Substrate Oxidation by Indoleamine 2,3-Dioxygenase: Evidence for a Common Reaction Mechanism [Protein Structure and Folding]

October 28th, 2015 by Booth, E. S., Basran, J., Lee, M., Handa, S., Raven, E. L.

The kynurenine pathway is the major route of L-tryptophan (L-Trp) catabolism in biology, leading ultimately to the formation of NAD+. The initial and rate-limiting step of the kynurenine pathway involves oxidation of L-Trp to N-formylkynurenine (NFK). This is an O2-dependent process and catalyzed by indoleamine 2,3 dioxygenase (IDO). More than sixty years after these enzymes were first isolated (1), the mechanism of their reaction is not established. We have examined the mechanism of substrate oxidation for a series of substituted tryptophan analogues by indoleamine 2,3-dioxygenase. We observe formation of a transient intermediate, assigned as a Compound II (ferryl) species, during oxidation of L-Trp, 1-Me-L-Trp and a number of other substrate analogues. The data are consistent with a common reaction mechanism for IDO-catalyzed oxidation of tryptophan and other tryptophan analogues.