylase