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Interaction of Carthamus tinctorius lignan arctigenin with the binding site of tryptophan-degrading enzyme indoleamine 2,3-dioxygenase.

ABSTRACT: Mediterranean Carthamus tinctorius (Safflower) is used for treatment of inflammatory conditions and neuropsychiatric disorders. Recently C. tinctorius lignans arctigenin and trachelogenin but not matairesinol were described to interfere with the activity of tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) in peripheral blood mononuclear cells in vitro. We examined a potential direct influence of compounds on IDO enzyme activity applying computational calculations based on 3D geometry of the compounds. The interaction pattern analysis and force field-based minimization was performed within LigandScout 3.03, the docking simulation with MOE 2011.10 using the X-ray crystal structure of IDO. Results confirm the possibility of an intense interaction of arctigenin and trachelogenin with the binding site of the enzyme, while matairesinol had no such effect.

SUBMITTER: Temml V

PROVIDER: S-EPMC3829989 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Interaction of Carthamus tinctorius lignan arctigenin with the binding site of tryptophan-degrading enzyme indoleamine 2,3-dioxygenase.

Temml Veronika V Kuehnl Susanne S Schuster Daniela D Schwaiger Stefan S Stuppner Hermann H Fuchs Dietmar D

FEBS open bio 20130907

Mediterranean Carthamus tinctorius (Safflower) is used for treatment of inflammatory conditions and neuropsychiatric disorders. Recently C. tinctorius lignans arctigenin and trachelogenin but not matairesinol were described to interfere with the activity of tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) in peripheral blood mononuclear cells in vitro. We examined a potential direct influence of compounds on IDO enzyme activity applying computational calculations based on 3D geometr ...[more]

PMID: 24251110

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Project description:Kynurenine (Kyn), a metabolite of tryptophan (Trp), is a key regulator of mammal immune responses such as cancer immune tolerance. Indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are main enzymes regulating the first and rate-limiting step of the Kyn pathway. To identify new small molecule inhibitors of TDO, we selected A172 glioblastoma cell line constitutively expressed TDO. Characterization of this cell line using kinase inhibitor library resulted in identification of MEK/ERK pathway-dependent TDO expression. After knowing the properties for TDO expression, we further proceeded to screen chemical library for TDO inhibitors. We previously determined that S-benzylisothiourea derivatives are enzymatic inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) and suggested that the isothiourea moiety could be an important pharmacophore for binding to heme. Based on this premise, we screened an in-house library composed of various isothiourea derivatives and identified a bisisothiourea derivative, PVZB3001, as an inhibitor of TDO. Interestingly, PVZB3001 also inhibited the enzymatic activity of IDO1 in both cell-based and cell-free assays but did not inhibit other heme enzymes. Molecular docking studies suggested the importance of isothiourea moieties at the ortho position of the phenyl ring for the inhibition of catalytic activity. PVZB3001 showed competitive inhibition against TDO, and this was supported by the docking simulation. PVZB3001 recovered natural killer (NK) cell viability and functions by inhibiting Kyn accumulation in conditioned medium of both IDO1- and TDO-expressing cells. Furthermore, oral administration of IDO1-overexpressing tumor-bearing mice with PVZB3001 significantly inhibited tumor growth. Thus, we identified a novel selective dual inhibitor of IDO1 and TDO using the Kyn production assay with a glioblastoma cell line. This inhibitor could be a useful pharmacological tool for modulating the Kyn pathway in a variety of experimental systems.

Project description:ObjectivesExtrahepatic tryptophan (Trp)-kynurenine (Kyn) metabolism via indoleamine 2,3-dioxygenase 1 (IDO1) induction was found to be associated with intrinsic immune regulation. However, the Trp-Kyn metabolism-associated immune regulation in dermatomyositis (DM) remains unknown. Therefore, we aimed to investigate the clinical relevance of the Trp-Kyn metabolism via IDO1 induction in DM.MethodsLiquid chromatography-mass spectrometry (HPLC-MS) was used to examine the serum Kyn and Trp concentrations in DM. In addition, we used X-tile software to determine the optimal cutoff value of the Kyn/Trp ratio, a surrogate marker for Trp-Kyn metabolism. Spearman analysis was performed to evaluate the association of Trp-Kyn metabolism with muscle enzymes and inflammatory markers.ResultsDM patients had significantly higher serum Kyn/Trp ratio (× 10-3) when compared with the healthy controls. The serum Kyn/Trp ratio was positively correlated with the levels of muscle enzymes and inflammatory markers. In addition, the serum Kyn/Trp ratio significantly decreased (36.89 (26.00-54.00) vs. 25.00 (18.00-37.00), P = 0.0006) after treatment. DM patients with high serum Kyn/Trp ratio had a significantly higher percentage of muscle weakness symptoms (62.5% vs. 20.0%, P = 0.019) and higher levels of LDH (316.0 (236.0-467.0) vs. 198.0 (144.0-256.0), P = 0.004) and AST (56.5 (35.0-92.2) vs. 23.0 (20.0-36.0), P = 0.002)) than those with low serum Kyn/Trp ratio. Multiple Cox regression analyses identified ln(Kyn/Trp) (HR 4.874, 95% CI 1.105-21.499, P = 0.036) as an independent prognostic predictor of mortality in DM.ConclusionsDM patients with enhanced Trp-Kyn metabolism at disease onset are characterized by more severe disease status and poor prognosis. Intrinsic immune regulation function via enhanced Trp-Kyn metabolism by IDO1 induction may be a potential therapeutic target in DM. Key Points • HPLC-MS identified increased serum Kyn/Trp ratio in DM patients, which positively correlated with levels of muscle enzymes and inflammatory markers and was downregulated upon treatment. • Cox regression analyses identified ln(Kyn/Trp) as an independent prognostic predictor of mortality in DM. • Monitoring intrinsic immune regulation function should be considered a potential therapeutic target in DM patients.

Dataset Information

Interaction of Carthamus tinctorius lignan arctigenin with the binding site of tryptophan-degrading enzyme indoleamine 2,3-dioxygenase.

Publications

Interaction of Carthamus tinctorius lignan arctigenin with the binding site of tryptophan-degrading enzyme indoleamine 2,3-dioxygenase.

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