Sequence Variants in Kynurenine Aminotransferase II (KAT II) Orthologs Determine Different Potencies of the Inhibitor <i>S</i>‐ESBA

Pellicciari, Roberto; Venturoni, Francesco; Bellocchi, Daniele; Carotti, Andrea; Marinozzi, Maura; Macchiarulo, Antonio; Amori, Laura; Schwarcz, Robert

doi:10.1002/cmdc.200800109

Cited by 29 publications

(42 citation statements)

References 19 publications

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“…L-Kynurenine sulfate ('kynurenine'; purity: 99.4%) was obtained from Sai Adventium (Hyderabad, India). (S)-4-(ethylsulfonyl)benzoylalanine (ESBA) was synthesized as described by Pellicciari et al (2008). Other chemicals were obtained from a variety of suppliers and were of the highest commercially available purity.…”

Section: Chemicalsmentioning

confidence: 99%

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Pocivavsek

Potter

et al. 2011

Neuropsychopharmacol

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Kynurenic acid (KYNA), an astrocyte-derived metabolite, antagonizes the a7 nicotinic acetylcholine receptor (a7nAChR) and, possibly, the glycine co-agonist site of the NMDA receptor at endogenous brain concentrations. As both receptors are involved in cognitive processes, KYNA elevations may aggravate, whereas reductions may improve, cognitive functions. We tested this hypothesis in rats by examining the effects of acute up-or downregulation of endogenous KYNA on extracellular glutamate in the hippocampus and on performance in the Morris water maze (MWM). Applied directly by reverse dialysis, KYNA (30-300 nM) reduced, whereas the specific kynurenine aminotransferase-II inhibitor (S)-4-(ethylsulfonyl)benzoylalanine (ESBA; 0.3-3 mM) raised, extracellular glutamate levels in the hippocampus. Co-application of KYNA (100 nM) with ESBA (1 mM) prevented the ESBA-induced glutamate increase. Comparable effects on hippocampal glutamate levels were seen after intra-cerebroventricular (i.c.v.) application of the KYNA precursor kynurenine (1 mM, 10 ml) or ESBA (10 mM, 10 ml), respectively. In separate animals, i.c.v. treatment with kynurenine impaired, whereas i.c.v. ESBA improved, performance in the MWM. I.c.v. co-application of KYNA (10 mM) eliminated the pro-cognitive effects of ESBA. Collectively, these studies show that KYNA serves as an endogenous modulator of extracellular glutamate in the hippocampus and regulates hippocampus-related cognitive function. Our results suggest that pharmacological interventions leading to acute reductions in hippocampal KYNA constitute an effective strategy for cognitive improvement. This approach might be especially useful in the treatment of cognitive deficits in neurological and psychiatric diseases that are associated with increased brain KYNA levels.

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Section: Chemicalsmentioning

confidence: 99%

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Pocivavsek

Potter

et al. 2011

Neuropsychopharmacol

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141

158

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“…Among the four KATs, KAT2 is the main isozyme responsible (>70%) for KYNA production in the human brain [16], and therefore the inhibition of KAT2 has become the target of investigations. (S)-4-(Ethyl sulfonyl)benzoylalanine ((S)-ESBA) is the first known reversible KAT2 inhibitor with a reported IC 50 at around 1 to 2 mM [17]. The next generation of hKAT2 inhibitors were BFF-122 and the cyclic hydroxamic acid PF-04859989, which were identified as potent and irreversible inhibitors of human KAT II with reported IC 50 s of around 0.1 to 1 µM [18].…”

Section: Introductionmentioning

confidence: 99%

Study of the Activity and Possible Mechanism of Action of a Reversible Inhibitor of Recombinant Human KAT-2: A Promising Lead in Neurodegenerative and Cognitive Disorders

et al. 2016

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Abnormal levels of kynurenic acid (KYNA) in the human brain are believed to be connected to several central nervous system (CNS) diseases, therefore compounds which affect the production of this crucial metabolite are of interest in CNS drug development. The majority of KYNA production is accounted for by kynurenine aminotransferase-2 (KAT-2) in the mammalian brain; hence this enzyme is one of the most interesting targets with which to modulate KYNA levels. Recently developed human KAT-2 inhibitors with high potencies are known to irreversibly bind to the enzyme cofactor, pyridoxal-5 1 -phosphate (PLP), which may lead to severe side effects due to the abundance of PLP-dependent enzymes. In this study, we report a reversible and competitive inhibitor of KAT-2. Its inhibitory activities were examined using HPLC and surface plasmon resonance (SPR) and compare favorably with other recently reported KAT-2 inhibitors. Our inhibitor, NS-1502, demonstrates suitable inhibitory activity, almost 10 times more potent than the known reversible KAT-2, (S)-ESBA.

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“…Moreover, infusion of 5 mM S-ESBA into the hippocampus of un-anaesthetized rats caused a decrease in extracellular KYNA levels, which returned to normal values soon after the removal of the drug [30]. However, it was concomitantly demonstrated that S-ESBA is a poor inhibitor of human recombinant KAT II [31].…”

Section: Introductionmentioning

confidence: 94%

“…In the resulting model of the hKAT II•S-ESBA complex, nine protein residues were proposed to be responsible for the complete shaping of the inhibitor binding pocket with only two of them (i.e. Leu40 and Pro76) differing between the human and rat enzyme [31]. Since docking studies have proposed that these two residues are the reason why S-ESBA fails to inhibit hKAT II, we asked whether the Leu40/Pro76 double mutant of the human enzyme would be more susceptible to inhibition by the same.…”

Section: Introductionmentioning

confidence: 99%

“…To understand the possible structural basis of this species-specificity of S-ESBA action, molecular docking experiments were performed [31], using the crystal structure of hKAT II in complex with L-KYN (PDB code: 2R2N) [21]. In the resulting model of the hKAT II•S-ESBA complex, nine protein residues were proposed to be responsible for the complete shaping of the inhibitor binding pocket with only two of them (i.e.…”

Section: Introductionmentioning

confidence: 99%

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

Casazza¹,

Rossi²,

Rizzi³

2011

CTMC

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Kynurenic acid (KYNA), one of the metabolites belonging to the kynurenine pathway, has been described as an important neuroprotective compound, its unbalancing being associated with several pathological conditions. In human brain, the majority of KYNA production is sustained by kynurenine aminotransferase II (KAT II). A selective KAT II inhibitor would be an important pharmacological tool, since it would reduce KYNA formation without causing complete depletion of this neuroprotector. (S)-(4)-(ethylsulfonyl)benzoylalanine (S-ESBA), described as a potent and selective inhibitor of rat KAT II, is unfortunately ineffective towards the human enzyme although the two orthologs share a remarkably high degree of sequence identity. We investigated the molecular basis for this intriguing species-specificity by adopting a site-directed mutagenesis and structural approach. We propose that the source of the inhibitor specificity toward the rat enzyme could reside on S-ESBA interaction/interference with a flexible loop that controls ligand admission to the active site by a classical induced-fit mechanism. Our data further highlights that even in case of highly conserved molecular targets, the flexibility of catalytically important structural elements can have a significant impact on the selectivity of inhibitor action.

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Sequence Variants in Kynurenine Aminotransferase II (KAT II) Orthologs Determine Different Potencies of the Inhibitor S‐ESBA

Cited by 29 publications

References 19 publications

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Study of the Activity and Possible Mechanism of Action of a Reversible Inhibitor of Recombinant Human KAT-2: A Promising Lead in Neurodegenerative and Cognitive Disorders

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

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