Article

Sugimoto, H. et al. Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase. Proc. Natl Acad. Sci. USA 103, 2611-2616

Yamagata University, Ямагата, Yamagata, Japan
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2006; 103(8):2611-6. DOI: 10.1073/pnas.0508996103
Source: PubMed

ABSTRACT

Human indoleamine 2,3-dioxygenase (IDO) catalyzes the cleavage of the pyrrol ring of L-Trp and incorporates both atoms of a molecule of oxygen (O2). Here we report on the x-ray crystal structure of human IDO, complexed with the ligand inhibitor 4-phenylimidazole and cyanide. The overall structure of IDO shows two alpha-helical domains with the heme between them. A264 of the flexible loop in the heme distal side is in close proximity to the iron. A mutant analysis shows that none of the polar amino acid residues in the distal heme pocket are essential for activity, suggesting that, unlike the heme-containing monooxygenases (i.e., peroxidase and cytochrome P450), no protein group of IDO is essential in dioxygen activation or proton abstraction. These characteristics of the IDO structure provide support for a reaction mechanism involving the abstraction of a proton from the substrate by iron-bound dioxygen. Inactive mutants (F226A, F227A, and R231A) retain substrate-binding affinity, and an electron density map reveals that 2-(N-cyclohexylamino)ethane sulfonic acid is bound to these residues, mimicking the substrate. These findings suggest that strict shape complementarities between the indole ring of the substrate and the protein side chains are required, not for binding, but, rather, to permit the interaction between the substrate and iron-bound dioxygen in the first step of the reaction. This study provides the structural basis for a heme-containing dioxygenase mechanism, a missing piece in our understanding of heme chemistry.

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    • "Células presentes neste microambiente com alta expressão de IDO, podem ser induzidas a um estado apoptótico pela carência de triptofano e pela ação de catabólitos tóxicos como a quinurenina , levando, principalmente as células T ativadas a apoptose , favorecendo a formação de um ambiente tolerogênico (Munn et al. 1998, Mellor et al. 2003, Saito et al. 2007). Sabe-se que a atividade bioquímica e funcional da IDO é estimulada, principalmente, pelo interferon-γ (INF-γ), pois o mesmo induz a transcrição da proteína (Strehlow et al. 1993, Kudo et al. 2004, Muller et al. 2005, Sugimoto et al. 2006). Contudo, pouco se conhece sobre a relação entre o estrógeno , um dos principais hormônios presentes durante o processo gestacional, e a IDO. "

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    • "Indoleamine 2,3-dioxygenase (IDO) has emerged as a pivotal modulator/regulator of the immune response [13], [28], [34]. IDO is a heme-containing cytosolic enzyme that is the rate limiting catalyst to the metabolism of the essential amino acid tryptophan within the kynurenine pathway [15], [16]. These genes contain interferon (IFN) response elements and therefore, IFNs are powerful inducers of IDO expression [23]. "
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    • "For synthesis of peptides we selected epitopes that are surface‐ oriented and hydrophilic [Sugimoto et al., 2006]. We determined three regions on the IDO1 protein sequence that had good hydrophilicity as predicted by the Lasergene software (DNAStar, WI). "
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