Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form

Micah T. Nelp, Patrick A. Kates, John T. Hunt, John A. Newitt, Aaron Balog, Derrick Maley, Xiao Zhu, Lynn Abell, Alban Allentoff, Robert Borzilleri, Hal A. Lewis, Zeyu Lin, Steven P. Seitz, Chunhong Yan, John Taylor Groves

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47 Scopus citations

Abstract

For cancer cells to survive and proliferate, they must escape normal immune destruction. One mechanism by which this is accomplished is through immune suppression effected by up-regulation of indoleamine 2,3-dioxygenase (IDO1), a heme enzyme that catalyzes the oxidation of tryptophan to N-formylkynurenine. On deformylation, kynurenine and downstream metabolites suppress T cell function. The importance of this immunosuppressive mechanism has spurred intense interest in the development of clinical IDO1 inhibitors. Herein, we describe the mechanism by which a class of compounds effectively and specifically inhibits IDO1 by targeting its apo-form. We show that the in vitro kinetics of inhibition coincide with an unusually high rate of intrinsic enzyme–heme dissociation, especially in the ferric form. X-ray crystal structures of the inhibitor–enzyme complexes show that heme is displaced from the enzyme and blocked from rebinding by these compounds. The results reveal that apo-IDO1 serves as a unique target for inhibition and that heme lability plays an important role in posttranslational regulation.

Original languageEnglish (US)
Pages (from-to)3249-3254
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number13
DOIs
StatePublished - Mar 27 2018

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Cancer
  • Heme
  • IDO1
  • Kynurenine

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    Nelp, M. T., Kates, P. A., Hunt, J. T., Newitt, J. A., Balog, A., Maley, D., Zhu, X., Abell, L., Allentoff, A., Borzilleri, R., Lewis, H. A., Lin, Z., Seitz, S. P., Yan, C., & Groves, J. T. (2018). Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form. Proceedings of the National Academy of Sciences of the United States of America, 115(13), 3249-3254. https://doi.org/10.1073/pnas.1719190115