Kynurenine Aminotransferase Research Articles

Excitotoxic lesions of the rat striatum: different responses of kynurenine pathway enzymes during ontogeny

Excitotoxic lesions of the adult rat striatum result in reactive gliosis and an associated increase in the activities of the astrocytic enzymes 3-hydroxyanthranilic acid oxygenase (3HAO) and kynurenine aminotransferase (KAT), which are responsible for the biosynthesis of the neurotoxin quinolinic acid and the neuroprotectant kynurenic acid, respectively. Unilateral ibotenate injections were made in the striatum of 7-, 14-, 21- and 28-day- and 2.5-month-old rats to study the reaction of 3HAO and KAT when injury is inflicted during ontogeny. By one week, all lesioned striata showed a > 50% decrease in the activity of the neuronal marker enzyme glutamic acid decarboxylase. At this timepoint, lesion-induced elevations in 3HAO activity increased progressively from 130 to 206, 280, 385 and 456% of the contralateral striatum in the five age groups studied. In contrast, in the same animals the respective increases in striatal KAT activity were 601, 350, 312, 259 and 159% ( n = 6–13 per group). In all age groups, statistically significant lesion-induced increases in 3HAO and KAT were seen up to 4 weeks after the ibotenate injection. Rats receiving an intrastriatal injection of ibotenate on postnatal day 7 also showed an increate in the striatal tissue level of kynurenic acid 1 week after the lesion. These data demonstrate that substantial qualitative differences exist between the immature and adult rat in the reaction of two glial enzymes to striatal injury. Moreover, the ability of the immature brain to mobilize kynurenic acid production preferentially may play a role in the brain's response to perinatal injury.

Regulation of the kynurenine metabolic pathway by interferon-gamma in murine cloned macrophages and microglial cells.

Several pieces of evidence suggest a major role for brain macrophages in the overproduction of neuroactive kynurenines, including quinolinic acid, in brain inflammatory conditions. In the present work, the regulation of kynurenine pathway enzymes by interferon-gamma (IFN-gamma) was studied in immortalized murine macrophages (MT2) and microglial (N11) cells. In both cell lines, IFN-gamma induced the expression of indoleamine 2,3-dioxygenase (IDO) activity. Whereas tumor necrosis factor-alpha did not affect enzyme induction by IFN-gamma, lipopolysaccharide modulated IDO activity differently in the two IFN-gamma-activated cell lines, causing a reduction of IDO expression in MT2 cells and an enhancement of IDO activity in N11 cells. Kynurenine aminotransferase, kynurenine 3-hydroxylase, and 3-hydroxyanthranilic acid dioxygenase appeared to be constitutively expressed in both cell lines. Kynurenine 3-hydroxylase activity was stimulated by IFN-gamma. It was notable that basal kynureninase activity was much higher in MT2 macrophages than in N11 microglial cells. In addition, IFN-gamma markedly stimulated the activity of this enzyme only in MT2 cells. IFN-gamma-treated MT2 cells, but not N11 cells, were able to produce detectable amounts of radiolabeled 3-hydroxyanthranilic and quinolinic acids from L-[5-3H] tryptophan. These results support the notion that activated invading macrophages may constitute one of the major sources of cerebral quinolinic acid during inflammation.

Cloning of rat and human kynurenine aminotransferase.

Kynurenic acid (KYNA), a normal component of the mammalian brain, has recently gained attention as a broad spectrum antagonist of ionotropic excitatory amino acid receptors (Stone et al., 1993). While in mammalian peripheral organs, KYNA is biosynthesized from L-kynurenine by several rather unspecific aminotransferases (Noguchi et al., 1975, Okuno et al, 1980), it appears that a single enzyme, kynurenine aminotransferase (KAT), is responsible for KYNA synthesis in the rat brain (Okuno et al., 1991a). In the human brain, on the other hand, two enzymes (KAT I and KAT II) have been characterized (Okuno et al., 1991b). These two KATs have distinct catalytic characteristics and can be physically separated by conventional techniques.KeywordsKynurenic AcidCysteine ConjugateKynurenine AminotransferaseHuman Brain cDNA LibraryKYNA SynthesisThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Kynurenine aminotransferases in the rat. Localization and characterization.

Kynurenine-2-oxoglutarate aminotransferase (kynurenine specific, designated here KAT-II) and kynurenine pyruvate aminotransferase (designated here KAT-I) activities were detected in the kidney using 2 microM kynurenine. The major activities were performed by KAT-II and the contributi-n of KAT-I is about 1/15. KAT-I activity was detected in all organs tested. The liver showed the highest KAT-I activity, however, the highest activity of glutamine transaminase-K (GTK) was detected in the kidney. KAT-I activity was well corresponded with GTK activity in all organs except liver. KAT-I or GTK activity of crude extract didn't inhibited by addition of glutamine either kynurenine. KAT-I or GTK activity of purified preparation, however, inhibited strongly addition of glutamine either kynurenine. KAT-I and GTK showed different pH optimum profile, but purified and crude preparation of those were similar. Phenylpyruvate or 2-oxo-4-methiolbutyrate reduced the inhibition of purified KAT-I activity by glutamine using 2 microM kynurenine. Phenylpyruvate changed the Km value for kynurenine and Vmax, suggesting conformational change of the enzyme.

Derivatives of kynurenine as inhibitors of rat brain kynurenine aminotransferase

The structural requirements of the catalytic site of kynurenine aminotransferase (KAT), the enzyme responsible for the conversion of l-kynurenine (KYN) to kynurenic acid (KYNA), were examined using analogs and derivatives of KYN. KYNA production from KYN was monitored in rat brain homogenates and brain tissue slices. Modification of KYN's acylalanine side chain or its ring amino group resulted in compounds which did not substantially affect KYNA synthesis. Ring chlorination in positions 3, 4, 5 and 6 yielded KYN analogs which interfered with KYNA production. l-5-Cl-KYN was the most active of the chlorinated kynurenines, and one of the most potent of several other 5-substituted kynurenines. l-5-Cl-KYN was an excellent substrate of KAT, yielding 6-Cl-KYNA. Finally, in kinetic studies, l-5-Cl-KYN ( K i = 5.4 μM) was found to have an approximately five times higher affinity to the enzyme than the natural substrate KYN ( K m = 28 μM).

Enantiospecific synthesis and in vitro activity of selective inhibitors of rat brain kynureninase and kynurenine-3-hydroxylase.

Chirality, a phenomenon of dissimetry, is a fundamental characteristic of biological systems. A large amount of endogenous compounds including drug-interacting macromulecules are chiral, thus giving rise to differences in the intermolecular energy involved in the interaction of the chiral drug and the biological target. As a result of such chiral discrimination, drug enantiomers may differ in their pharmacodynamic and pharmacokinetic effects. Due to such differences, particularly in vivo the use of 1:1 mixture of enantiomers (racemates), often fails to display, and occasionally masks the properties of each enantiomer. In searching of selective inhibitors of tryptophane catabolism enzymes, we identified two classes of potent and selective inhibitors represented by 2’-methoxy-benzoylalanine (R,S)-1 and 3’, 4’-dichloro-benzoylalanine (R,S)-2, acting respectively as kynureninase and kynuren- ine 3-hydroxylase selective inhibitors with no activity on the kynurenic acid synthesising enzyme (Kynurenine aminotransferase). Moreover, it is noteworthy that the unsubstituted benzoyl-alanine (R, S)-3, even though endowed with lower potency and selectivity, is by itself an inhibitor of kynurenine-3-hydroxylase.KeywordsAnthranilic AcidSuccinic AnhydrideTransient Cerebral IschemiaTrifluoroacetic AnhydrideChiral DiscriminationThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Kynurenine aminotransferase in hypercholesterolemic rats.

Nicotinic acid is used in the treatment of atherosclerosis for its hypolipidemic effects (Kritchevsky, 1971; Levy, 1980; Grundy et al., 1981; Altschul et al., 1995), which reduce triglycerides and also cholesterol. In mammals, nicotinic acid derives from the metabolism of tryptophan along the kynurenine pathway. But kynurenine can also be metabolized to kynurenic acid by means of kynurenine aminotransferase (KAT). An abnormal activity of this enzyme should reduce kynurenine and consequently the biosynthesis in nicotinic acid.

In vivo inhibition of kynurenine aminotransferase activity by isonicotinic acid hydrazide in rats.

It is known that the anti-tuberculosis drug, isonicotinic acid hydrazide (INH), causes pellagra, a niacin deficiency syndrome, and peripheral neuritis in humans. We investigated the effects of INH on the metabolism of tryptophan to niacin in rats fed on a niacin-free diet. The activity of kynurenine aminotransferase was significantly inhibited by feeding a diet containing INH and by an injection of INH, and the urinary excretion of xanthurenic acid, the side-reaction product of the conversion pathway of tryptophan to niacin, was below the limit of detection. The inhibition of kynurenine aminotransferase and the resulting decreased formation of xanthurenic acid generally mean a higher conversion ratio of tryptophan to niacin. However, the conversion ratio was no different between the control and INH groups.

Cloning and Functional Expression of a Soluble Form of Kynurenine/α -Aminoadipate Aminotransferase from Rat Kidney

Several aminotransferases with kynurenine aminotransferase (KAT) activity are able to convert L-kynurenine into kynurenic acid, a putative endogenous modulator of glutamatergic neurotransmission. In the rat, one of the described KAT isoforms has been found to correspond to glutamine transaminase K. In addition, rat kidney alpha-aminoadipate aminotransferase (AadAT) also shows KAT activity. In this report, we describe the isolation of a cDNA clone encoding the soluble form of this aminotransferase isoenzyme from rat (KAT/AadAT). Degenerate oligonucleotides were designed from the amino acid sequences of rat kidney KAT/AadAT tryptic peptides for use as primers for reverse transcription-polymerase chain reaction of rat kidney RNA. The resulting polymerase chain reaction fragment was used to screen a rat kidney cDNA library and to isolate a cDNA clone encoding KAT/AadAT. Analysis of the combined DNA sequences indicated the presence of a single 1275-base pair open reading frame coding for a soluble protein of 425 amino acid residues. KAT/AadAT appears to be structurally homologous to aspartate aminotransferase in the pyridoxal 5'-phosphate binding domain. RNA blot analysis of rat tissues, including brain, revealed a single species of KAT/AadAT mRNA of approximately 2.1 kilobases. HEK-293 cells transfected with the KAT/AadAT cDNA exhibited both KAT and AadAT activities with enzymatic properties similar to those reported for the rat native protein.

Metabolism of [5-3H]kynurenine in the rat brain in vivo: evidence for the existence of a functional kynurenine pathway.

The incorporation of tritium-label into quinolinic acid (QUIN), kynurenic acid (KYNA), and other kynurenine (KYN) pathway metabolites was studied in normal and QUIN-lesioned rat striata after a focal injection of [5-3H]KYN in vivo. The time course of metabolite accumulation was examined 15 min to 4 h after injection of [5-3H]KYN, and the concentration dependence of KYN metabolism was studied in rats killed 2 h after injection of 1.5-1,500 microM [5-3H]KYN. Labeled QUIN, KYNA, 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid, and xanthurenic acid (XA) were recovered from the striatum in every experiment. Following injection of 15 microM [5-3H]KYN, a lesion-induced increase in KYN metabolism was noted. Thus, the proportional recoveries of [3H]KYNA (5.0 vs. 1.8%), [3H]3-HK (20.9 vs. 4.5%), [3H]XA (1.5 vs. 0.4%), and [3H]QUIN (3.6 vs. 0.6%) were markedly elevated in the lesioned striatum. Increases in KYN metabolism in lesioned tissue were evident at all time points and KYN concentrations used. Lesion-induced increases of the activities of kynurenine-3-hydroxylase (3.6-fold), kynureninase (7.6-fold), kynurenine aminotransferase (1.8-fold), and 3-hydroxyanthranilic acid oxygenase (4.2-fold) likely contributed to the enhanced flux through the pathway in the lesioned striatum. These data provide evidence for the existence of a functional KYN pathway in the normal rat brain and for a substantial increase in flux after neuronal ablation. This method should be of value for in vivo studies of cerebral KYN pathway function and dysfunction.

Metabolism of l‐Tryptophan to Kynurenate and Quinolinate in the Central Nervous System: Effects of 6‐Chlorotryptophan and 4‐Chloro‐3‐Hydroxyanthranilate

The metabolism of L-tryptophan to the neuroactive kynurenine pathway metabolites, L-kynurenine, kynurenate and quinolinate, and the effects of two inhibitors of quinolinate synthesis (6-chlorotryptophan and 4-chloro-3-hydroxyanthranilate) were investigated by mass spectrometric assays in cultured cells and in vivo. Cell lines obtained from astrocytoma, neuroblastoma, macrophage/monocytes, lung, and liver metabolized L-[13C6]-tryptophan to L-[13C6]kynurenine and [13C6]kynurenate, particularly after indoleamine-2,3-dioxygenase induction by interferon-gamma. Kynurenine aminotransferase activity was measurable in all cell types examined but was unaffected by interferon-gamma. These results suggest that many cell types can be sources of kynurenate following immune activation. In vivo synthesis of L-[13C6]kynurenine and [13C6]kynurenate from L-[13C6]tryptophan was studied in the CSF of macaques infected with poliovirus, as a model of inflammatory neurologic disease. The effects of 6-chlorotryptophan and 4-chloro-3-hydroxyanthranilate on the synthesis of kynurenate were different. 6-Chlorotryptophan attenuated formation of L-[13C6]kynurenine and [13C6]kynurenate and was converted to 4-chlorokynurenine and 7-chlorokynurenate. It may be an effective prodrug for the delivery of 7-chlorokynurenate, which is a potent antagonist of NMDA receptors. In contrast, 4-chloro-3-hydroxyanthranilate did not reduce accumulation of L-[13C6]kynurenine and [13C6]kynurenate. 6-Chlorotryptophan and 4-chloro-3-hydroxyanthranilate are useful tools to manipulate concentrations of quinolinate and kynurenate in the animal models of neurologic disease to evaluate physiological roles of these neuroactive metabolites.

Electrical kindling is associated with a lasting increase in the extracellular levels of kynurenic acid in the rat hippocampus

Endogenous kynurenic acid (KYNA), an excitory amino acid receptor antagonist with antineurotoxic and anticonvulsant activity, was assessed by microdialysis in the hippocampus of kindled rats. One week after the completion of amygdala or hippocampal kindling (stage 5), the dialysate concentration of KYNA in the hippocampus of both hemispheres was 1.7 ± 0.1-fold higher than in shams ( P < 0.01). Veratridine (50 μM), applied through the probe, reduced extracellular KYNA by 28% within 1 h in controls ( P < 0.05), but was ineffective in stage 5 kindled rats. At the preconvulsive stage 2, dialysate KYNA concentration and the effect of veratridine were similar to controls. The activity of KYNA's biosynthetic enzyme, kynurenine aminotransferase, did not change in the hippocampus 1 week after stage 5 seizures. These data indicate an enhanced liberation of KYNA in the hippocampus of fully kindled animals due to an impairment of normal regulatory mechanisms. This may be of relevance for the control of hippocampal excitability during epileptogenesis.

Response of kynurenine pathway enzymes to pregnancy and dietary level of vitamin B-6

The kynurenine pathway of tryptophan metabolism produces several neuroactive metabolites including 3-hydroxykynurenine, kynurenic acid, and quinolinic acid. This pathway is sensitive to reductions in vitamin B-6 availability because two key enzymes, kynurenine aminotransferase (KAT) and kynureninase (KYNase), require pyridoxal 5′-phosphate. During pregnancy abnormal concentrations of kynurenine metabolites are also found. We measured the effects of pregnancy and vitamin B-6 availability on KAT and KYNase in liver. DBA/2Ibg and A/Ibg mice were fed diets containing 0.25, 0.5, 2.0, 3.6, or 7.0 mg/kg pyridoxine-HCl (PN-HCl) for 4 weeks. Mitochondrial KAT and cytosolic KYNase were measured in control mice and pregnant mice on gestational days 16–18. The response of the two inbred strains was similar throughout. There were no marked alterations in KAT activity as a function of diet or pregnancy. In contrast, KYNase activities were significantly reduced by dietary restriction of vitamin B-6, and pregnant mice had significantly lower activity than nonpregnant controls for all but the highest dietary level of PN-HCl. These data show that pregnancy has a more pronounced effect on KYNase activity than vitamin B-6 restriction, and that the effects of pregnancy and diet are additive. The alteration in the kynurenine pathway in pregnancy is due to a reduction in KYNase activity, which is resistant to alleviation by vitamin B-6 supplementation.

L-α-Aminoadipic acid as a regulator of kynurenic acid production in the hippocampus: a microdialysis study in freely moving rats

l-α-Aminoadipic acid is a lysine metabolite with neuroexcitatory properties, and has previously been shown to inhibit the production of the broad spectrum excitatory amino acid receptor antagonist kynurenic acid in brain tissue slices. The effects of l-α-aminoadipic acid on the levels of extracellular kynurenic acid were now studied by microdialysis in the dorsal hippocampus of freely moving rats. Application of l-α-aminoadipic acid through the microdialysis probe dose dependently decreased both the concentration of endogenous kynurenic acid and of kynurenic acid which was produced de novo from its bioprecursor l-kynurenine (500 μM applied through the probe). 500 μM l-α-aminoadipic acid lowered the kynurenic acid concentration in the dialysate by 47% and 28% with and without precursor loading, respectively, whereas d-α-aminoadipic acid was without effect. Co-administration of 500 μM l-α-aminoadipic acid with 50 μM veratridine, which by itself produces a substantial decrease in the levels of extracellular kynurenic acid, did not result in a further reduction in kynurenic acid concentrations. Extensive neuronal degeneration caused by an intrahippocampal injection of quinolinic acid (120 nmol) did not interfere with the effect of l-α-aminoadipic acid. Taken together, these data suggest that the effect of l-α-aminoadipic acid on extracellular kynurenic acid levels is likely due to its direct action on astrocytes, which are known to harbor kynurenic acid's biosynthetic enzyme, kynurenine aminotransferase. l-α-Aminoadipic acid may modulate kynurenic acid function in the brain and thus play a role in the pathogenesis of neurodegenerative and seizure disorders.

Identification of a mitochondrial form of kynurenine aminotransferase/glutamine transaminase K from rat brain

A soluble aminotransferase with kynurenine aminotransferase (KAT) activity has been recently isolated from rat brain. This enzyme corresponds to a cytosolic form of glutamine transaminase K (GTK). In addition to the cytosolic enzyme, a mitochondrial-associated form of this KAT/GTK also exists. In the present work we have isolated a rat brain cDNA clone encoding a KAT/GTK enzyme identical to the soluble form but carrying an additional stretch of 32 amino acids at its NH 2-terminus. Several structural features of this sequence resemble those of leader peptides for mitochondrial import. Evidence that the isolated cDNA encoded for mitochondrial KAT/GTK was obtained after transfection of HEK-293 cells with the cDNA coding for this new KAT/GTK isoenzyme. In fact, a significant enrichment of both KAT and GTK enzymatic activities was found in the crude mitochondrial fraction of the transfected cells.

Dysfunction of brain kynurenic acid metabolism in Huntington's disease: focus on kynurenine aminotransferases

The levels of the neuroprotective excitatory amino acid receptor antagonist kynurenic acid (KYNA) have been previously shown to be reduced in several regions of the brain of Huntington's disease (HD) patients. Thus, KYNA has been speculatively linked to the pathogenesis of HD. We have examined KYNA levels and the activity of its two biosynthetic enzymes (kynurenine aminotransferases (KAT) I and II) in 12 regions of brains from late-stage HD patients and control donors ( n = 17 each). KYNA levels were measured in the original tissue homogenate. Using [ 3H]kynurenine as the substrate, enzyme activities were determined in dialyzed tissue homogenates. KYNA levels in the caudate nucleus decreased from 733 ± 95 in controls to 401 ± 62 fmol/mg tissue in HD ( p < 0.01). The activity of both enzymes was highest in cortical areas (e.g. control frontal cortex: KAT I: 148 ± 18 fmol/mg tissue/h; KAT II: 25 ± 2 fmol/mg tissue/h). The activities of both KAT I and KAT II, when expressed per mg original weight, showed significant decreases (48–55%) in the HD putamen ( p < 0.01). Trends toward lower enzyme activities and KYNA concentrations were detected in other brain areas as well. Kinetic analyses, performed in putamen and cerebellum, showed an approximately 3-fold increase in K m values for both KAT I and KAT II in the putamen only. V max values remained unchanged in the HD brain. These findings indicate a selective impairment in KYNA biosynthesis in the neostriatum of HD patients, possibly due to the loss of (an) endogenous KAT activators). Future studies should examine whether the demonstrated dysfunction in the production of the endogenous neuroprotecive agent KYNA is causally related to the neurodegenerative process in HD.

Cloning and Characterization of a Soluble Kynurenine Aminotransferase from Rat Brain: Identity with Kidney Cysteine Conjugate β‐Lyase

In this study, we describe the cloning and characterization of a soluble form of kynurenine aminotransferase (KAT, EC 2.6.1.7) present in rat brain. Soluble KAT was purified from rat kidney and the amino acid sequences of four tryptic peptides determined. These peptides were found to belong to the amino acid sequence reported for rat kidney soluble cysteine conjugate beta-lyase, indicating that rat kidney KAT and beta-lyase represent the same molecular entity. Oligonucleotide probes derived from the beta-lyase cDNA were then used as primers for PCR of reverse-transcribed rat brain poly(A)+ RNA. After subcloning of the resulting PCR fragment and sequencing of the isolated rat brain clone, its oligonucleotide sequence was found to be identical to that reported for the beta-lyase cDNA. Further evidence that the isolated rat brain clone encoded for KAT was obtained by transfecting HEK-293 cells with a construct containing the coding sequence for the enzyme. The transfected cells exhibited KAT activity and, in the presence of 2 mM pyruvate and 2-oxoglutarate, the Km values for L-kynurenine were 1.2 mM and 86.3 microM, respectively. Northern blot analysis of rat kidney, liver, and brain RNA revealed a single species of KAT/beta-lyase mRNA of approximately 2.1 kb.

Production of the nmda/glycine receptor antagonist 7-chlorokynurenic acid in vivo

Activation of excitatory amino acid receptors by endogenous excitotoxins results in degenerative changes characteristic of neurodegenerative brain diseases such as Huntington's disease. Excitatory amino acid receptors are present in the highest concentration in the striatum, the hippocampal region, and the temporal lobe. The most potent, naturally occurring excitatory amino acid receptor antagonist is kynurenic acid (KYNA) which acts preferentially on N-methyl-d-aspartate (NMDA) receptors. KYNA is produced from l-kynurenine, by the action of the enzymes kynurenine aminotransferases (KAT I and KAT II). Several inhibitors of mitochondrial energy metabolism result in an indirect excitotoxic neuronal degeneration. We examined whether systemic administration of the mitochondrial toxin 3-nitroproprionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, which also acts by an indirect excitotoxic mechanism, would produce alterations in the immunohistochemical pattern of KAT I. Our present investigations demonstrate that after 15 days of administration of 3-NP, an inhibitor of mitochondrial Complex II, the most severe depletion of KAT I occurred in the striatum; less severe depletion occurred in other brain areas investigated, following a striatum > hippocampus > temporal cortex gradient. The alterations induced by 15 days of 3-NP treatment were less conspicuous in 6-week-old (young) animals than in 3-month-old adults. In these adult animals, 3-NP induced necrotic cores in the striatum, characterized by destruction of neuronal and glial elements, similar to that seen in the histologic and neurochemical features of Huntington's disease. It appears that immunohistochemical depletion of KAT after administration of 3-NP to adult animals may contribute to the pathological processes that characterize Huntington's disease.

An investigation of the activities of 3-hydroxykynureninase and kynurenine aminotransferase in the brain in Huntington's disease.

Previous reports have indicated abnormalities in the concentrations of metabolites of the tryptophan/kynurenine pathway in the brain in Huntington's disease. These have included an increase in 3-hydroxykynurenine and both increases and decreases in kynurenic acid. The activities of two enzymes involved in the metabolism of these compounds, 3-hydroxykynureninase and kynurenine aminotransferase, have been determined in post mortem brain tissue taken from Huntington's disease patients and control subjects.

Note added to ‘Histamine metabolites in cerebrospinal fluid of patients with chronic schizophrenia: Their relationships to levels of other aminergic transmitters and ratings of symptoms’ Schizophrenia Research 14 (2) 1995 pp 93–104

The kynurenine pathway of tryptophan degradation generates several neuroactive compounds. Of those, kynurenic acid is an N-methyl-d-aspartate (NMDA) and alpha7 nicotinic receptor antagonist. The kynurenic acid hypothesis of schizophrenia is built upon the fact that kynurenic acid blocks glutamate receptors and is elevated in schizophrenia. Kynurenic acid tightly controls glutamatergic and dopaminergic neurotransmission and elevated brain levels appear related to psychotic symptoms and cognitive impairments. Contributing to enhanced production of kynurenic acid, the expression and enzyme activity of kynurenine 3-monooxygenase (KMO) are reduced in schizophrenia and in bipolar patients with a history of psychosis. The kynurenine pathway is also critically regulated by cytokines, and, indeed, the pro-inflammatory cytokines interleukin (IL)-1β and IL-6 are elevated in schizophrenia and bipolar disorder and stimulate the production of kynurenic acid. One physiological mechanism controlling the activity of the kynurenine pathway originates from the protein sorting nexin 7 (SNX7). This glial signaling pathway initiates a caspase-8-driven activation of IL-1β that induces tryptophan-2,3-dioxygenase 2 (TDO2), an enzyme in the kynurenine pathway. A recent study shows that a genetic variation resulting in decreased expression of SNX7 is linked to increased central levels of kynurenic acid and ultimately to psychosis and cognitive dysfunction in bipolar disorder. Experimental studies highlight the detrimental effects of increased synthesis of kynurenic acid during sensitive periods of early brain development. Furthermore, experimental studies strongly support inhibition of kynurenine aminotransferase (KAT) II as a novel target and a valuable pharmacological strategy in the treatment of psychosis and for improving cognitive performance relevant for schizophrenia.This article is part of the Special Issue entitled ‘The Kynurenine Pathway in Health and Disease’.