A cytochrome P450 CYP87A4 imparts sterol side-chain cleavage in digoxin biosynthesis
Abstract Digoxin extracted from the foxglove plant is a widely prescribed natural product for treating heart failure. It is listed as an essential medicine by the World Health Organization. However, how the foxglove plant synthesizes digoxin is mostly unknown, especially the cytochrome P450 sterol s...
| Main Authors: | , , , , |
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| Format: | Article |
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Nature Portfolio
2023-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39719-4 |
| _version_ | 1797784555116036096 |
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| author | Emily Carroll Baradwaj Ravi Gopal Indu Raghavan Minakshi Mukherjee Zhen Q. Wang |
| author_facet | Emily Carroll Baradwaj Ravi Gopal Indu Raghavan Minakshi Mukherjee Zhen Q. Wang |
| author_sort | Emily Carroll |
| collection | DOAJ |
| description | Abstract Digoxin extracted from the foxglove plant is a widely prescribed natural product for treating heart failure. It is listed as an essential medicine by the World Health Organization. However, how the foxglove plant synthesizes digoxin is mostly unknown, especially the cytochrome P450 sterol side chain cleaving enzyme (P450scc), which catalyzes the first and rate-limiting step. Here we identify the long-speculated foxglove P450scc through differential transcriptomic analysis. This enzyme converts cholesterol and campesterol to pregnenolone, suggesting that digoxin biosynthesis starts from both sterols, unlike previously reported. Phylogenetic analysis indicates that this enzyme arises from a duplicated cytochrome P450 CYP87A gene and is distinct from the well-characterized mammalian P450scc. Protein structural analysis reveals two amino acids in the active site critical for the foxglove P450scc’s sterol cleavage ability. Identifying the foxglove P450scc is a crucial step toward completely elucidating digoxin biosynthesis and expanding the therapeutic applications of digoxin analogs in future work. |
| first_indexed | 2024-03-13T00:41:34Z |
| format | Article |
| id | doaj.art-55aa15c6be9c488f94797f5dd2c20c9b |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T00:41:34Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj.art-55aa15c6be9c488f94797f5dd2c20c9b2023-07-09T11:17:39ZengNature PortfolioNature Communications2041-17232023-07-0114111110.1038/s41467-023-39719-4A cytochrome P450 CYP87A4 imparts sterol side-chain cleavage in digoxin biosynthesisEmily Carroll0Baradwaj Ravi Gopal1Indu Raghavan2Minakshi Mukherjee3Zhen Q. Wang4Department of Biological Sciences, University at Buffalo, the State University of New YorkDepartment of Biological Sciences, University at Buffalo, the State University of New YorkDepartment of Biological Sciences, University at Buffalo, the State University of New YorkDepartment of Biological Sciences, University at Buffalo, the State University of New YorkDepartment of Biological Sciences, University at Buffalo, the State University of New YorkAbstract Digoxin extracted from the foxglove plant is a widely prescribed natural product for treating heart failure. It is listed as an essential medicine by the World Health Organization. However, how the foxglove plant synthesizes digoxin is mostly unknown, especially the cytochrome P450 sterol side chain cleaving enzyme (P450scc), which catalyzes the first and rate-limiting step. Here we identify the long-speculated foxglove P450scc through differential transcriptomic analysis. This enzyme converts cholesterol and campesterol to pregnenolone, suggesting that digoxin biosynthesis starts from both sterols, unlike previously reported. Phylogenetic analysis indicates that this enzyme arises from a duplicated cytochrome P450 CYP87A gene and is distinct from the well-characterized mammalian P450scc. Protein structural analysis reveals two amino acids in the active site critical for the foxglove P450scc’s sterol cleavage ability. Identifying the foxglove P450scc is a crucial step toward completely elucidating digoxin biosynthesis and expanding the therapeutic applications of digoxin analogs in future work.https://doi.org/10.1038/s41467-023-39719-4 |
| spellingShingle | Emily Carroll Baradwaj Ravi Gopal Indu Raghavan Minakshi Mukherjee Zhen Q. Wang A cytochrome P450 CYP87A4 imparts sterol side-chain cleavage in digoxin biosynthesis Nature Communications |
| title | A cytochrome P450 CYP87A4 imparts sterol side-chain cleavage in digoxin biosynthesis |
| title_full | A cytochrome P450 CYP87A4 imparts sterol side-chain cleavage in digoxin biosynthesis |
| title_fullStr | A cytochrome P450 CYP87A4 imparts sterol side-chain cleavage in digoxin biosynthesis |
| title_full_unstemmed | A cytochrome P450 CYP87A4 imparts sterol side-chain cleavage in digoxin biosynthesis |
| title_short | A cytochrome P450 CYP87A4 imparts sterol side-chain cleavage in digoxin biosynthesis |
| title_sort | cytochrome p450 cyp87a4 imparts sterol side chain cleavage in digoxin biosynthesis |
| url | https://doi.org/10.1038/s41467-023-39719-4 |
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