Substrate Oxidation by Indoleamine 2,3-Dioxygenase: EVIDENCE FOR A COMMON REACTION MECHANISM.
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.
From the Department of Chemistry, University of Leicester, University Road, Leicester LE1 7RH, Great Britain, United Kingdom and.
Elizabeth S
ES
Booth
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.
Jaswir
J
Basran
From the Department of Chemistry, University of Leicester, University Road, Leicester LE1 7RH, Great Britain, United Kingdom and.
Michael
M
Lee
From the Department of Chemistry, University of Leicester, University Road, Leicester LE1 7RH, Great Britain, United Kingdom and.
Sandeep
S
Handa
From the Department of Chemistry, University of Leicester, University Road, Leicester LE1 7RH, Great Britain, United Kingdom and emma.raven@le.ac.uk.
Emma L
EL
Raven
D002384:Catalysis; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000737:chemistry* / Q000378:metabolism; D007737:Kynurenine / Q000737:chemistry* / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry* / Q000378:metabolism; D013379:Substrate Specificity; D014364:Tryptophan / Q000737:chemistry* / Q000378:metabolism
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D014364:Tryptophan; D010100:Oxygen
dioxygenase; enzyme mechanism; heme; indoleamine 2,3-dioxygenase; substrate specificity; tryptophan