Hydrogen peroxide-mediated neuronal cell death induced by an endogenous neurotoxin, 3-hydroxykynurenine.

Okuda, Suguru; Nishiyama, Nobuyoshi; Saito, Hiroshi; Katsuki, Hiroshi

doi:10.1073/pnas.93.22.12553

Cited by 265 publications

(235 citation statements)

References 31 publications

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“…The second neurotoxic Trp metabolite is 3-HAA, which is unstable under physiological conditions. Upon spontaneous auto-oxidation, 3-HAA produces reactive radical species, which in turn induce oxidative stress and apoptosis in neurons [57][58][59].…”

Section: Possible Mechanisms Of Ido-mediated Tolerance Inductionmentioning

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: Possible Mechanisms Of Ido-mediated Tolerance Inductionmentioning

confidence: 99%

IDO expression in the brain: a double-edged sword

2007

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“…Once formed through the enzymatic hydroxylation at the C3 position of its immediate precursor, L-kynurenine (L-KYN) (3-5), 3-HK can undergo spontaneous oxidation, which in turn can result in free radical generation and apoptotic cell death (6)(7)(8). The abnormal levels of 3-HK that have been recorded in the brains of patients with AIDS-dementia complex (9) and Huntington's disease (10) support a role for this molecule in the etiology and progression of fatal neurodegenerative diseases in humans (11,12).…”

mentioning

confidence: 99%

Crystal structure of the Anopheles gambiae 3-hydroxykynurenine transaminase

Rossi

Garavaglia²,

Giovenzana³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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In Anopheles gambiae, the vector for the most deadly malaria parasite Plasmodium falciparum, xanthurenic acid (XA) plays a key role in parasite gametogenesis and fertility. In mosquitoes, XA is produced by transamination of 3-hydroxykynurenine (3-HK), a reaction that represents the main route to prevent the accumulation of the potentially toxic 3-HK excess. Interfering with XA metabolism in A. gambiae therefore appears an attractive avenue for the development of malaria transmission-blocking drugs and insecticides. We have determined the crystal structure of A. gambiae 3-HK transaminase in its pyridoxal 5 -phosphate form and in complex with a newly synthesized competitive enzyme inhibitor. Structural inspection of the enzyme active site reveals the key molecular determinants for ligand recognition and catalysis. Major contributions toward inhibitor binding are provided by a salt bridge between the inhibitor carboxylate and Arg-356 and by a remarkable hydrogen bond network involving the anthranilic moiety of the inhibitor and backbone atoms of residues Gly-25 and Asn-44. This study may be useful for the structurebased design of specific enzyme inhibitors of potential interest as antimalarial agents.kynurenine pathway ͉ xanthurenic acid

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“…Kynurenine can be oxidized by kynurenine monooxygenase (KMO, EC 1.14.13.9) to form 3-HK. Although 3-HK is a natural metabolite, it is oxidized easily under physiological conditions, stimulating the production of reactive oxygen species (Okuda et al, 1996(Okuda et al, ,1998Wei et al, 2000). For example, 3-HK can induce apoptosis of neuron cells at micromolar concentrations (Wei et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…In mammals, both kynurenine and 3-HK can be hydrolyzed by kynureninase (EC 3.7.1.3) to anthranilic acid and 3-hydroxyanthranilic acid and the latter two compounds can be either completely oxidized to CO 2 and H 2 O through a complicated biochemical pathway or used to synthesize NAD(P) + (Stone, 1993). Although there have been a number of reports discussing the toxicity of 3-HK in mammals (Okuda et al, 1996(Okuda et al, ,1998Wei et al, 2000), 3-HK, produced under normal physiological conditions, does not seem to cause any problems in mammals as it can be hydrolyzed and further oxidized via the glutaryl-CoA pathway.…”

Section: Introductionmentioning

confidence: 99%

The tryptophan oxidation pathway in mosquitoes with emphasis on xanthurenic acid biosynthesis

Han¹,

Beerntsen²,

Li³

2007

Journal of Insect Physiology

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Oxidation of tryptophan to kynurenine and 3-hydroxykynurenine (3-HK) is the major catabolic pathway in mosquitoes. However, 3-HK is oxidized easily under physiological conditions, resulting in the production of reactive radical species. To overcome this problem, mosquitoes have developed an efficient mechanism to prevent 3-HK from accumulating by converting this chemically reactive compound to the chemically stable xanthurenic acid. Interestingly, 3-HK is a precursor for the production of compound eye pigments during the pupal and early adult stages; consequently, mosquitoes need to preserve and transport 3-HK for compound eye pigmentation in pupae and adults. This review summarizes the tryptophan oxidation pathway, compares and contrasts the mosquito tryptophan oxidation pathway with other model species, and discusses possible driving forces leading to the functional adaptation and evolution of enzymes involved in the mosquito tryptophan oxidation pathway.

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Hydrogen peroxide-mediated neuronal cell death induced by an endogenous neurotoxin, 3-hydroxykynurenine.

Abstract: (4,5).

Cited by 265 publications

References 31 publications

IDO expression in the brain: a double-edged sword

IDO expression in the brain: a double-edged sword

Crystal structure of the Anopheles gambiae 3-hydroxykynurenine transaminase

The tryptophan oxidation pathway in mosquitoes with emphasis on xanthurenic acid biosynthesis

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