Enzymic formation of d-kynurenine from d-tryptophan

Higuchi, Kiyoshi; Hayaishi, Osamu

doi:10.1016/0003-9861(67)90256-1

Cited by 115 publications

(67 citation statements)

References 15 publications

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“…The second enzyme is the indoleamine 2,3-dioxygenase (IDO), which represents the first and rate-limiting enzyme of the kynurenine pathway in extrahepatic tissues. This enzyme was first described by Higuchi et al [1]. IDO is a hemecontaining enzyme that catalyzes the oxidative cleavage of the Trp pyrrol ring, thereby producing N-formyl-kynurenine, which is then further degraded along the kynurenine pathway (Fig.…”

Section: Introductionmentioning

confidence: 99%

IDO expression in the brain: a double-edged sword

2007

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The tryptophan-catabolizing enzyme indoleamine-2,3-dioxygenase (IDO) initiates the first and ratelimiting step of the kynurenine pathway. It is induced by proinflammatory cytokines such as interferon-β and interferon-γ and has established effects in the control of intracellular parasites. The recent detection of its decisive function in immune tolerance at the maternal-fetal interface stimulated various studies unraveling its regulatory effect on T cells in many pathologies. In the brain, IDO can be induced in microglia by interferon-γ-producing T helper (Th) 1 cells, thereby initiating a negative feedback loop which downmodulates neuroinflammation in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). This protective effect could to be counteracted by the production of neurotoxic metabolites of the kynurenine pathway such as quinolinic acid, which are produced upon IDO induction. Some metabolites of the kynurenine pathway can pass the blood-brain barrier and thus could act as neurotoxins, e.g., during systemic infection. In this paper, we give a brief overview on established immune regulatory functions of IDO, review recent data on IDO expression in the brain, and propose that autoimmune neuroinflammation and the increasingly appreciated neuronal damage in MS are linked by Th1-mediated IDO induction through subsequent synthesis of toxic metabolites of tryptophan.

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Section: Introductionmentioning

confidence: 99%

IDO expression in the brain: a double-edged sword

2007

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“…This monomeric intracellular enzyme degrades the essential amino acid tryptophan. It leads directly to an opening of the indole ring of tryptophan, thus forming N-formylkynurenine, which rapidly degrades to L-kynurenine [6]. The strongest known inducer is IFN-c, shown in cultured fibroblasts [7], macrophages [8], dendritic cells [9] and many cancer cell lines [10].…”

Section: Introductionmentioning

confidence: 99%

Function of indoleamine 2,3‐dioxygenase in corneal allograft rejection and prolongation of allograft survival by over‐expression

et al. 2006

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Indoleamine 2,3-dioxygenase (IDO) suppresses T cell responses by its action in catabolising tryptophan. It is important in maintenance of immune privilege in the placenta. We investigated the activity of IDO in the cornea, following corneal transplantation and the effect of IDO over-expression in donor corneal endothelium on the survival of corneal allografts. IDO expression was analysed and functional activity was quantified in normal murine cornea and in corneas following transplantation as allografts. Low levels of IDO, at both mRNA and protein levels, was detected in the normal cornea, up-regulated by IFN-c and TNF. Expression of IDO in cornea was significantly increased following corneal transplantation. However, inhibition of IDO activity in vivo had no effect on graft survival. Following IDO cDNA transfer, murine corneal endothelial cells expressed functional IDO, which was effective at inhibiting allogeneic T cell proliferation. Over-expression of IDO in donor corneal allografts resulted in prolonged graft survival. While, on one hand, our data indicate that IDO may augment corneal immune privilege, up-regulated IDO activity following cytokine stimulation may serve to inhibit inflammatory cellular responses. While increasing IDO mRNA expression was found in allogeneic corneas at rejection, over-expression in donor cornea was found to significantly extend survival of allografts.

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“…Identification of the non-hepatic tryptophan catabolizing enzyme, indoleamine 2,3-deoxygenase (IDO; EC 1.13.11.42; originally D-tryptophan pyrrolase) was first reported in 1963 (Higuchi and Hayaishi, 1967;Higuchi et al, 1963). IDO, also known as IDO1, catalyzes the first and rate-limiting step that converts tryptophan to N-formyl-kynurenine, a process that utilizes oxidative cleavage of the 2,3 double bond in the indole ring resulting in the biosynthesis of nicotinamide adenine dinucleotide (NAD) (Takikawa, 2005).…”

Section: Diversity Of Ido-related Immunoregulatory Enzymesmentioning

confidence: 99%

Inflammatory programming and immune modulation in cancer by IDO

Smith¹,

Prendergast²

2013

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Immune dysregulation is one of the hallmarks of tumor growth and progression, a key event that allows for tumor evasion of the host immune system. More recent cancer modalities are embracing combinations incorporating immunotherapy with more traditional chemotherapy and radiotherapy. Traditional approaches are difficult to tolerate for the patient and become less effective as tumors evolve to survive these treatments. Immunotherapy has the benefit of reduced toxicity as it utilizes the patient's own immune system to identify and eliminate tumor cells. One mechanism manipulated by tumors is upregulation of the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO). In this review, we focus on the mechanism by which tumors use IDO to evade detection by T cell immunity, as well as on novel small molecules that inhibit it as a cancer therapeutic strategy. Diversity of IDO-related immunoregulatory enzymes

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Enzymic formation of d-kynurenine from d-tryptophan

Cited by 115 publications

References 15 publications

IDO expression in the brain: a double-edged sword

IDO expression in the brain: a double-edged sword

Function of indoleamine 2,3‐dioxygenase in corneal allograft rejection and prolongation of allograft survival by over‐expression

Inflammatory programming and immune modulation in cancer by IDO

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