Measurement of Rat Brain Kynurenine Aminotransferase at Physiological Kynurenine Concentrations

Okuno, Etsuo; Schmidt, Werner; Parks, Deborah A.; Nakamura, Masayuki; Schwarcz, Robert

doi:10.1111/j.1471-4159.1991.tb03783.x

Cited by 89 publications

(47 citation statements)

References 32 publications

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“…Mammalian KATs have been studied extensively because these enzymes are responsible for the production of kynurenic acid, which is a nonselective blocker of excitatory receptors and plays an important physiological role in protecting the N-methyl-D-aspartate receptors of the central nervous system from being overstimulated by excitotoxin (19,20). They also have glutamine transaminase K and aminoadipate aminotransferase activities (21)(22)(23). However, results from this study suggest that the mosquito HKT is quite different compared with mammalian KATs.…”

Section: Discussioncontrasting

confidence: 48%

3-Hydroxykynurenine Transaminase Identity with Alanine Glyoxylate Transaminase

Han

Fang

2002

Journal of Biological Chemistry

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This study describes the functional characterization of a specific mosquito transaminase responsible for catalyzing the transamination of 3-hydroxykynurenine (3-HK) to xanthurenic acid (XA). The enzyme was purified from Aedes aegypti larvae by ammonium sulfate fractionation, heat treatment, and various chromatographic techniques, plus non-denaturing electrophoresis. The purified transaminase has a relative molecular mass of 42,500 by SDS-PAGE. N-terminal and internal sequencing of the purified protein and its tryptic fragments resolved a partial N-terminal sequence of 19 amino acid residues and 3 partial internal peptide sequences with 7, 10, and 7 amino acid residues. Using degenerate primers based on the partial internal sequences for PCR amplification and cDNA library screening, a full-length cDNA clone with a 1,167-bp open reading frame was isolated. Its deduced amino acid sequence consists of 389 amino acid residues with a predicted molecular mass of 43,239 and shares 45-46% sequence identity with mammalian alanine glyoxylate transaminases. Northern analysis shows the active transcription of the enzyme in larvae and developing eggs. Substrate specificity analysis of this mosquito transaminase demonstrates that the enzyme is active with 3-HK, kynurenine, or alanine substrates. The enzyme has greater affinity and catalytic efficiency for 3-HK than for kynurenine and alanine. The biochemical characteristics of the enzyme in conjunction with the profiles of 3-HK transaminase activity and XA accumulation during mosquito development clearly point out its physiological function in the 3-HK to XA pathway. Our data suggest that the mosquito transaminase was evolved in a manner precisely reflecting the physiological requirement of detoxifying 3-HK produced in the tryptophan oxidation pathway in the mosquito. 3-HK1 is a natural metabolite in the tryptophan oxidation pathway. However, it is oxidized easily, stimulating the production of reactive oxygen species (1-5). 3-HK concentration is elevated in the brains of patients with AIDS-related dementia (6), Huntington's disease (7,8), and hepatic encephalopathy (9). Recently it has been reported that 3-HK, at low micromolar concentrations, induces apoptosis of neurons prepared from the rat striatum (3, 4, 10). In insects, injection of 3-HK into adult Neobellieria bullata caused instant paralysis, which was followed by death (11). 3-HK also is present in the mammalian lens, where its oxidation product might cross-link lens proteins and contribute to nuclear cataract formation (12-15). To maintain physiological conditions, it apparently is critical for living organisms to be able to tightly regulate the level of 3-HK, thereby preventing overaccumulation of 3-HK.Although 3-HK is toxic to living organisms, the tryptophan to 3-HK pathway is actually the major branch pathway of tryptophan catabolism in mammals. Fortunately, mammals have kynureninase that can efficiently hydrolyze 3-HK to alanine and 3-hydroxyanthranilic acid, and the latter can be eventually oxidized to CO 2 an...

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Section: Discussioncontrasting

confidence: 48%

3-Hydroxykynurenine Transaminase Identity with Alanine Glyoxylate Transaminase

Han

Fang

2002

Journal of Biological Chemistry

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“…Rat brain also contains a mitochondrial form of this aminotransferase, which differs from cytosolic KAT/GTK exclusively for the presence of an NH 2 -terminal leader peptide, which targets the protein to the mitochondrial matrix (15). Whereas it has been claimed that in rats, a single pyruvate-preferring enzyme with KAT activity may be of physiological relevance in the cerebral synthesis of kynurenic acid (16,17), whether in rat brain other aminotransferase forms are involved in the biosynthesis of kynurenic acid remains to be established. Noteworthy, the presence of AadAT activity has also been described in rat brain (see Ref.…”

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confidence: 99%

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

Buchli

Alberati-Giani

Malherbe

et al. 1995

Journal of Biological Chemistry

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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 ␣-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 transcriptionpolymerase 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 ϳ2.1 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.

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“…The former is likely to be the main pathway in the CNS, because there, histamine is mainly methylated. In addition, regional CNS levels of IAA (G.D.P., unpublished data) correlated with those of histidine transaminase (also termed kynurenine aminotransferase) (10) but not with those of histamine or its synthetic enzyme, and inhibition of histamine synthesis did not markedly affect IAA levels (11)(12)(13). Pulse-chase studies showed IAA could be conjugated with phosphoribosyl-pyrophosphate (while hydrolyzing ATP) to produce an IAA-ribotide (14)(15)(16)(17).…”

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Imidazoleacetic acid-ribotide: An endogenous ligand that stimulates imidazol(in)e receptors

Prell

Martinelli

Holstein

et al. 2004

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

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We identified the previously unknown structures of ribosylated imidazoleacetic acids in rat, bovine, and human tissues to be imidazole-4-acetic acid-ribotide (IAA-RP) and its metabolite, imidazole-4-acetic acid-riboside. We also found that IAA-RP has physicochemical properties similar to those of an unidentified substance(s) extracted from mammalian tissues that interacts with imidazol(in)e receptors (I-Rs). [''Imidazoline,'' by consensus (International Union of Pharmacology), includes imidazole, imidazoline, and related compounds. We demonstrate that the imidazole IAA-RP acts at I-Rs, and because few (if any) imidazolines exist in vivo, we have adopted the term ''imidazol(in)e-Rs.''] The latter regulate multiple functions in the CNS and periphery. We now show that IAA-RP (i) is present in brain and tissue extracts that exhibit I-R activity; (ii) is present in neurons of brainstem areas, including the rostroventrolateral medulla, a region where drugs active at I-Rs are known to modulate blood pressure; (iii) is present within synaptosome-enriched fractions of brain where its release is Ca 2؉ -dependent, consistent with transmitter function; (iv) produces I-R-linked effects in vitro (e.g., arachidonic acid and insulin release) that are blocked by relevant antagonists; and (v) produces hypertension when microinjected into the rostroventrolateral medulla. Our data also suggest that IAA-RP may interact with a novel imidazol(in)e-like receptor at this site. We propose that IAA-RP is a neuroregulator acting via I-Rs.clonidine-displacing substance (CDS) ͉ hypertension ͉ pancreatic beta cells ͉ anti-IAA-RP antibodies ͉ histamine

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Measurement of Rat Brain Kynurenine Aminotransferase at Physiological Kynurenine Concentrations

Cited by 89 publications

References 32 publications

3-Hydroxykynurenine Transaminase Identity with Alanine Glyoxylate Transaminase

3-Hydroxykynurenine Transaminase Identity with Alanine Glyoxylate Transaminase

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

Imidazoleacetic acid-ribotide: An endogenous ligand that stimulates imidazol(in)e receptors

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