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Sci Rep. 2016 Oct 20;6:35169. doi: 10.1038/srep35169.

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

Author information

1
Department of Physiology and Biophysics Albert Einstein College of Medicine Bronx, NY 10461, USA.
2
Department of Biological Sciences Northeast Structural Genomics Consortium Columbia University New York, NY 10027, USA.
3
Departments of Cellular and Molecular Pharmacology, Pharmaceutical Chemistry, and Bioengineering and Therapeutic Sciences, The Liver Center, University of California at San Francisco San Francisco, CA 94158, USA.

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.

PMID:
27762317
PMCID:
PMC5071832
DOI:
10.1038/srep35169
[Indexed for MEDLINE]
Free PMC Article

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