Melatonin Activation by Cytochrome P450 Isozymes: How Does CYP1A2 Compare to CYP1A1?
Cytochrome P450 enzymes are versatile enzymes found in most biosystems that catalyze mono-oxygenation reactions as a means of biosynthesis and biodegradation steps. In the liver, they metabolize xenobiotics, but there are a range of isozymes with differences in three-dimensional structure and protei...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/4/3651 |
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| author | Thirakorn Mokkawes Sam P. de Visser |
| author_facet | Thirakorn Mokkawes Sam P. de Visser |
| author_sort | Thirakorn Mokkawes |
| collection | DOAJ |
| description | Cytochrome P450 enzymes are versatile enzymes found in most biosystems that catalyze mono-oxygenation reactions as a means of biosynthesis and biodegradation steps. In the liver, they metabolize xenobiotics, but there are a range of isozymes with differences in three-dimensional structure and protein chain. Consequently, the various P450 isozymes react with substrates differently and give varying product distributions. To understand how melatonin is activated by the P450s in the liver, we did a thorough molecular dynamics and quantum mechanics study on cytochrome P450 1A2 activation of melatonin forming 6-hydroxymelatonin and <i>N</i>-acetylserotonin products through aromatic hydroxylation and <i>O</i>-demethylation pathways, respectively. We started from crystal structure coordinates and docked substrate into the model, and obtained ten strong binding conformations with the substrate in the active site. Subsequently, for each of the ten substrate orientations, long (up to 1 μs) molecular dynamics simulations were run. We then analyzed the orientations of the substrate with respect to the heme for all snapshots. Interestingly, the shortest distance does not correspond to the group that is expected to be activated. However, the substrate positioning gives insight into the protein residues it interacts with. Thereafter, quantum chemical cluster models were created and the substrate hydroxylation pathways calculated with density functional theory. These relative barrier heights confirm the experimental product distributions and highlight why certain products are obtained. We make a detailed comparison with previous results on CYP1A1 and identify their reactivity differences with melatonin. |
| first_indexed | 2024-03-11T08:43:02Z |
| format | Article |
| id | doaj.art-7b8d200db3714f0ea0b35f785235f989 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T08:43:02Z |
| publishDate | 2023-02-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-7b8d200db3714f0ea0b35f785235f9892023-11-16T21:02:59ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01244365110.3390/ijms24043651Melatonin Activation by Cytochrome P450 Isozymes: How Does CYP1A2 Compare to CYP1A1?Thirakorn Mokkawes0Sam P. de Visser1Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UKManchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UKCytochrome P450 enzymes are versatile enzymes found in most biosystems that catalyze mono-oxygenation reactions as a means of biosynthesis and biodegradation steps. In the liver, they metabolize xenobiotics, but there are a range of isozymes with differences in three-dimensional structure and protein chain. Consequently, the various P450 isozymes react with substrates differently and give varying product distributions. To understand how melatonin is activated by the P450s in the liver, we did a thorough molecular dynamics and quantum mechanics study on cytochrome P450 1A2 activation of melatonin forming 6-hydroxymelatonin and <i>N</i>-acetylserotonin products through aromatic hydroxylation and <i>O</i>-demethylation pathways, respectively. We started from crystal structure coordinates and docked substrate into the model, and obtained ten strong binding conformations with the substrate in the active site. Subsequently, for each of the ten substrate orientations, long (up to 1 μs) molecular dynamics simulations were run. We then analyzed the orientations of the substrate with respect to the heme for all snapshots. Interestingly, the shortest distance does not correspond to the group that is expected to be activated. However, the substrate positioning gives insight into the protein residues it interacts with. Thereafter, quantum chemical cluster models were created and the substrate hydroxylation pathways calculated with density functional theory. These relative barrier heights confirm the experimental product distributions and highlight why certain products are obtained. We make a detailed comparison with previous results on CYP1A1 and identify their reactivity differences with melatonin.https://www.mdpi.com/1422-0067/24/4/3651enzyme catalysismolecular dynamicsquantum mechanicsinorganic reaction mechanismshydroxylationregioselectivity |
| spellingShingle | Thirakorn Mokkawes Sam P. de Visser Melatonin Activation by Cytochrome P450 Isozymes: How Does CYP1A2 Compare to CYP1A1? International Journal of Molecular Sciences enzyme catalysis molecular dynamics quantum mechanics inorganic reaction mechanisms hydroxylation regioselectivity |
| title | Melatonin Activation by Cytochrome P450 Isozymes: How Does CYP1A2 Compare to CYP1A1? |
| title_full | Melatonin Activation by Cytochrome P450 Isozymes: How Does CYP1A2 Compare to CYP1A1? |
| title_fullStr | Melatonin Activation by Cytochrome P450 Isozymes: How Does CYP1A2 Compare to CYP1A1? |
| title_full_unstemmed | Melatonin Activation by Cytochrome P450 Isozymes: How Does CYP1A2 Compare to CYP1A1? |
| title_short | Melatonin Activation by Cytochrome P450 Isozymes: How Does CYP1A2 Compare to CYP1A1? |
| title_sort | melatonin activation by cytochrome p450 isozymes how does cyp1a2 compare to cyp1a1 |
| topic | enzyme catalysis molecular dynamics quantum mechanics inorganic reaction mechanisms hydroxylation regioselectivity |
| url | https://www.mdpi.com/1422-0067/24/4/3651 |
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