Interactions between nitric oxide and indoleamine 2,3-dioxygenase

Ben J. Samelson-Jones, Syun-Ru Yeh

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Indoleamine 2,3-dioxygenase (IDO) is a heme-containing enzyme, which catalyzes the initial and rate-determining step of L-tryptophan (L-Trp) metabolism via the kynurenine pathway in nonhepatic tissues. Similar to inducible nitric oxide synthase (iNOS), IDO is induced by interferon-γ and lipopolysaccharide in the inflammatory response. In vivo studies indicate that the nitric oxide (NO) produced by iNOS inhibits IDO activity by directly interacting with it and by promoting its degradation through the proteasome pathway. In this work, the molecular mechanisms underlying the interactions between NO and human recombinant IDO (hIDO) were systematically studied with optical absorption and resonance Raman spectroscopies. Resonance Raman data show that the heme prosthetic group in the NO-bound hIDO is situated in a unique protein environment and adopts an out-of-plane deformed geometry that is sensitive to L-Trp binding. Under mildly acidic conditions, the proximal heme iron-His bond is prone to rupture, resulting in a five-coordinate (5C) NO-bound species. The bond breakage reaction induces significant conformational changes in the protein matrix, which may account for the NO-induced inactivation of hIDO and its enhanced proteasome-linked degradation in vivo. Moreover, it was found that the NO-induced bond breakage reaction occurs more rapidly in the ferrous protein than in the ferric protein and is fully inhibited by L-Trp binding. The spectroscopic data presented here not only provide the first glimpse of the possible regulatory mechanism of hIDO by NO in the cell at the molecular level, but they also suggest that the NO-dependent regulation can be modulated by cellular factors, such as the NO abundance, pH, redox environment, and L-Trp availability.

Original languageEnglish (US)
Pages (from-to)8527-8538
Number of pages12
JournalBiochemistry
Volume45
Issue number28
DOIs
StatePublished - Jul 18 2006

Fingerprint

Indoleamine-Pyrrole 2,3,-Dioxygenase
Nitric Oxide
Tryptophan
Heme
Nitric Oxide Synthase Type II
Proteasome Endopeptidase Complex
Proteins
Kynurenine
Degradation
Raman Spectrum Analysis
Prosthetics
Metabolism
Light absorption
Interferons
Oxidation-Reduction
Lipopolysaccharides
Raman spectroscopy
Rupture
Iron
Availability

ASJC Scopus subject areas

  • Biochemistry

Cite this

Interactions between nitric oxide and indoleamine 2,3-dioxygenase. / Samelson-Jones, Ben J.; Yeh, Syun-Ru.

In: Biochemistry, Vol. 45, No. 28, 18.07.2006, p. 8527-8538.

Research output: Contribution to journalArticle

Samelson-Jones, Ben J. ; Yeh, Syun-Ru. / Interactions between nitric oxide and indoleamine 2,3-dioxygenase. In: Biochemistry. 2006 ; Vol. 45, No. 28. pp. 8527-8538.
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