Divergent multifunctional P450s-empowered biosynthesis of bioactive tripterifordin and cryptic atiserenoids in Aconitum implies convergent evolution

Fei Luo, Qian Zhou, Feilong Chen, Xinyu Liu, Tsan-Yu Chiu, Guo-Yuan Zhu and Ancheng C. Huang ()
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Fei Luo: Southern University of Science and Technology
Qian Zhou: Southern University of Science and Technology
Feilong Chen: Southern University of Science and Technology
Xinyu Liu: Southern University of Science and Technology
Tsan-Yu Chiu: BGI Research
Guo-Yuan Zhu: Macau University of Science and Technology
Ancheng C. Huang: Southern University of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Diterpenoids exhibit remarkable structural diversity and bioactivities, shaped primarily by the tandem actions of skeleton-forming terpene synthases (TPSs) and cytochrome P450 monooxygenases. The ent-kaurene and ent-atiserene are labdane-derived diterpene scaffolds for the biosynthesis of diverse bioactive diterpenoids and diterpene alkaloids, including the clinically used analgesic 3-acetylaconitine and anti-arrhythmic guan-fu base A in Aconitum spp., yet what and how P450s drive their structural and functional diversification remain largely unexplored. Here, via mining the transcriptomes of Aconitum carmichaelii and Aconitum coreanum followed by functional validation, we discover nine TPSs capable of furnishing the ent-kaurene, ent-atiserene or 16α-hydroxy-ent-kaurene scaffold and 14 divergent P450s, of which eight are multifunctional, catalyzing oxidation at seven different sites of the scaffolds. Protein analysis and mutagenesis experiments reveal key residues tuning the P450 activity and product profiles, shedding light on how they diverge functionally. The discovered TPSs and P450s enable combinatorial biosynthesis of tripterifordin, guan-fu diterpenoid A, and 14 novel atiserenoids, with some exhibiting allelopathic activity. Intriguingly, Tripterygium wilfordii-derived tripterifordin was detected in A. coreanum, revealing convergent biosynthesis of tripterifordin. Our findings highlight P450 plasticity in selective diterpene oxidation and allow for accessing tripterifordin and derivatives, paving ways for elucidating downstream diterpenoid pathways via synthetic biology.

Date: 2025
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DOI: 10.1038/s41467-025-61188-0

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