Electron transfer engineering of artificially designed cell factory for complete biosynthesis of steroids
Abstract Biosynthesis of steroids by artificially designed cell factories often involves numerous nicotinamide adenine dinucleotide phosphate (NADPH)-dependent enzymes that mediate electron transfer reactions. However, the unclear mechanisms of electron transfer from regeneration to the final delive...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58926-9 |
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| _version_ | 1849709752661049344 |
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| author | Qihang Chen Wenqian Wei Zikai Chao Rui Qi Jianhong He Huating Chen Ke Wang Xinglong Wang Yijian Rao Jingwen Zhou |
| author_facet | Qihang Chen Wenqian Wei Zikai Chao Rui Qi Jianhong He Huating Chen Ke Wang Xinglong Wang Yijian Rao Jingwen Zhou |
| author_sort | Qihang Chen |
| collection | DOAJ |
| description | Abstract Biosynthesis of steroids by artificially designed cell factories often involves numerous nicotinamide adenine dinucleotide phosphate (NADPH)-dependent enzymes that mediate electron transfer reactions. However, the unclear mechanisms of electron transfer from regeneration to the final delivery to the NADPH-dependent active centers limit systematically engineering electron transfer to improve steroids production. Here, we elucidate the electron transfer mechanisms of NADPH-dependent enzymes for systematically engineer electron transfer of Saccharomyces cerevisiae, including step-by-step engineering the electron transfer residues of 7-Dehydrocholesterol reductase (DHCR7) and P450 sterol side chain cleaving enzyme (P450scc), electron transfer components for directing carbon flux, and NADPH regeneration pathways, for high-level production of the cholesterol (1.78 g/L) and pregnenolone (0.83 g/L). The electron transfer engineering (ETE) process makes the electron transfer chains shorter and more stable which significantly accelerates deprotonation and proton coupled electron transfer process. This study underscores the significance of ETE strategies in steroids biosynthesis and expands synthetic biology approaches. |
| format | Article |
| id | doaj-art-9f867aaca14747fab044e4b9d52516d3 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-9f867aaca14747fab044e4b9d52516d32025-08-20T03:15:09ZengNature PortfolioNature Communications2041-17232025-04-0116111910.1038/s41467-025-58926-9Electron transfer engineering of artificially designed cell factory for complete biosynthesis of steroidsQihang Chen0Wenqian Wei1Zikai Chao2Rui Qi3Jianhong He4Huating Chen5Ke Wang6Xinglong Wang7Yijian Rao8Jingwen Zhou9Key Laboratory of Industrial Biotechnology, Ministry of Education and School of Biotechnology, Jiangnan University, 1800 Lihu RoadKey Laboratory of Industrial Biotechnology, Ministry of Education and School of Biotechnology, Jiangnan University, 1800 Lihu RoadKey Laboratory of Industrial Biotechnology, Ministry of Education and School of Biotechnology, Jiangnan University, 1800 Lihu RoadKey Laboratory of Industrial Biotechnology, Ministry of Education and School of Biotechnology, Jiangnan University, 1800 Lihu RoadKey Laboratory of Industrial Biotechnology, Ministry of Education and School of Biotechnology, Jiangnan University, 1800 Lihu RoadKey Laboratory of Industrial Biotechnology, Ministry of Education and School of Biotechnology, Jiangnan University, 1800 Lihu RoadKey Laboratory of Industrial Biotechnology, Ministry of Education and School of Biotechnology, Jiangnan University, 1800 Lihu RoadKey Laboratory of Industrial Biotechnology, Ministry of Education and School of Biotechnology, Jiangnan University, 1800 Lihu RoadKey Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education and School of Biotechnology, Jiangnan University, 1800 Lihu RoadKey Laboratory of Industrial Biotechnology, Ministry of Education and School of Biotechnology, Jiangnan University, 1800 Lihu RoadAbstract Biosynthesis of steroids by artificially designed cell factories often involves numerous nicotinamide adenine dinucleotide phosphate (NADPH)-dependent enzymes that mediate electron transfer reactions. However, the unclear mechanisms of electron transfer from regeneration to the final delivery to the NADPH-dependent active centers limit systematically engineering electron transfer to improve steroids production. Here, we elucidate the electron transfer mechanisms of NADPH-dependent enzymes for systematically engineer electron transfer of Saccharomyces cerevisiae, including step-by-step engineering the electron transfer residues of 7-Dehydrocholesterol reductase (DHCR7) and P450 sterol side chain cleaving enzyme (P450scc), electron transfer components for directing carbon flux, and NADPH regeneration pathways, for high-level production of the cholesterol (1.78 g/L) and pregnenolone (0.83 g/L). The electron transfer engineering (ETE) process makes the electron transfer chains shorter and more stable which significantly accelerates deprotonation and proton coupled electron transfer process. This study underscores the significance of ETE strategies in steroids biosynthesis and expands synthetic biology approaches.https://doi.org/10.1038/s41467-025-58926-9 |
| spellingShingle | Qihang Chen Wenqian Wei Zikai Chao Rui Qi Jianhong He Huating Chen Ke Wang Xinglong Wang Yijian Rao Jingwen Zhou Electron transfer engineering of artificially designed cell factory for complete biosynthesis of steroids Nature Communications |
| title | Electron transfer engineering of artificially designed cell factory for complete biosynthesis of steroids |
| title_full | Electron transfer engineering of artificially designed cell factory for complete biosynthesis of steroids |
| title_fullStr | Electron transfer engineering of artificially designed cell factory for complete biosynthesis of steroids |
| title_full_unstemmed | Electron transfer engineering of artificially designed cell factory for complete biosynthesis of steroids |
| title_short | Electron transfer engineering of artificially designed cell factory for complete biosynthesis of steroids |
| title_sort | electron transfer engineering of artificially designed cell factory for complete biosynthesis of steroids |
| url | https://doi.org/10.1038/s41467-025-58926-9 |
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