Neurotoxic and neurobehavioral effects of kynurenines in adult insects

Cerstiaens, Anja; Huybrechts, Jurgen; Kotanen, Stephen; Lebeau, Ilya; Meylaers, Karen; Loof, Arnold De; Schoofs, Liliane

doi:10.1016/j.bbrc.2003.11.051

Cited by 43 publications

(33 citation statements)

References 28 publications

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“…As summarized in Table 3, all of the four analyzed kynurenines inhibited the Ag-HisTDO catalyzed conversion of L-Trp to NFK. In particular KA and XA, the final KP metabolites in mosquitoes, together with 3-HK, a highly cytotoxic KP intermediate (Chiou et al, 1998;Cerstiaens et al, 2003), displayed the most powerful activity, determining more than 50% enzyme inhibition at 100 mM concentration.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, cumulating data from in vivo and in vitro models underline the centrality of the KP metabolites in the physiology of the vast majority of animal species. In insects, kynurenines are implicated in a variety of biological functions, ranging from eye development and tissue remodelling during metamorphosis, to modulation of complex behaviours (Li et al, 1999;Chiou et al, 1998;Cerstiaens et al, 2003;Savvateeva et al, 2000;Smirnov et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Purification and biochemical characterization of a recombinant Anopheles gambiae tryptophan 2,3-dioxygenase expressed in Escherichia coli

Paglino

Lombardo

Arcà

et al. 2008

Insect Biochemistry and Molecular Biology

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Purification and biochemical characterization of a recombinant Anopheles gambiae tryptophan 2,3-dioxygenase expressed in Escherichia coli

Paglino

Lombardo

Arcà

et al. 2008

Insect Biochemistry and Molecular Biology

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“…Further, renal IDO expression may be deleterious during inflammation, because it enhances tubular cell injury 15. Kynurenines and IDO also are implicated in the pathophysiology of neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, and kynurenines have been shown to be neurotoxic 10, 16–19. Tryptophan degradation increases in rheumatoid arthritis20 and development of collagen-induced arthritis in mice is associated with increased IDO activity and enhanced tryptophan catabolism 21.…”

Section: Introductionmentioning

confidence: 99%

Indoleamine 2,3-dioxygenase overexpression causes kynurenine-modification of proteins, fiber cell apoptosis and cataract formation in the mouse lens

Mailankot

Staniszewska

Butler

et al. 2009

Laboratory Investigation

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Indoleamine 2,3-dioxygenase (IDO) is the first enzyme in the kynurenine pathway. The kynurenines formed in this pathway chemically modify proteins and cause apoptosis in cells. Evidence suggests that kynurenines and their protein modifications are involved in cataract formation, but this has yet to be directly demonstrated. We generated transgenic mouse lines (Tg) that overexpress human IDO in the lens. Homozygous Tg (homTg) lenses had higher IDO immunoreactivity, ~4.5 times greater IDO mRNA, and ~8 times higher IDO activity compared to lenses from hemizygous Tg animals (hemTg). The kynurenine content was 3-fold higher in homTg than hemTg but was not detected in Wt lenses. Kynurenine-modifications were ~2.6 times greater in homTg than hemTg or Wt. HomTg lenses had vacuoles in the epithelium and cortical fiber cells. Kynurenine-modifications coincided with apoptosis in the secondary fiber cells of homTg lenses. Caspase-3 and -9 activities were markedly higher in homTg than in hemTg and Wt. The GSH content was ~36% lower in homTg compared to hemTg and Wt lenses. HomTg animals also developed bilateral cataracts within 3 months of birth. Together these data demonstrate that IDO-mediated production of kynurenines results in defects in fiber cell differentiation and their apoptosis and suggest that IDO activity is kept low in the lens to prevent deleterious effects by kynurenines.

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“…Indeed, several invertebrate species, which depend on the kynurenine pathway for dietary tryptophan oxidation, are highly sensitive to perturbations in the physiological balance of its intermediate metabolites (13,14). In particular, the exogenous administration of 3-HK in adult insects profoundly affects locomotive activity and can culminate in irreversible paralysis and death (15,16). The biochemical description of the kynurenine pathway from a number of vertebrates revealed that 3-HK can undergo two alternative fates: either (i) it is hydrolyzed by a specific kynureninase to alanine and 3-hydroxyanthranilic acid, feeding the de novo synthesis of the essential cofactor NAD (17), or (ii) it can be directly converted into the more chemically stable compound xanthurenic acid (XA) by irreversible transamination.…”

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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Neurotoxic and neurobehavioral effects of kynurenines in adult insects

Cited by 43 publications

References 28 publications

Purification and biochemical characterization of a recombinant Anopheles gambiae tryptophan 2,3-dioxygenase expressed in Escherichia coli

Purification and biochemical characterization of a recombinant Anopheles gambiae tryptophan 2,3-dioxygenase expressed in Escherichia coli

Indoleamine 2,3-dioxygenase overexpression causes kynurenine-modification of proteins, fiber cell apoptosis and cataract formation in the mouse lens

Crystal structure of the Anopheles gambiae 3-hydroxykynurenine transaminase

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