Molecular Basis for Catalysis and Substrate-mediated Cellular Stabilization of Human Tryptophan 2,3-dioxygenase

Overview

Journal Sci Rep

Specialty Science

Date 2016 Oct 21

PMID 27762317

Citations 43

Authors

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

Affiliations

Soon will be listed here.

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 O 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 on the C 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.

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References

McRee D . XtalView/Xfit--A versatile program for manipulating atomic coordinates and electron density. J Struct Biol. 1999; 125(2-3):156-65. DOI: 10.1006/jsbi.1999.4094. View

Rovira C, Parrinello M . Harmonic and anharmonic dynamics of Fe-CO and Fe-O(2) in heme models. Biophys J. 2000; 78(1):93-100. PMC: 1300620. DOI: 10.1016/S0006-3495(00)76575-1. View

Vagin A, Teplyakov A . An approach to multi-copy search in molecular replacement. Acta Crystallogr D Biol Crystallogr. 2000; 56(Pt 12):1622-4. DOI: 10.1107/s0907444900013780. View

Sono M, Roach M, Coulter E, Dawson J . Heme-Containing Oxygenases. Chem Rev. 1996; 96(7):2841-2888. DOI: 10.1021/cr9500500. View

Adams P, Grosse-Kunstleve R, Hung L, Ioerger T, McCoy A, Moriarty N . PHENIX: building new software for automated crystallographic structure determination. Acta Crystallogr D Biol Crystallogr. 2002; 58(Pt 11):1948-54. DOI: 10.1107/s0907444902016657. View

Takikawa O . Biochemical and medical aspects of the indoleamine 2,3-dioxygenase-initiated L-tryptophan metabolism. Biochem Biophys Res Commun. 2005; 338(1):12-9. DOI: 10.1016/j.bbrc.2005.09.032. View

Sugimoto H, Oda S, Otsuki T, Hino T, Yoshida T, Shiro Y . Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase. Proc Natl Acad Sci U S A. 2006; 103(8):2611-6. PMC: 1413787. DOI: 10.1073/pnas.0508996103. View

Forouhar F, Anderson J, Mowat C, Vorobiev S, Hussain A, Abashidze M . Molecular insights into substrate recognition and catalysis by tryptophan 2,3-dioxygenase. Proc Natl Acad Sci U S A. 2007; 104(2):473-8. PMC: 1766409. DOI: 10.1073/pnas.0610007104. View

Zhang Y, Kang S, Mukherjee T, Bale S, Crane B, Begley T . Crystal structure and mechanism of tryptophan 2,3-dioxygenase, a heme enzyme involved in tryptophan catabolism and in quinolinate biosynthesis. Biochemistry. 2007; 46(1):145-55. DOI: 10.1021/bi0620095. View

10.

Khan J, Forouhar F, Tao X, Tong L . Nicotinamide adenine dinucleotide metabolism as an attractive target for drug discovery. Expert Opin Ther Targets. 2007; 11(5):695-705. DOI: 10.1517/14728222.11.5.695. View

11.

Batabyal D, Yeh S . Human tryptophan dioxygenase: a comparison to indoleamine 2,3-dioxygenase. J Am Chem Soc. 2007; 129(50):15690-701. DOI: 10.1021/ja076186k. View

12.

Chung L, Li X, Sugimoto H, Shiro Y, Morokuma K . Density functional theory study on a missing piece in understanding of heme chemistry: the reaction mechanism for indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase. J Am Chem Soc. 2008; 130(37):12299-309. DOI: 10.1021/ja803107w. View

13.

Thackray S, Bruckmann C, Anderson J, Campbell L, Xiao R, Zhao L . Histidine 55 of tryptophan 2,3-dioxygenase is not an active site base but regulates catalysis by controlling substrate binding. Biochemistry. 2008; 47(40):10677-84. DOI: 10.1021/bi801202a. View

14.

Pabarcus M, Hoe N, Sadeghi S, Patterson C, Wiertz E, Correia M . CYP3A4 ubiquitination by gp78 (the tumor autocrine motility factor receptor, AMFR) and CHIP E3 ligases. Arch Biochem Biophys. 2008; 483(1):66-74. PMC: 2881844. DOI: 10.1016/j.abb.2008.12.001. View

15.

Batabyal D, Yeh S . Substrate-protein interaction in human tryptophan dioxygenase: the critical role of H76. J Am Chem Soc. 2009; 131(9):3260-70. PMC: 4535339. DOI: 10.1021/ja807969a. View

16.

Kanai M, Funakoshi H, Takahashi H, Hayakawa T, Mizuno S, Matsumoto K . Tryptophan 2,3-dioxygenase is a key modulator of physiological neurogenesis and anxiety-related behavior in mice. Mol Brain. 2009; 2:8. PMC: 2673217. DOI: 10.1186/1756-6606-2-8. View

17.

Lewis-Ballester A, Batabyal D, Egawa T, Lu C, Lin Y, Marti M . Evidence for a ferryl intermediate in a heme-based dioxygenase. Proc Natl Acad Sci U S A. 2009; 106(41):17371-6. PMC: 2765089. DOI: 10.1073/pnas.0906655106. View

18.

Gupta R, Fu R, Liu A, Hendrich M . EPR and Mössbauer spectroscopy show inequivalent hemes in tryptophan dioxygenase. J Am Chem Soc. 2010; 132(3):1098-109. PMC: 4251817. DOI: 10.1021/ja908851e. View

19.

Davydov R, Chauhan N, Thackray S, Anderson J, Papadopoulou N, Mowat C . Probing the ternary complexes of indoleamine and tryptophan 2,3-dioxygenases by cryoreduction EPR and ENDOR spectroscopy. J Am Chem Soc. 2010; 132(15):5494-500. PMC: 2903012. DOI: 10.1021/ja100518z. View

20.

Chung L, Li X, Sugimoto H, Shiro Y, Morokuma K . ONIOM study on a missing piece in our understanding of heme chemistry: bacterial tryptophan 2,3-dioxygenase with dual oxidants. J Am Chem Soc. 2010; 132(34):11993-2005. DOI: 10.1021/ja103530v. View