Evolutionary tuning of a biosynthetic gene cluster drives furanocoumarin accumulation and diversification

Xiaoxu Han; Miaoxian Guo; Peng Yang; Donghua Hu; Yuanxia Chen; Yujie Jia; Hongcui Pei; Jiantao Tan; Elsayed Nishawy; Zefu Lu; Anthony Twamley; Garth Maker; Li Wang

doi:10.1038/s41467-026-74337-w

Evolutionary tuning of a biosynthetic gene cluster drives furanocoumarin accumulation and diversification

Nat Commun. 2026 Jun 16. doi: 10.1038/s41467-026-74337-w. Online ahead of print.

Authors

Xiaoxu Han^#^{1

2

3}, Miaoxian Guo^#^{1

4}, Peng Yang^#², Donghua Hu^{1

5}, Yuanxia Chen¹, Yujie Jia^{1

4}, Hongcui Pei⁶, Jiantao Tan⁷, Elsayed Nishawy^{8

9}, Zefu Lu⁶, Anthony Twamley⁴, Garth Maker³, Li Wang¹⁰

Affiliations

¹ Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Key Laboratory of Synthetic Biology, Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China.
² Hunan Provincial Key Laboratory for Synthetic Biology of Traditional Chinese Medicine, School of Pharmaceutical Sciences, Hunan University of Medicine, Huaihua, China.
³ College of Environmental and Life Sciences, Murdoch University, Murdoch, WA, Australia.
⁴ School of Agriculture and Food Science, University College Dublin, Belfield, Ireland.
⁵ College of Plant Science and Technology, Huazhong Agricultural University, Wuhan, China.
⁶ Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing, China.
⁷ Rice Research Institute, Guangdong Academy of Agricultural Sciences, Key Laboratory of Genetics and Breeding of High-Quality Rice in Southern China (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs, Guangdong Key Laboratory of Rice Science and Technology, Guangdong Rice Engineering Laboratory, Guangzhou, China.
⁸ Laboratory of Genomics and Genome Editing, South Sinai Regional Plant Gene Bank, Desert Research Center, Cairo, Egypt.
⁹ Research, Development and Innovation Center for Converging Sciences and Emerging Technologies (RDI CoSET Center), Benha National University, El-Obour City, Egypt.
¹⁰ Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Key Laboratory of Synthetic Biology, Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China. wangli03@caas.cn.

^# Contributed equally.

PMID: 42304001
DOI: 10.1038/s41467-026-74337-w

Abstract

Deciphering evolutionary drivers of biosynthetic pathways could enhance bioactive compound production. In Angelica, interspecific variation in furanocoumarins (FCs) accumulation reflects divergent pathway evolution. Here, we conduct comparative genomics between high-FC Angelica sensu stricto (s.s.) and low-FC Angelica sensu lato (s.l.) species. We reveal an FC biosynthetic gene cluster (BGC) comprising core enzymes (p-coumaroyl-CoA 2'-hydroxylases (C2'Hs), prenyltransferases (PTs)) and peripheral O-methyltransferases (OMTs). The ancestral Angelica s.l. clade retains an FC BGC configuration with OMTs on separate chromosomes and PTs performing only C-prenylation. In contrast, Angelica s.s. evolves an FC BGC, where core enzymes and OMTs co-localise on the same chromosome, with C2'H copy number expansion correlating with elevated expression and PTs enabling both C- and O-prenylation, collectively enhancing FC production and structural diversity. These findings elucidate how BGC architecture, gene copy number and functional innovation collectively drive phytochemical innovation, providing a blueprint for engineering medicinal FC biosynthesis.

Abstract

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