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

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

doi:10.1073/pnas.1719190115

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

Journal Article · Mon Mar 12 00:00:00 EDT 2018 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1719190115· OSTI ID:1545837

Nelp, Micah T. ^[1]; Kates, Patrick A. ^[1]; Hunt, John T. ^[2]; Newitt, John A. ^[2]; Balog, Aaron ^[2]; Maley, Derrick ^[2]; Zhu, Xiao ^[2]; Abell, Lynn ^[2]; Allentoff, Alban ^[2]; Borzilleri, Robert ^[2]; Lewis, Hal A. ^[2]; Lin, Zeyu ^[2]; Seitz, Steven P. ^[2]; Yan, Chunhong ^[2];

^[1]

Princeton Univ., NJ (United States)
Bristol-Myers Squibb Co., Princeton, NJ (United States)

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 toN-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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Institutes of Health (NIH)

Grant/Contract Number:: GM036298

OSTI ID:: 1545837

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, Issue 13; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 114 works

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59 BASIC BIOLOGICAL SCIENCES
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kynurenine

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

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