Immune-modulating enzyme indoleamine 2,3-dioxygenase is effectively inhibited by targeting its apo-form.
Proc Natl Acad Sci U S A
; 115(13): 3249-3254, 2018 03 27.
Article
in En
| MEDLINE
| ID: mdl-29531094
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Enzyme Inhibitors
/
Indoleamine-Pyrrole 2,3,-Dioxygenase
Limits:
Humans
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2018
Document type:
Article