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Molecular basis for catalysis and substrate-mediated cellular stabilization of human tryptophan 2,3-dioxygenase

Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) play a central role in tryptophan metabolism and are involved in many cellular and disease processes. Here we report the crystal structure of human TDO (hTDO) in a ternary complex with the substrates L-Trp and O(2) and in a binar...

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Detalles Bibliográficos
Autores principales: Lewis-Ballester, Ariel, Forouhar, Farhad, Kim, Sung-Mi, Lew, Scott, Wang, YongQiang, Karkashon, Shay, Seetharaman, Jayaraman, Batabyal, Dipanwita, Chiang, Bing-Yu, Hussain, Munif, Correia, Maria Almira, Yeh, Syun-Ru, Tong, Liang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5071832/
https://www.ncbi.nlm.nih.gov/pubmed/27762317
http://dx.doi.org/10.1038/srep35169
Descripción
Sumario:Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) play a central role in tryptophan metabolism and are involved in many cellular and disease processes. Here we report the crystal structure of human TDO (hTDO) in a ternary complex with the substrates L-Trp and O(2) and in a binary complex with the product N-formylkynurenine (NFK), defining for the first time the binding modes of both substrates and the product of this enzyme. The structure indicates that the dioxygenation reaction is initiated by a direct attack of O(2) on the C(2) atom of the L-Trp indole ring. The structure also reveals an exo binding site for L-Trp, located ~42 Å from the active site and formed by residues conserved among tryptophan-auxotrophic TDOs. Biochemical and cellular studies indicate that Trp binding at this exo site does not affect enzyme catalysis but instead it retards the degradation of hTDO through the ubiquitin-dependent proteasomal pathway. This exo site may therefore provide a novel L-Trp-mediated regulation mechanism for cellular degradation of hTDO, which may have important implications in human diseases.