Inhibition of indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase by beta-carboline and indole derivatives.
beta-Carboline derivatives inhibited both indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase activities from various sources. Among them, norharman is most potent for both enzymes from mammalian sources. Kinetic studies revealed that norharman is uncompetitive (Ki = 0.12 mM) with L-tryptophan for rabbit intestinal indoleamine 2,3-dioxygenase, and linearly competitive (Ki = 0.29 mM) with L-tryptophan for mouse liver tryptophan 2,3-dioxygenase. In addition, some beta-carbolines selectively inhibited one enzyme or the other. Pseudomonad tryptophan 2,3-dioxygenase was inhibited by a different spectrum of beta-carbolines. Such a selective inhibition by the structure of substrate analogs is more evident by the use of indole derivatives. Indole-3-acetamide, indole-3-acetonitrile and indole-3-acrylic acid exhibited a potent inhibition for mammalian tryptophan 2,3-dioxygenase, while they moderately inhibited the pseudomonad enzyme. However, they showed no inhibition for indoleamine 2,3-dioxygenase. These results suggest the difference of the structures of the active sites among these enzymes from various sources.
D000818:Animals; D001667:Binding, Competitive; D002243:Carbolines / Q000494:pharmacology*; D006247:Harmine / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007421:Intestine, Small / Q000201:enzymology; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D051379:Mice; D010105:Oxygenases / Q000037:antagonists & inhibitors*; D011551:Pseudomonas fluorescens / Q000201:enzymology; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors*
D002243:Carbolines; D007211:Indoles; D006247:Harmine; D010105:Oxygenases; D014366:Tryptophan Oxygenase