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

Ariel Lewis-Ballester, Farhad Forouhar, Sung Mi Kim, Scott Lew, Yongqiang Wang, Shay Karkashon, Jayaraman Seetharaman, Dipanwita Batabyal, Bing Yu Chiang, Munif Hussain, Maria Almira Correia, Syun Ru Yeh, Liang Tong

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Abstract

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 O2 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 O2 on the C2 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.

Original languageEnglish (US)
Article number35169
JournalScientific reports
Volume6
DOIs
StatePublished - Oct 20 2016

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    Lewis-Ballester, A., Forouhar, F., Kim, S. M., Lew, S., Wang, Y., Karkashon, S., Seetharaman, J., Batabyal, D., Chiang, B. Y., Hussain, M., Correia, M. A., Yeh, S. R., & Tong, L. (2016). Molecular basis for catalysis and substrate-mediated cellular stabilization of human tryptophan 2,3-dioxygenase. Scientific reports, 6, [35169]. https://doi.org/10.1038/srep35169