Gram-Scale Preparation of Cannflavin A from Hemp (<i>Cannabis sativa</i> L.) and Its Inhibitory Effect on Tryptophan Catabolism Enzyme Kynurenine-3-Monooxygenase
Inhibitors targeting kynurenine-3-monooxygenase (KMO), an enzyme in the neurotoxic kynurenine pathway (KP), are potential therapeutics for KP metabolites-mediated neuroinflammatory and neurodegenerative disorders. Although phytochemicals from <i>Cannabis</i> (<i>C. sativa</i>...
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MDPI AG
2022-09-01
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| author | Tess Puopolo Tanran Chang Chang Liu Huifang Li Xu Liu Xian Wu Hang Ma Navindra P. Seeram |
| author_facet | Tess Puopolo Tanran Chang Chang Liu Huifang Li Xu Liu Xian Wu Hang Ma Navindra P. Seeram |
| author_sort | Tess Puopolo |
| collection | DOAJ |
| description | Inhibitors targeting kynurenine-3-monooxygenase (KMO), an enzyme in the neurotoxic kynurenine pathway (KP), are potential therapeutics for KP metabolites-mediated neuroinflammatory and neurodegenerative disorders. Although phytochemicals from <i>Cannabis</i> (<i>C. sativa</i> L.) have been reported to show modulating effects on enzymes involved in the KP metabolism, the inhibitory effects of <i>C. sativa</i> compounds, including phytocannabinoids and non-phytocannabinoids (i.e., cannflavin A; CFA), on KMO remain unknown. Herein, CFA (purified from hemp aerial material at a gram-scale) and a series of phytocannabinoids were evaluated for their anti-KMO activity. CFA showed the most active inhibitory effect on KMO, which was comparable to the positive control Ro 61-8048 (IC<sub>50</sub> = 29.4 vs. 5.1 μM, respectively). Furthermore, a molecular docking study depicted the molecular interactions between CFA and the KMO protein and a biophysical binding assay with surface plasmon resonance (SPR) technique revealed that CFA bound to the protein with a binding affinity of <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mn>4.1</mn><mo>×</mo><msup><mrow><mn>10</mn></mrow><mrow><mo>−</mo><mn>5</mn></mrow></msup><mo> </mo><mi mathvariant="normal">M</mi></mrow></semantics></math></inline-formula>. A competitive SPR binding analysis suggested that CFA and Ro 61-8048 bind to the KMO protein in a competitive manner. Our findings show that <i>C. sativa</i> derived phytochemicals, including CFA, are potential KMO inhibitors, which provides insight into the development of therapeutics targeting the KP and its related pathological conditions. |
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| spelling | doaj.art-4575383c84bf4228ac23121d4e044ecd2023-11-23T22:59:14ZengMDPI AGBiology2079-77372022-09-011110141610.3390/biology11101416Gram-Scale Preparation of Cannflavin A from Hemp (<i>Cannabis sativa</i> L.) and Its Inhibitory Effect on Tryptophan Catabolism Enzyme Kynurenine-3-MonooxygenaseTess Puopolo0Tanran Chang1Chang Liu2Huifang Li3Xu Liu4Xian Wu5Hang Ma6Navindra P. Seeram7Bioactive Botanical Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USAState Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, ChinaBioactive Botanical Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USABioactive Botanical Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USAYunnan Hempmon Pharmaceutical Co., Ltd., Kunming 650032, ChinaDepartment of Kinesiology, Nutrition, and Health, Miami University, Oxford, OH 45056, USABioactive Botanical Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USABioactive Botanical Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USAInhibitors targeting kynurenine-3-monooxygenase (KMO), an enzyme in the neurotoxic kynurenine pathway (KP), are potential therapeutics for KP metabolites-mediated neuroinflammatory and neurodegenerative disorders. Although phytochemicals from <i>Cannabis</i> (<i>C. sativa</i> L.) have been reported to show modulating effects on enzymes involved in the KP metabolism, the inhibitory effects of <i>C. sativa</i> compounds, including phytocannabinoids and non-phytocannabinoids (i.e., cannflavin A; CFA), on KMO remain unknown. Herein, CFA (purified from hemp aerial material at a gram-scale) and a series of phytocannabinoids were evaluated for their anti-KMO activity. CFA showed the most active inhibitory effect on KMO, which was comparable to the positive control Ro 61-8048 (IC<sub>50</sub> = 29.4 vs. 5.1 μM, respectively). Furthermore, a molecular docking study depicted the molecular interactions between CFA and the KMO protein and a biophysical binding assay with surface plasmon resonance (SPR) technique revealed that CFA bound to the protein with a binding affinity of <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mn>4.1</mn><mo>×</mo><msup><mrow><mn>10</mn></mrow><mrow><mo>−</mo><mn>5</mn></mrow></msup><mo> </mo><mi mathvariant="normal">M</mi></mrow></semantics></math></inline-formula>. A competitive SPR binding analysis suggested that CFA and Ro 61-8048 bind to the KMO protein in a competitive manner. Our findings show that <i>C. sativa</i> derived phytochemicals, including CFA, are potential KMO inhibitors, which provides insight into the development of therapeutics targeting the KP and its related pathological conditions.https://www.mdpi.com/2079-7737/11/10/1416<i>Cannabis sativa</i> L.cannflavin Akynurenine pathwaytryptophaninflammationneurodegeneration |
| spellingShingle | Tess Puopolo Tanran Chang Chang Liu Huifang Li Xu Liu Xian Wu Hang Ma Navindra P. Seeram Gram-Scale Preparation of Cannflavin A from Hemp (<i>Cannabis sativa</i> L.) and Its Inhibitory Effect on Tryptophan Catabolism Enzyme Kynurenine-3-Monooxygenase Biology <i>Cannabis sativa</i> L. cannflavin A kynurenine pathway tryptophan inflammation neurodegeneration |
| title | Gram-Scale Preparation of Cannflavin A from Hemp (<i>Cannabis sativa</i> L.) and Its Inhibitory Effect on Tryptophan Catabolism Enzyme Kynurenine-3-Monooxygenase |
| title_full | Gram-Scale Preparation of Cannflavin A from Hemp (<i>Cannabis sativa</i> L.) and Its Inhibitory Effect on Tryptophan Catabolism Enzyme Kynurenine-3-Monooxygenase |
| title_fullStr | Gram-Scale Preparation of Cannflavin A from Hemp (<i>Cannabis sativa</i> L.) and Its Inhibitory Effect on Tryptophan Catabolism Enzyme Kynurenine-3-Monooxygenase |
| title_full_unstemmed | Gram-Scale Preparation of Cannflavin A from Hemp (<i>Cannabis sativa</i> L.) and Its Inhibitory Effect on Tryptophan Catabolism Enzyme Kynurenine-3-Monooxygenase |
| title_short | Gram-Scale Preparation of Cannflavin A from Hemp (<i>Cannabis sativa</i> L.) and Its Inhibitory Effect on Tryptophan Catabolism Enzyme Kynurenine-3-Monooxygenase |
| title_sort | gram scale preparation of cannflavin a from hemp i cannabis sativa i l and its inhibitory effect on tryptophan catabolism enzyme kynurenine 3 monooxygenase |
| topic | <i>Cannabis sativa</i> L. cannflavin A kynurenine pathway tryptophan inflammation neurodegeneration |
| url | https://www.mdpi.com/2079-7737/11/10/1416 |
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