Selective and competitive inhibition of kynurenine aminotransferase 2 by glycyrrhizic acid and its analogues

Yukihiro Yoshida, Hidetsugu Fujigaki, Koichi Kato, Kyoka Yamazaki, Suwako Fujigaki, Kazuo Kunisawa, Yasuko Yamamoto, Akihiro Mouri, Akifumi Oda, Toshitaka Nabeshima, Kuniaki Saito

Research output: Contribution to journalArticle

Abstract

The enzyme kynurenine aminotransferase (KAT) catalyses the conversion of kynurenine (KYN) to kynurenic acid (KYNA). Although the isozymes KAT1–4 have been identified, KYNA is mainly produced by KAT2 in brain tissues. KNYA is an antagonist of N-methyl-D-aspartate and α-7-nicotinic acetylcholine receptors, and accumulation of KYNA in the brain has been associated with the pathology of schizophrenia. Therefore, KAT2 could be exploited as a therapeutic target for the management of schizophrenia. Although currently available KAT2 inhibitors irreversibly bind to pyridoxal 5′-phosphate (PLP), inhibition via this mechanism may cause adverse side effects because of the presence of other PLP-dependent enzymes. Therefore, we identified novel selective KAT2 inhibitors by screening approximately 13,000 molecules. Among these, glycyrrhizic acid (GL) and its analogues, glycyrrhetinic acid (GA) and carbenoxolone (CBX), were identified as KAT2 inhibitors. These compounds were highly selective for KAT2 and competed with its substrate KYN, but had no effects on the other 3 KAT isozymes. Furthermore, we demonstrated that in complex structures that were predicted in docking calculations, GL, GA and CBX were located on the same surface as the aromatic ring of KYN. These results indicate that GL and its analogues are highly selective and competitive inhibitors of KAT2.

Original languageEnglish
Article number10243
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - 01-12-2019

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kynurenine-oxoglutarate transaminase
Glycyrrhizic Acid
Kynurenic Acid
Kynurenine
Carbenoxolone
Glycyrrhetinic Acid
Pyridoxal Phosphate
Isoenzymes
Schizophrenia
Brain
Nicotinic Receptors
N-Methylaspartate
Enzymes
Pathology
Inhibition (Psychology)

All Science Journal Classification (ASJC) codes

  • General

Cite this

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title = "Selective and competitive inhibition of kynurenine aminotransferase 2 by glycyrrhizic acid and its analogues",
abstract = "The enzyme kynurenine aminotransferase (KAT) catalyses the conversion of kynurenine (KYN) to kynurenic acid (KYNA). Although the isozymes KAT1–4 have been identified, KYNA is mainly produced by KAT2 in brain tissues. KNYA is an antagonist of N-methyl-D-aspartate and α-7-nicotinic acetylcholine receptors, and accumulation of KYNA in the brain has been associated with the pathology of schizophrenia. Therefore, KAT2 could be exploited as a therapeutic target for the management of schizophrenia. Although currently available KAT2 inhibitors irreversibly bind to pyridoxal 5′-phosphate (PLP), inhibition via this mechanism may cause adverse side effects because of the presence of other PLP-dependent enzymes. Therefore, we identified novel selective KAT2 inhibitors by screening approximately 13,000 molecules. Among these, glycyrrhizic acid (GL) and its analogues, glycyrrhetinic acid (GA) and carbenoxolone (CBX), were identified as KAT2 inhibitors. These compounds were highly selective for KAT2 and competed with its substrate KYN, but had no effects on the other 3 KAT isozymes. Furthermore, we demonstrated that in complex structures that were predicted in docking calculations, GL, GA and CBX were located on the same surface as the aromatic ring of KYN. These results indicate that GL and its analogues are highly selective and competitive inhibitors of KAT2.",
author = "Yukihiro Yoshida and Hidetsugu Fujigaki and Koichi Kato and Kyoka Yamazaki and Suwako Fujigaki and Kazuo Kunisawa and Yasuko Yamamoto and Akihiro Mouri and Akifumi Oda and Toshitaka Nabeshima and Kuniaki Saito",
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Selective and competitive inhibition of kynurenine aminotransferase 2 by glycyrrhizic acid and its analogues. / Yoshida, Yukihiro; Fujigaki, Hidetsugu; Kato, Koichi; Yamazaki, Kyoka; Fujigaki, Suwako; Kunisawa, Kazuo; Yamamoto, Yasuko; Mouri, Akihiro; Oda, Akifumi; Nabeshima, Toshitaka; Saito, Kuniaki.

In: Scientific reports, Vol. 9, No. 1, 10243, 01.12.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Selective and competitive inhibition of kynurenine aminotransferase 2 by glycyrrhizic acid and its analogues

AU - Yoshida, Yukihiro

AU - Fujigaki, Hidetsugu

AU - Kato, Koichi

AU - Yamazaki, Kyoka

AU - Fujigaki, Suwako

AU - Kunisawa, Kazuo

AU - Yamamoto, Yasuko

AU - Mouri, Akihiro

AU - Oda, Akifumi

AU - Nabeshima, Toshitaka

AU - Saito, Kuniaki

PY - 2019/12/1

Y1 - 2019/12/1

N2 - The enzyme kynurenine aminotransferase (KAT) catalyses the conversion of kynurenine (KYN) to kynurenic acid (KYNA). Although the isozymes KAT1–4 have been identified, KYNA is mainly produced by KAT2 in brain tissues. KNYA is an antagonist of N-methyl-D-aspartate and α-7-nicotinic acetylcholine receptors, and accumulation of KYNA in the brain has been associated with the pathology of schizophrenia. Therefore, KAT2 could be exploited as a therapeutic target for the management of schizophrenia. Although currently available KAT2 inhibitors irreversibly bind to pyridoxal 5′-phosphate (PLP), inhibition via this mechanism may cause adverse side effects because of the presence of other PLP-dependent enzymes. Therefore, we identified novel selective KAT2 inhibitors by screening approximately 13,000 molecules. Among these, glycyrrhizic acid (GL) and its analogues, glycyrrhetinic acid (GA) and carbenoxolone (CBX), were identified as KAT2 inhibitors. These compounds were highly selective for KAT2 and competed with its substrate KYN, but had no effects on the other 3 KAT isozymes. Furthermore, we demonstrated that in complex structures that were predicted in docking calculations, GL, GA and CBX were located on the same surface as the aromatic ring of KYN. These results indicate that GL and its analogues are highly selective and competitive inhibitors of KAT2.

AB - The enzyme kynurenine aminotransferase (KAT) catalyses the conversion of kynurenine (KYN) to kynurenic acid (KYNA). Although the isozymes KAT1–4 have been identified, KYNA is mainly produced by KAT2 in brain tissues. KNYA is an antagonist of N-methyl-D-aspartate and α-7-nicotinic acetylcholine receptors, and accumulation of KYNA in the brain has been associated with the pathology of schizophrenia. Therefore, KAT2 could be exploited as a therapeutic target for the management of schizophrenia. Although currently available KAT2 inhibitors irreversibly bind to pyridoxal 5′-phosphate (PLP), inhibition via this mechanism may cause adverse side effects because of the presence of other PLP-dependent enzymes. Therefore, we identified novel selective KAT2 inhibitors by screening approximately 13,000 molecules. Among these, glycyrrhizic acid (GL) and its analogues, glycyrrhetinic acid (GA) and carbenoxolone (CBX), were identified as KAT2 inhibitors. These compounds were highly selective for KAT2 and competed with its substrate KYN, but had no effects on the other 3 KAT isozymes. Furthermore, we demonstrated that in complex structures that were predicted in docking calculations, GL, GA and CBX were located on the same surface as the aromatic ring of KYN. These results indicate that GL and its analogues are highly selective and competitive inhibitors of KAT2.

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