Electron transfer engineering of artificially designed cell factory for complete biosynthesis of steroids

Qihang Chen, Wenqian Wei, Zikai Chao, Rui Qi, Jianhong He, Huating Chen, Ke Wang, Xinglong Wang, Yijian Rao and Jingwen Zhou ()
Additional contact information
Qihang Chen: 1800 Lihu Road
Wenqian Wei: 1800 Lihu Road
Zikai Chao: 1800 Lihu Road
Rui Qi: 1800 Lihu Road
Jianhong He: 1800 Lihu Road
Huating Chen: 1800 Lihu Road
Ke Wang: 1800 Lihu Road
Xinglong Wang: 1800 Lihu Road
Yijian Rao: 1800 Lihu Road
Jingwen Zhou: 1800 Lihu Road

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58926-9

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