人工环氧酶重塑混源萜类天然产物合成路径

孙玉莉; 叶宇轩

doi:10.12211/2096-8280.2026-097

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人工环氧酶重塑混源萜类天然产物合成路径

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- 人工环氧酶重塑混源萜类天然产物合成路径
- Artificial Epoxidase Streamlines Meroterpenoid Synthesis
- 合成生物学 2026年页码：1-7
- 作者机构：
  
  西湖大学，浙江省功能分子精密合成重点实验室，浙江杭州 310030
- 作者简介：
  
  孙玉莉（1994—），女，助理研究员，博士，研究方向为新酶创制与应用。
  叶宇轩（1991—），男，特聘研究员，博士，博士生导师。研究方向为新酶创制与应用。
- 基金信息：
  
  国家重点研发计划(2022YFA1505600);国家自然科学基金(22471223);浙江省重点实验室建设项目(202SZY01063);浙江省自然科学基金(XHD24B0101);化学-生物合成国家重点实验室开放项目(sklscbs202502)
- DOI：10.12211/2096-8280.2026-097
  中图分类号： Q816
- 收稿：2026-09-02，
  
  修回：2026-10-23，
  
  网络首发：2026-10-28，
- 稿件说明：
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孙玉莉，叶宇轩. 人工环氧酶重塑混源萜类天然产物合成路径［J］. 合成生物学， 2026， 7. DOI： 10.12211/2096-8280.2026-097

SUN Yuli， YE Yuxuan. Artificial Epoxidase Streamlines Meroterpenoid Synthesis［J］. Synthetic Biology Journal， 2026， 7. DOI： 10.12211/2096-8280.2026-097
孙玉莉，叶宇轩. 人工环氧酶重塑混源萜类天然产物合成路径［J］. 合成生物学， 2026， 7. DOI： 10.12211/2096-8280.2026-097 DOI：

SUN Yuli， YE Yuxuan. Artificial Epoxidase Streamlines Meroterpenoid Synthesis［J］. Synthetic Biology Journal， 2026， 7. DOI： 10.12211/2096-8280.2026-097 DOI：

摘要

烯烃不对称环氧化是构建手性含氧结构的重要反应，在生物活性分子合成中具有广泛应用。经典小分子催化体系已能够高效实现多类烯烃的不对称环氧化，但对于缺乏近端导向基团、处于相似化学环境中的多个烯烃，实现位点选择性和立体选择性的协同控制仍具有挑战。近期，上海交通大学李健团队与中国医学科学院药用植物研究所张卫东团队通过定向进化将P450BM3改造为高区域选择性和对映选择性的人工环氧酶EPO6，实现了法尼醇内部C6=C7双键的选择性不对称环氧化，并完成十克级产物制备。在此基础上，作者将酶催化与多烯环化等化学转化相结合，以显著缩短的路线完成多种混源萜类天然产物的合成。该工作为化学–酶法协同的复杂分子高效合成提供了新的研究范式。本文介绍该人工环氧酶的开发及其在天然产物全合成中的应用，重点分析酶催化独特的分子识别能力如何突破传统化学催化中的位点选择性限制，并讨论生物催化如何通过创造传统方法难以实现的逆合成切断，拓展复杂分子的合成设计空间。

Abstract

Asymmetric epoxidation of alkenes is an important transformation for constructing chiral oxygenated motifs and has been widely applied in the synthesis of complex natural products and pharmaceuticals. Although small-molecule catalysts have enabled highly efficient asymmetric epoxidation of diverse alkenes

simultaneous control over site- and stereoselectivity remains challenging. Recently

the groups led by LI Jian at Shanghai Jiao Tong University and ZHANG Weidong at the Institute of Medicinal Plant Development

Chinese Academy of Medical Sciences

engineered P450

BM3

into a highly regio- and enantioselective artificial epoxidase

EPO6. The evolved enzyme selectively epoxidizes the internal C6=C7 alkene of farnesol and enables decagram-scale preparation of the corresponding chiral epoxide. By integrating this biocatalytic transformation with chemical reactions

the authors substantially streamlined the synthesis of a number of terpenoid natural products. This work illustrates that engineered enzymes can provide transformations with selectivity profiles complementary to those of small-molecule catalysts

thereby creating unconventional retrosynthetic disconnections and expanding the design space for complex-molecule synthesis. This article discusses the development of the artificial epoxidase and its application in natural product synthesis

with particular emph

asis on how enzyme-mediated molecular recognition can overcome site-selectivity limitations encountered in conventional chemical catalysis.

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references

XIA Q H , GE H Q , YE C P , et al . Advances in homogeneous and heterogeneous catalytic asymmetric epoxidation [J ] . Chemical Reviews , 2005 , 105 ( 5 ): 1603 - 1662 .

曾涛 , 张曙盛 , 付建国 , 等 . 防风中亥茅酚及亥茅酚苷的不对称合成 [J ] . 有机化学 , 2024 , 44 ( 9 ): 2862 - 2868 .

ZENG T , ZHAG S S , FU J G , et al . Asymmetric Synthesis of Hamaudol and sec-O-Glucosylhamaudol in Saposhnikovia divaricata (Turcz.) Schischk [J ] . Chin . J . Org. Chem. 2024 , 44 ( 9 ): 2862 - 2868 .

ABE H , FUJIMAKI M , NAKAGAWA E , et al . Enantioselective total synthesis of sagittacin E and related natural products [J ] . Chemical Communications , 2018 , 54 ( 49 ): 6165 - 6168 .

KATSUKI T , SHARPLESS K B . The first practical method for asymmetric epoxidation [J ] . Journal of the American Chemical Society , 1980 , 102 ( 18 ): 5974 - 5976 .

TU Y , WANG Z X , SHI Y . An efficient asymmetric epoxidation method for trans-olefins mediated by a fructose-derived chiral ketone [J ] . Journal of the American Chemical Society , 1996 , 118 ( 40 ): 9806 - 9807 .

ZHANG W , LOEBACH J L , WILSON S R , et al . Enantioselective epoxidation of unfunctionalized olefins catalyzed by (salen)manganese complexes [J ] . Journal of the American Chemical Society , 1990 , 112 ( 7 ): 2801 - 2803 .

SNYDER S A , COREY E J . Concise total syntheses of palominol, dolabellatrienone, β-araneosene, and isoedunol via an enantioselective Diels-Alder macrobicyclization [J ] . Journal of the American Chemical Society , 2006 , 128 ( 3 ): 740 - 742 .

SURENDRA K , COREY E J . A short enantioselective total synthesis of the fundamental pentacyclic triterpene lupeol [J ] . Journal of the American Chemical Society , 2009 , 131 ( 39 ): 13928 - 13929 .

BARRETT A G M , MA T K , MIES T . Recent developments in polyene cyclizations and their applications in natural product synthesis [J ] . Synthesis , 2019 , 51 ( 1 ): 67 - 82 .

COREY E J , HA D C . Total synthesis of venustatriol [J ] . Tetrahedron Letters , 1988 , 29 ( 26 ): 3171 - 3174 .

CARRERAS J , LIVENDAHL M , MCGONIGAL P R , et al . Gold(I) as an artificial cyclase: short stereodivergent syntheses of (-)-epiglobulol and (-)-4β,7α- and (-)-4α,7α-aromadendrandenoids [J ] . Angewandte Chemie International Edition , 2014 , 53 ( 19 ): 4896 - 4899 .

FOO K , USUI I , GOTZ D C G , et al . Scalable, enantioselective synthesis of germacrenes and related sesquiterpenes inspired by terpene cyclase phase logic [J ] . Angewandte Chemie International Edition , 2012 , 51 ( 46 ): 11491 - 11495 .

VILOTIJEVIC I , JAMISON T F . Epoxide-opening cascades in the synthesis of polycyclic polyether natural products [J ] . Angewandte Chemie International Edition , 2009 , 48 ( 29 ): 5250 - 5281 .

LICHTOR P A , MILLER S J . Combinatorial evolution of site- and enantioselective catalysts for polyene epoxidation [J ] . Nature Chemistry , 2012 , 4 ( 12 ): 990 - 995 .

ZWICK C R III , RENATA H . Harnessing the biocatalytic potential of iron- and α-ketoglutarate-dependent dioxygenases in natural product total synthesis [J ] . Natural Product Reports , 2020 , 37 ( 8 ): 1065 - 1079 .

LI J , AMATUNI A , RENATA H . Recent advances in the chemoenzymatic synthesis of bioactive natural products [J ] . Current Opinion in Chemical Biology , 2020 , 55 : 111 - 118 .

HONG B K , LUO T P , LEI X G . Late-stage diversification of natural products [J ] . ACS Central Science , 2020 , 6 ( 5 ): 622 - 635 .

WANG J X , YIN Y P , ZHANG Q , et al . Artificial farnesol epoxidase enables a concise synthesis of meroterpenoids [J ] . Science , 2025 , 389 ( 6716 ): 732 - 735 .

张发光 , 曲戈 , 孙周通 , 等 . 从化学合成到生物合成—天然产物全合成新趋势 [J ] . 合成生物学 , 2021 , 2 ( 5 ): 674 - 696 .

ZHANG F G , QU G , SUN Z T , et al . From chemical synthesis to biosynthesis: trends toward total synthesis of natural products [J ] . Synthetic Biology Journal , 2021 , 2 ( 5 ): 674 - 696 .

SAVILE C K , JANEY J M , MUNDORFF E C , et al . Biocatalytic asymmetric synthesis of chiral amines from ketones applied to sitagliptin manufacture [J ] . Science , 2010 , 329 ( 5989 ): 305 - 309 .

PENG C , WU W L , YE Y X , et al . 16-step scalable chemoenzymatic synthesis of tetrodotoxin [J ] . Journal of the American Chemical Society , 2026 , 148 ( 5 ): 4873 - 4879 .

LI J , LI F Z , KING-SMITH E , et al . Merging chemoenzymatic and radical-based retrosynthetic logic for rapid and modular synthesis of oxidized meroterpenoids [J ] . Nature Chemistry , 2020 , 12 ( 2 ): 173 - 179 .

CUI H Y , SU Y F , DEAN T J , et al . Enzyme specificity prediction using cross-attention graph neural networks [J ] . Nature , 2025 , 647 ( 8090 ): 639 - 647 .

WANG H , GAO B , CHENG H L , et al . Unmasking the reverse catalytic activity of 'ene'-reductases for asymmetric carbonyl desaturation [J ] . Nature Chemistry , 2024 , 17 ( 1 ): 74 - 82 .

CAO S X , ZHU Y Y , LEI J C , et al . Biocatalytic site- and stereoselective carbonyl desaturation for late-stage functionalization of cyclic ketones [J ] . Nature Chemistry , 2026 , 18 ( 4 ): 731 - 740 .

YANG W , WANG S Z , LEE G R , et al . The past, present and future of de novo protein design [J ] . Nature , 2026 , 652 ( 8112 ): 1139 - 1152 .

KIM D , WOODBURY S M , AHERN W , et al . Computational design of metallohydrolases [J ] . Nature , 2026 , 649 ( 8095 ): 246 - 253 .

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