Inhibition Mechanisms of Human Indoleamine 2,3 Dioxygenase 1

Ariel Lewis-Ballester, Shay Karkashon, Dipanwita Batabyal, Thomas L. Poulos, Syun-Ru Yeh

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan dioxygenase (hTDO) catalyze the same dioxygenation reaction of Trp to generate N-formyl kynurenine (NFK). They share high structural similarity, especially in the active site. However, hIDO1 possesses a unique inhibitory substrate binding site (Si) that is absent in hTDO. In addition, in hIDO1, the indoleamine group of the substrate Trp is H-bonded to S167 through a bridging water, while that in hTDO is directly H-bonded to H76. Here we show that Trp binding to the Si site or the mutation of S167 to histidine in hIDO1 retards its turnover activity, and that the inhibited activity can be rescued by an effector, 3-indole ethanol (IDE). Kinetic studies reveal that the inhibited activity introduced by Trp binding to the Si site is a result of retarded recombination of the ferryl moiety with Trp epoxide to form NFK, and that IDE reverses the effect by preventing Trp from binding to the Si site. In contrast, the abolished activity induced by the S167H mutation is primarily a result of ~5000-fold reduction in the O2 binding rate constant, possibly due to the blockage of a ligand delivery tunnel, and that IDE binding to the Si site reverses the effect by reopening the tunnel. The data offer new insights into structure-based design of hIDO1-selective inhibitors.

Original languageEnglish (US)
JournalJournal of the American Chemical Society
DOIs
StateAccepted/In press - Apr 5 2018

Fingerprint

Ethanol
Dioxygenases
Binding Sites
Tryptophan
Tunnels
Kynurenine
Hydrogen
Binding sites
Substrates
Rate constants
Ligands
Mutation
Epoxy Compounds
Kinetics
Histidine
Genetic Recombination
Catalytic Domain
human indoleamine 2,3-dioxygenase 1
Water
tryptophol

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Inhibition Mechanisms of Human Indoleamine 2,3 Dioxygenase 1. / Lewis-Ballester, Ariel; Karkashon, Shay; Batabyal, Dipanwita; Poulos, Thomas L.; Yeh, Syun-Ru.

In: Journal of the American Chemical Society, 05.04.2018.

Research output: Contribution to journalArticle

Lewis-Ballester, Ariel ; Karkashon, Shay ; Batabyal, Dipanwita ; Poulos, Thomas L. ; Yeh, Syun-Ru. / Inhibition Mechanisms of Human Indoleamine 2,3 Dioxygenase 1. In: Journal of the American Chemical Society. 2018.
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