Biochemical and Structural Investigations on Kynurenine Aminotransferase II: An Example of Conformation-Driven Species-Specific Inhibition?

Casazza, V.; Rossi, Franca; Rizzi, Menico

doi:10.2174/156802611794863599

Cited by 5 publications

(4 citation statements)

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“…It has been supposed that this difference in inhibitory activity may arise from the presence in the catalytic site of human KATII of two hydrophobic residues, Leu40 and Pro76, which are replaced by polar serines in the rat enzyme [57]. Recently [114], a human KATII double mutant harboring the serines characterizing the rat ortholog active site was generated in order to investigate the molecular basis for ESBA species specificity. The site-directed mutagenesis approach did not provide any experimental support to explain the striking difference in ESBA inhibitory efficiency towards rat and human KATII, and underlined the need for more in-depth biochemical investigations aimed at deciphering the mechanism of ESBA inhibition.…”

Section: Esba and Csa -Inhibitors And/or Substrates?mentioning

confidence: 99%

Human kynurenine aminotransferase II – reactivity with substrates and inhibitors

et al. 2011

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Kynurenine aminotransferase (KAT) is a pyridoxal 5′‐phosphate‐dependent enzyme that catalyzes the conversion of kynurenine, an intermediate of the tryptophan degradation pathway, into kynurenic acid, an endogenous antagonist of ionotropic excitatory amino acid receptors in the central nervous system. KATII is the prevalent isoform in mammalian brain and a drug target for the treatment of schizophrenia. We have carried out a spectroscopic and functional characterization of both the human wild‐type KATII and a variant carrying the active site mutation Tyr142→Phe. The transamination and the β‐lytic activity of KATII towards the substrates kynurenine and α‐aminoadipate, the substrate analog β‐chloroalanine and the inhibitors (R)‐2‐amino‐4‐(4‐(ethylsulfonyl))‐4‐oxobutanoic acid and cysteine sulfinate were investigated with both conventional assays and a novel continuous spectrophotometric assay. Furthermore, for high‐throughput KATII inhibitor screenings, an endpoint assay suitable for 96‐well plates was also developed and tested. The availability of these assays and spectroscopic analyses demonstrated that (R)‐2‐amino‐4‐(4‐(ethylsulfonyl))‐4‐oxobutanoic acid and cysteine sulfinate, reported to be KATII inhibitors, are poor substrates that undergo slow transamination.

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Section: Esba and Csa -Inhibitors And/or Substrates?mentioning

confidence: 99%

Human kynurenine aminotransferase II – reactivity with substrates and inhibitors

et al. 2011

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“…Involvement of kynurenic acid in these neurochemical and behavioural effects of ESBA were prevented by the simultaneous administration of kynurenine or kynurenic acid itself. Unfortunately, later work indicated that ESBA was much less active as an inhibitor of the human KAT enzyme because of a higher molecular flexibility in the region of the substrate binding site (Casazza et al ., ).…”

Section: Drug Developmentmentioning

confidence: 97%

The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders

Stone

Darlington

2013

British J Pharmacology

215

179

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Understanding the neurochemical basis for cognitive function is one of the major goals of neuroscience, with a potential impact on the diagnosis, prevention and treatment of a range of psychiatric and neurological disorders. In this review, the focus will be on a biochemical pathway that remains under-recognized in its implications for brain function, even though it can be responsible for moderating the activity of two neurotransmitters fundamentally involved in cognition -glutamate and acetylcholine. Since this pathway -the kynurenine pathway of tryptophan metabolism -is induced by immunological activation and stress, it also stands in a unique position to mediate the effects of environmental factors on cognition and behaviour. Targeting the pathway for new drug development could, therefore, be of value not only for the treatment of existing psychiatric conditions, but also for preventing the development of cognitive disorders in response to environmental pressures. The neurochemistry of cognitionThe neural complexity of cognitive function makes it exceptionally difficult to identify specific neurochemical substrates, especially those that could provide pharmacologically relevant targets for the prevention or treatment of cognitive dysfunction (Millan et al., 2012). Most of the recognized neurotransmitters in the CNS have been linked with some aspect of cognition either as primary factors or as systems whose activity is modified as a secondary consequence of a neurochemically distinct previous event. Among the major candidates with a putatively primary role in cognition are the monoamines norepinephrine, dopamine and 5-hydroxytryptamine (5HT) (Dalley et al., 2004;Sarter et al., 2007;Robert and Benoit, 2008;Tadaiesky et al., 2008), although dopamine has received most attention because of its potential links to the cognitive dysfunction seen in schizophrenia and Parkinson's disease (Tadaiesky et al., 2008;Xu et al., 2012), with roles in executive functioning and perceptual response speed that are affected in both disorders (Backman et al., 2010). Several other neurotransmitter systems, such as those releasing histamine and neuropeptides have been implicated in cognitive performance or its modification by drugs (Minzenberg and Carter, 2008).The two systems which have received by far the greatest attention to date are those releasing glutamate or acetylcholine as their transmitters. Both these systems have wellestablished roles in various aspects of cognitive function, with the focus of interest being on glutamate receptors sensitive to the synthetic ligand NMDA (Castellano et al., 2001;Newcomer and Krystal, 2001;Neill et al., 2010). These systems are of particular relevance to this review since the primary compounds of interest -quinolinic acid and kynurenic acid -both have prominent actions on them. Conversely, little is known of the possible interactions between the kynurenine pathway and other systems contributing to cognitive function, so the focus of this review will be limited to glutamatergic and cholinergi...

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“…Additionally, recent reports have established that sequence variants in human and rat KAT II cause significant cross-species enzyme potency shifts for inhibitor 4. 19,20 Our primary objective was to identify a selective, brain-penetrant tool compound for further exploration of KAT II inhibition in preclinical models of schizophrenia and cognition. Identification of a series of KAT II inhibitors with submicromolar binding affinity at both the rat and the human isoforms of KAT II would facilitate preclinical studies and clinical candidate identification.…”

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confidence: 99%

“…Several recent studies have employed the selective tool compounds ( S )-ESBA ( 4 ) and BFF-122 ( 5 , Figure ) via central administration for study of KAT II inhibition in preclinical models. − However, identification of brain-penetrant KAT II inhibitors with druglike properties remains a challenge. Additionally, recent reports have established that sequence variants in human and rat KAT II cause significant cross-species enzyme potency shifts for inhibitor 4 . , Our primary objective was to identify a selective, brain-penetrant tool compound for further exploration of KAT II inhibition in preclinical models of schizophrenia and cognition. Identification of a series of KAT II inhibitors with submicromolar binding affinity at both the rat and the human isoforms of KAT II would facilitate preclinical studies and clinical candidate identification.…”

mentioning

confidence: 99%

Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia

Dounay

Anderson

Bechle

et al. 2012

ACS Med. Chem. Lett.

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Kynurenine aminotransferase (KAT) II has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and other psychiatric disorders. Following a high-throughput screen, cyclic hydroxamic acid PF-04859989 was identified as a potent and selective inhibitor of human and rat KAT II. An X-ray crystal structure and (13)C NMR studies of PF-04859989 bound to KAT II have demonstrated that this compound forms a covalent adduct with the enzyme cofactor, pyridoxal phosphate (PLP), in the active site. In vivo pharmacokinetic and efficacy studies in rat show that PF-04859989 is a brain-penetrant, irreversible inhibitor and is capable of reducing brain kynurenic acid by 50% at a dose of 10 mg/kg (sc). Preliminary structure-activity relationship investigations have been completed and have identified the positions on this scaffold best suited to modification for further optimization of this novel series of KAT II inhibitors.

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Biochemical and Structural Investigations on Kynurenine Aminotransferase II: An Example of Conformation-Driven Species-Specific Inhibition?

Cited by 5 publications

References 37 publications

Human kynurenine aminotransferase II – reactivity with substrates and inhibitors

Human kynurenine aminotransferase II – reactivity with substrates and inhibitors

The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders

Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia

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