Substrate Oxidation by Indoleamine 2,3-Dioxygenase: EVIDENCE FOR A COMMON REACTION MECHANISM* |
| |
Authors: | Elizabeth S. Booth Jaswir Basran Michael Lee Sandeep Handa Emma L. Raven |
| |
Affiliation: | From the ‡Department of Chemistry, University of Leicester, University Road, Leicester LE1 7RH, Great Britain, United Kingdom and ;§Department of Molecular and Cellular Biology and Henry Wellcome Laboratories for Structural Biology, Henry Wellcome Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, Great Britain, United Kingdom |
| |
Abstract: | 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. This is an O2-dependent process and catalyzed by indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase. More than 60 years after these dioxygenase enzymes were first isolated (Kotake, Y., and Masayama, I. (1936) Z. Physiol. Chem. 243, 237–244), the mechanism of the reaction is not established. We examined the mechanism of substrate oxidation for a series of substituted tryptophan analogues by indoleamine 2,3-dioxygenase. We observed formation of a transient intermediate, assigned as a Compound II (ferryl) species, during oxidation of l-Trp, 1-methyl-l-Trp, and a number of other substrate analogues. The data are consistent with a common reaction mechanism for indoleamine 2,3-dioxygenase-catalyzed oxidation of tryptophan and other tryptophan analogues. |
| |
Keywords: | dioxygenase enzyme mechanism heme substrate specificity tryptophan indoleamine 2 3-dioxygenase |
|
|