1. Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form.
- Author
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Nelp, Micah T., Kates, Patrick A., Hunt, John T., Newitt, John A., Balog, Aaron, Maley, Derrick, Xiao Zhu, Abell, Lynn, Allentoff, Alban, Borzilleri, Robert, Lewis, Hal A., Zeyu Lin, Seitz, Steven P., Chunhong Yan, and Groves, John T.
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IMMUNOREGULATION , *INDOLEAMINE 2,3-dioxygenase , *IMMUNOSUPPRESSION , *KYNURENINE , *T cells , *PHYSIOLOGY - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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