1-methyl-dl-tryptophan, β-(3-benzofuranyl)-dl-alanine (the oxygen analog of tryptophan), and β-[3-benzo(b)thienyl]-dl-alanine (the sulfur analog of tryptophan) are competitive inhibitors for indoleamine 2,3-dioxygenase

Cady, Susan G.; Sono, Masanori

doi:10.1016/0003-9861(91)90142-6

Cited by 274 publications

(238 citation statements)

References 24 publications

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“…This finding is in accord with previous published data that demonstrate independence between sickness behavior and depressive-like behavior in response to LPS. 10 Since its first characterization as a competitive inhibitor of IDO, 37 1-MT has become the compound of reference for IDO-blocking studies. 21,22,[38][39][40] Its ability to block IDO activation in response to LPS is demonstrated in the present study by the decreased kynurenine/ tryptophan ratio that is observed in both the periphery and the brain of 1-MT-treated mice.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

O’Connor

Lawson²,

André³

et al. 2008

Mol Psychiatry

1,123

992

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Although elevated activity of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) has been proposed to mediate comorbid depression in inflammatory disorders, its causative role has never been tested. We report that peripheral administration of lipopolysaccharide (LPS) activates IDO and culminates in a distinct depressive-like behavioral syndrome, measured by increased duration of immobility in both the forced-swim and tail suspension tests. Blockade of IDO activation either indirectly with the anti-inflammatory tetracycline derivative minocycline, that attenuates LPS-induced expression of proinflammatory cytokines, or directly with the IDO antagonist 1-methyltryptophan (1-MT), prevents development of depressive-like behavior. Both minocycline and 1-MT normalize the kynurenine/tryptophan ratio in the plasma and brain of LPS-treated mice without changing the LPS-induced increase in turnover of brain serotonin. Administration of L-kynurenine, a metabolite of tryptophan that is generated by IDO, to naive mice dose dependently induces depressive-like behavior. These results implicate IDO as a critical molecular mediator of inflammation-induced depressive-like behavior, probably through the catabolism of tryptophan along the kynurenine pathway.

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Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

O’Connor

Lawson²,

André³

et al. 2008

Mol Psychiatry

1,123

992

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show abstract

“…Characterization was conducted with the natural substrates of the enzyme, i.e. D-and L-tryptophan [12], and also using the inhibitor 1-methyl-D,L-tryptophan [29]. We checked that the colorimetric assay gave similar results to the HPLC analyses.…”

Section: Biochemical Characterization Of Purified Human Indodomentioning

confidence: 99%

Molecular evidence that melatonin is enzymatically oxidized in a different manner than tryptophan: investigations with both indoleamine 2,3-dioxygenase and myeloperoxidase

Ferry

Ubeaud

Lambert³

et al. 2005

Biochemical Journal

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The catabolism of melatonin, whether naturally occurring or ingested, takes place via two pathways: ∼ 70 % can be accounted for by conjugation (sulpho-and glucurono-conjugation), and ∼ 30 % by oxidation. It is commonly thought that the interferoninduced enzyme indoleamine 2,3-dioxygenase (EC 1.13.11.42), which oxidizes tryptophan, is also responsible for the oxidation of 5-hydroxytryptamine (serotonin) and its derivative, melatonin. Using the recombinant enzyme expressed in Escherichia coli, we show in the present work that indoleamine 2,3-dioxygenase indeed cleaves tryptophan; however, under the same conditions, it is incapable of cleaving the two other indoleamines. By contrast, myeloperoxidase (EC 1.11.1.7) is capable of cleaving the indole moiety of melatonin. However, when using the peroxidase conditions of assay -with H 2 O 2 as co-substrate -indoleamine 2,3-dioxygenase is able to cleave melatonin into its main metabolite, a kynurenine derivative. The present work establishes that the oxidative metabolism of melatonin is due, in the presence of H 2 O 2 , to the activities of both myeloperoxidase and indoleamine 2,3-dioxygenase (with lower potency), since both enzymes have K m values for melatonin in the micromolar range. Under these conditions, several indolic compounds can be cleaved by both enzymes, such as tryptamine and 5-hydroxytryptamine. Furthermore, melatonin metabolism results in a kynurenine derivative, the pharmacological action of which remains to be studied, and could amplify the mechanisms of action of melatonin.

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“…Indeed, results from in vitro and in vivo studies have suggested an improvement of the efficacy of therapeutic vaccination or chemotherapy by concomitant administration of an IDO inhibitor thus highlighting IDO as an attractive target. 12,13,[15][16][17] Until recently, the best known IDO inhibitors 18 displayed affinities in the micromolar range and comprised mainly Trp derivatives such as 1-methyltryptophan (1MT) 19 (K i = 37 lM) or b-carbolines (K i $0.12 mM). 20 Other indole-based IDO inhibitors, such as brassinin 21,22 and methylthiohydantoin-tryptophan (MTH-Trp) 13 have been described.…”

Section: Introductionmentioning

confidence: 99%

“…4,19 Despite the uncompetitive inhibition kinetics, the authors showed through spectroscopic studies that PIM binds into the active site of IDO. Moreover, they discovered a preferred binding of PIM to the inactive ferric (Fe 3+ ) form of the enzyme, which may explain this apparent discrepancy.…”

Section: Introductionmentioning

confidence: 99%

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Indol-2-yl ethanones as novel indoleamine 2,3-dioxygenase (IDO) inhibitors

Dolušić

Larrieu

Blanc

et al. 2011

Bioorganic & Medicinal Chemistry

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a b s t r a c tIndoleamine 2,3-dioxygenase (IDO) is a heme dioxygenase which has been shown to be involved in the pathological immune escape of diseases such as cancer. The synthesis and structure-activity relationships (SAR) of a novel series of IDO inhibitors based on the indol-2-yl ethanone scaffold is described. In vitro and in vivo biological activities have been evaluated, leading to compounds with IC 50 values in the micromolar range in both tests. Introduction of small substituents in the 5-and 6-positions of the indole ring, indole N-methylation and variations of the aromatic side chain are all well tolerated. An iron coordinating group on the linker is a prerequisite for biological activity, thus corroborating the virtual screening results.

show abstract

1-methyl-dl-tryptophan, β-(3-benzofuranyl)-dl-alanine (the oxygen analog of tryptophan), and β-[3-benzo(b)thienyl]-dl-alanine (the sulfur analog of tryptophan) are competitive inhibitors for indoleamine 2,3-dioxygenase

Cited by 274 publications

References 24 publications

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

Molecular evidence that melatonin is enzymatically oxidized in a different manner than tryptophan: investigations with both indoleamine 2,3-dioxygenase and myeloperoxidase

Indol-2-yl ethanones as novel indoleamine 2,3-dioxygenase (IDO) inhibitors

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