Crystal structure and mechanism of tryptophan 2,3-dioxygenase, a heme enzyme involved in tryptophan catabolism and in quinolinate biosynthesis.
The structure of tryptophan 2,3-dioxygenase (TDO) from Ralstonia metallidurans was determined at 2.4 A. TDO catalyzes the irreversible oxidation of l-tryptophan to N-formyl kynurenine, which is the initial step in tryptophan catabolism. TDO is a heme-containing enzyme and is highly specific for its substrate l-tryptophan. The structure is a tetramer with a heme cofactor bound at each active site. The monomeric fold, as well as the heme binding site, is similar to that of the large domain of indoleamine 2,3-dioxygenase, an enzyme that catalyzes the same reaction except with a broader substrate tolerance. Modeling of the putative (S)-tryptophan hydroperoxide intermediate into the active site, as well as substrate analogue and mutagenesis studies, are consistent with a Criegee mechanism for the reaction.
Zhang
Yang
Y
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA.
Kang
Seong A
SA
Mukherjee
Tathagata
T
Bale
Shridhar
S
Crane
Brian R
BR
Begley
Tadhg P
TP
Ealick
Steven E
SE
D001665:Binding Sites; D018360:Crystallography, X-Ray; D005998:Glycine / Q000235:genetics / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010084:Oxidation-Reduction; D017510:Protein Folding; D017378:Quinolinic Acid / Q000378:metabolism*; D043367:Ralstonia / Q000145:classification / Q000201:enzymology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014364:Tryptophan / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000737:chemistry* / Q000378:metabolism*
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D006418:Heme; D014364:Tryptophan; D014366:Tryptophan Oxygenase; D017378:Quinolinic Acid; D005998:Glycine