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
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...
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| Format: | Article |
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MDPI AG
2016-06-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/21/7/856 |
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| author | Alireza Nematollahi Guanchen Sun Gayan S. Jayawickrama Jane R. Hanrahan W. Bret Church |
| author_facet | Alireza Nematollahi Guanchen Sun Gayan S. Jayawickrama Jane R. Hanrahan W. Bret Church |
| author_sort | Alireza Nematollahi |
| collection | DOAJ |
| description | 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′-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. |
| first_indexed | 2024-12-22T19:07:06Z |
| format | Article |
| id | doaj.art-38f51e7a20c7405fa8f0fd024c3838de |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-22T19:07:06Z |
| publishDate | 2016-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-38f51e7a20c7405fa8f0fd024c3838de2022-12-21T18:15:46ZengMDPI AGMolecules1420-30492016-06-0121785610.3390/molecules21070856molecules21070856Study of the Activity and Possible Mechanism of Action of a Reversible Inhibitor of Recombinant Human KAT-2: A Promising Lead in Neurodegenerative and Cognitive DisordersAlireza Nematollahi0Guanchen Sun1Gayan S. Jayawickrama2Jane R. Hanrahan3W. Bret Church4Group in Biomolecular Structure and Informatics, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, AustraliaGroup in Biomolecular Structure and Informatics, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, AustraliaGroup in Biomolecular Structure and Informatics, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, AustraliaFaculty of Pharmacy, University of Sydney, Sydney, NSW 2006, AustraliaGroup in Biomolecular Structure and Informatics, Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, AustraliaAbnormal 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′-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.http://www.mdpi.com/1420-3049/21/7/856Kynurenine aminotransferase-2(S)-ESBAPF-04859989BFF-122SPR |
| spellingShingle | Alireza Nematollahi Guanchen Sun Gayan S. Jayawickrama Jane R. Hanrahan W. Bret Church 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 Molecules Kynurenine aminotransferase-2 (S)-ESBA PF-04859989 BFF-122 SPR |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Kynurenine aminotransferase-2 (S)-ESBA PF-04859989 BFF-122 SPR |
| url | http://www.mdpi.com/1420-3049/21/7/856 |
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