X-ray structure and reaction mechanism of human indoleamine 2,3-dioxygenase

Sugimoto, Hiroshi; Oda, Shun-ichiro; Otsuki, Tetsuo; Yotsuya, Keiko; Hino, Tsuneo; Yoshida, Tadashi; Shiro, Yoshitsugu

doi:10.1016/j.ics.2007.07.049

Cited by 5 publications

(9 citation statements)

References 23 publications

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“…Structural Data for Azole Compounds. Structural data was available for three of the compounds, 4-phenylimidazole (compound 1a, PDB ID 2d0t), 19 4-(5-Cl-phenyl)-imidazole (compound 1b, PDB ID 6e42), 38 and MMG-0358 (compound 4e, PDB ID 6r63). 15 All the three compounds bind similarly to the heme iron of IDO1 through an azole ring nitrogen (Figure 4A−C).…”

Section: Resultsmentioning

confidence: 99%

“…Data were processed with the XDS Program Package. 97 Structures were solved by molecular replacement using Phaser-MR and chain A of PDB entry 2d0t 19 as the model. Manual model building and structure refinement were carried out in Phenix Suite 98 using coot 99 software and phenix-refine, respectively.…”

Section: -Phenylisoxazole (21)mentioning

confidence: 99%

“…MM-GBSA Calculations. Starting from the crystal structure 2d0t of the complex between hIDO1 and compound 1a, 19 we removed chain B, the N-cyclohexyltaurine molecules, and the resolved water molecules. For all other compounds, ligand 1a was replaced by the docked conformation of the respective ligand.…”

Section: -Phenylisoxazole (21)mentioning

confidence: 99%

“…Imidazoles are classical heme binders, and 4-phenylimidazole is a known IDO1 ligand 18 and the first cocrystallized IDO1 inhibitor. 19 Structure-based optimization of this chemotype yielded the 2-hydroxy-substituted phenyl derivative (IC 50 4.8 μM) as the most active compound. 20 Subsequent development also used pocket B (Figure 1) and led to the discovery of navoximod (Figure 1), first disclosed in the patent literature and more recently in the scientific literature.…”

Section: Introductionmentioning

confidence: 99%

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Azole-Based Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors

et al. 2021

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The heme enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays an essential role in immunity, neuronal function, and aging through catalysis of the rate-limiting step in the kynurenine pathway of tryptophan metabolism. Many IDO1 inhibitors with different chemotypes have been developed, mainly targeted for use in anti-cancer immunotherapy. Lead optimization of direct heme iron-binding inhibitors has proven difficult due to the remarkable selectivity and sensitivity of the heme−ligand interactions. Here, we present experimental data for a set of closely related small azole compounds with more than 4 orders of magnitude differences in their inhibitory activities, ranging from millimolar to nanomolar levels. We investigate and rationalize their activities based on structural data, molecular dynamics simulations, and density functional theory calculations. Our results not only expand the presently known four confirmed chemotypes of sub-micromolar heme binding IDO1 inhibitors by two additional scaffolds but also provide a model to predict the activities of novel scaffolds.

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Section: Resultsmentioning

confidence: 99%

Section: -Phenylisoxazole (21)mentioning

confidence: 99%

Section: -Phenylisoxazole (21)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Azole-Based Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors

et al. 2021

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“…Although IDO1 and TDO are heme dioxygenases catalyzing exactly the same reaction, their sequences are fundamentally different and do not exhibit common origins. The crystal structure of human IDO1 was first reported in holo form with IDO1 inhibitors (Sugimoto et al, 2006) and then with tryptophan (Luo et al, 2018). In contrast to TDO, IDO1 exhibits a monomeric conformation (45 kDa), which contains a unique catalytic site including a heme cofactor (Figure 7).…”

Section: Ido1 Structure and Physicochemical Propertiesmentioning

confidence: 99%

Systemic tryptophan homeostasis

Klaessens

Stroobant

Plaen

et al. 2022

Front. Mol. Biosci.

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Tryptophan is an essential amino acid, which is not only a building block for protein synthesis, but also a precursor for the biosynthesis of co-enzymes and neuromodulators, such as NAD/NADP(H), kynurenic acid, melatonin and serotonin. It also plays a role in immune homeostasis, as local tryptophan catabolism impairs T-lymphocyte mediated immunity. Therefore, tryptophan plasmatic concentration needs to be stable, in spite of large variations in dietary supply. Here, we review the main checkpoints accounting for tryptophan homeostasis, including absorption, transport, metabolism and elimination, and we discuss the physiopathology of disorders associated with their dysfunction. Tryptophan is catabolized along the kynurenine pathway through the action of two enzymes that mediate the first and rate-limiting step of the pathway: indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO). While IDO1 expression is restricted to peripheral sites of immune modulation, TDO is massively expressed in the liver and accounts for 90% of tryptophan catabolism. Recent data indicated that the stability of the TDO protein is regulated by tryptophan and that this regulation allows a tight control of tryptophanemia. TDO is stabilized when tryptophan is abundant in the plasma, resulting in rapid degradation of dietary tryptophan. In contrast, when tryptophan is scarce, TDO is degraded by the proteasome to avoid excessive tryptophan catabolism. This is triggered by the unmasking of a degron in a non-catalytic tryptophan-binding site, resulting in TDO ubiquitination by E3 ligase SKP1-CUL1-F-box. Deficiency in TDO or in the hepatic aromatic transporter SLC16A10 leads to severe hypertryptophanemia, which can disturb immune and neurological homeostasis.

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X-ray Emission Spectroscopy of Single Protein Crystals Yields Insights into Heme Enzyme Intermediates

Emamian

Ireland

Purohit

et al. 2022

Preprint

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Enzyme reactivity is often enhanced by changes in oxidation state, spin state, and metal-ligand covalency of associated metallocofactors. The development of spectroscopic methods for studying these processes coincidentally with structural rearrangements is essential for elucidating metalloenzyme mechanisms. Herein, we demonstrate the feasibility of collecting X-ray emission spectra of metalloenzyme crystals at a 3rd generation synchrotron source. In particular, we report the development of a von Hamos spectrometer for the collection of Fe Kβ emission optimized for analysis of dilute biological samples. We further showcase its application in crystals of the immunosuppressive heme-dependent enzyme indoleamine 2,3-dioxygenase. Spectra from protein crystals in different states were compared with relevant reference compounds. Complementary density functional calculations assessing covalency support our spectroscopic analysis and identify active site conformations that correlate to high- and low-spin states. These experiments validate the suitability of an X-ray emission approach for determining spin states of previously uncharacterized metalloenzyme reaction intermediates.

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X-ray structure and reaction mechanism of human indoleamine 2,3-dioxygenase

Cited by 5 publications

References 23 publications

Azole-Based Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors

Azole-Based Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors

Systemic tryptophan homeostasis

X-ray Emission Spectroscopy of Single Protein Crystals Yields Insights into Heme Enzyme Intermediates

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