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J. Biol. Chem., Vol. 282, Issue 33, 23778-23787, August 17, 2007

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Post-translational Regulation of Human Indoleamine 2,3-Dioxygenase Activity by Nitric Oxide^*

Shane R. Thomas¹², Andrew C. Terentis¹, Hong Cai, Osamu Takikawa^¶, Aviva Levina^||, Peter A. Lay^||, Mohammed Freewan, and Roland Stocker³

From the Centre for Vascular Research, Faculty of Medicine, University of New South Wales, Sydney 2052, Australia, Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, Florida 33431, ^¶National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Aichi 474-8522, Japan, and ^||School of Chemistry, University of Sydney, Sydney 2006, Australia

The heme protein indoleamine 2,3-dioxygenase (IDO) is induced by the proinflammatory cytokine interferon- (IFN) and plays an important role in the immune response by catalyzing the oxidative degradation of L-tryptophan (Trp) that contributes to immune suppression and tolerance. Here we examined the mechanism by which nitric oxide (NO) inhibits human IDO activity. Exposure of IFN-stimulated human monocyte-derived macrophages (MDM) to NO donors had no material impact on IDO mRNA or protein expression, yet exposure of MDM or transfected COS-7 cells expressing active human IDO to NO donors resulted in reversible inhibition of IDO activity. NO also inhibited the activity of purified recombinant human IDO (rhIDO) in a reversible manner and this correlated with NO binding to the heme of rhIDO. Optical absorption and resonance Raman spectroscopy identified NO-inactivated rhIDO as a ferrous iron (Fe^II)-NO-Trp adduct. Stopped-flow kinetic studies revealed that NO reacted most rapidly with Fe^II rhIDO in the presence of Trp. These findings demonstrate that NO inhibits rhIDO activity reversibly by binding to the active site heme to trap the enzyme as an inactive nitrosyl-Fe^II enzyme adduct with Trp bound and O₂ displaced. Reversible inhibition by NO may represent an important mechanism in controlling the immune regulatory actions of IDO.

Received for publication, January 24, 2007 , and in revised form, May 24, 2007.

^* This work was supported in part by National Health and Medical Research Council (NHMRC) Project Grants 350916 (to S. R. T.) and 000371 (to R. S.) and a University of New South Wales Medical Faculty Research Project Grant (to S. R. T.). The research was also supported by a Florida Atlantic University new faculty start-up grant (to A. C. T.), an Australian Research Council (ARC) equipment grant for the purchase of the stop-flow instrument (to P. A. L.), and an ARC Discovery Grant, including an Australian professorial fellowship (to P. A. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ These authors made an equal contribution to this work.

³ Supported by a NHMRC senior principal research fellowship, a University of Sydney professorial fellowship, and the University of Sydney Medical Foundation. Current address: Centre for Vascular Research, Dept. of Pathology, The University of Sydney, Medical Foundation Bldg. K25, 92-94 Parramatta Rd., Camperdown New South Wales 2006, Australia.

² Supported by NHMRC R. D. Wright Career Development Award 401113. To whom correspondence should be addressed: Centre for Vascular Research, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2052, Australia. Tel.: 61-2-9385-2582; Fax: 61-2-9385-1389; E-mail: shane.thomas{at}unsw.edu.au.

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