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Structural and functional analyses of human tryptophan 2,3‐dioxygenase
Author(s) -
Meng Bing,
Wu Dong,
Gu Jianhua,
Ouyang Songying,
Ding Wei,
Liu ZhiJie
Publication year - 2014
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.24653
Subject(s) - tryptophan , indole test , kynurenine pathway , kynurenine , chemistry , cofactor , indoleamine 2,3 dioxygenase , biochemistry , enzyme , tetramer , heme , active site , stereochemistry , biology , amino acid
Tryptophan 2,3‐dioxygenase (TDO), one of the two key enzymes in the kynurenine pathway, catalyzes the indole ring cleavage at the C2‐C3 bond of l ‐tryptophan. This is a rate‐limiting step in the regulation of tryptophan concentration in vivo , and is thus important in drug discovery for cancer and immune diseases. Here, we report the crystal structure of human TDO (hTDO) without the heme cofactor to 2.90 Å resolution. The overall fold and the tertiary assembly of hTDO into a tetramer, as well as the active site architecture, are well conserved and similar to the structures of known orthologues. Kinetic and mutational studies confirmed that eight residues play critical roles in l ‐tryptophan oxidation. Proteins 2014; 82:3210–3216. © 2014 Wiley Periodicals, Inc.