Enzymatic （4+2）- and （2+2）-cycloaddition reactions: fundamentals and applications of regio- and stereoselectivity

TANG Zhijun; HU Youcai; LIU Wen

doi:10.12211/2096-8280.2023-081

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Enzymatic （4+2）- and （2+2）-cycloaddition reactions: fundamentals and applications of regio- and stereoselectivity

Comment | 更新时间：2025-03-19

- Enzymatic （4+2）- and （2+2）-cycloaddition reactions: fundamentals and applications of regio- and stereoselectivity
- Synthetic Biology Journal Vol. 5, Issue 3, Pages: 401-407(2024)
- 作者机构：
  
  1.中国科学院上海有机化学研究所，生命过程小分子调控全国重点实验室，上海 200032
  2.中国医学科学院&北京协和医学院药物研究所，天然药物活性物质与功能国家重点实验室，北京 100050
- 作者简介：
- 基金信息：
- DOI：10.12211/2096-8280.2023-081
  CLC： Q816
- Received：20 November 2023，
  
  Revised：2023-12-11，
  
  Published：30 June 2024
- 稿件说明：
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汤志军，胡友财，刘文. 酶促4+2和2+2环加成反应：区域与立体选择性的理解与应用［J］. 合成生物学， 2024， 5（3）： 401-407

TANG Zhijun， HU Youcai， LIU Wen. Enzymatic （4+2）- and （2+2）-cycloaddition reactions： fundamentals and applications of regio- and stereoselectivity［J］. Synthetic Biology Journal， 2024， 5（3）： 401-407
汤志军，胡友财，刘文. 酶促4+2和2+2环加成反应：区域与立体选择性的理解与应用［J］. 合成生物学， 2024， 5（3）： 401-407 DOI： 10.12211/2096-8280.2023-081.

TANG Zhijun， HU Youcai， LIU Wen. Enzymatic （4+2）- and （2+2）-cycloaddition reactions： fundamentals and applications of regio- and stereoselectivity［J］. Synthetic Biology Journal， 2024， 5（3）： 401-407 DOI： 10.12211/2096-8280.2023-081.

摘要

4+2和2+2环加成反应均是构筑环结构的重要有机化学反应，在复杂天然产物、手性药物的化学合成和生物合成方面有广泛的应用。发现、发展包括4+2和2+2在内的酶促环加成反应，是当前化学生物学研究的热点之一。近期，国际、国内研究团队相继报道了多个酶促4+2和2+2环加成反应，解析了环化酶的蛋白结构和催化机制，设计了新的环化酶，或通过定向进化实现了不同类型环加成反应的区域和立体选择性调控。相关研究为采用合成生物学的策略设计和优化新型环加成酶提供了理论基础和成功范例，有利于促进酶促反应在有机合成领域的应用。

Abstract

The (4+2)- and (2+2)-cycloadditions are important chemical reactions for constructing ring structures

with broad applications in the chemical synthesis and biosynthesis of complex natural products and chiral drugs. The discovery and development of enzymatic cycloaddition reactions

including both (4+2)- and (2+2)-cycloadditions

are currently hot topics in the field of chemical biology. Recently

several international and domestic research groups have successively reported multiple enzymatic (4+2)- and (2+2)-cycloadditions

revealing related protein structures and enzymatic mechanisms

designing new artificial cyclases

and developed different types of regio- and selective cycloaddition reactions through protein engineering. These studies provide a theoretical basis and successful examples for the design and optimization of novel cyclases using synthetic biology strategy

and will promote applications of the enzymatic reactions in organic synthesis.

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references

HUISGEN R . Cycloadditions—Definition, classification, and characterization [J ] . Angewandte Chemie International Edition , 1968 , 7 ( 5 ): 321 - 328 .

JEON B S , WANG S A , RUSZCZYCKY M W , et al . Natural[4+2]-cyclases [J ] . Chemical Reviews , 2017 , 117 ( 8 ): 5367 - 5388 .

TANG Z J , WANG H B , LIU W . Enzyme-associated pericyclic reactions [M/OL ] // Comprehensive natural products Ⅲ . Amsterdam : Elsevier , 2020 : 187 - 227 [2023-10-01] . https://www.sciencedirect.com/science/article/abs/pii/B9780124095472146827?via%3Dihub https://www.sciencedirect.com/science/article/abs/pii/B9780124095472146827?via%3Dihub .

KIM H J , RUSZCZYCKY M W , CHOI S H , et al . Enzyme-catalysed [4+2] cycloaddition is a key step in the biosynthesis of spinosyn A [J ] . Nature , 2011 , 473 ( 7345 ): 109 - 112 .

TIAN Z H , SUN P , YAN Y , et al . An enzymatic [4+2]cyclization cascade creates the pentacyclic core of pyrroindomycins [J ] . Nature Chemical Biology , 2015 , 11 ( 4 ): 259 - 265 .

ZHENG Q F , GUO Y J , YANG L L , et al . Enzyme-dependent[4+2] cycloaddition depends on lid-like interaction of the N-terminal sequence with the catalytic core in PyrI4 [J ] . Cell Chemical Biology , 2016 , 23 ( 3 ): 352 - 360 .

ZHENG Q F , GONG Y K , GUO Y J , et al . Structural insights into a flavin-dependent [4+2 ] cyclase that catalyzes trans -decalin formation in pyrroin domycin biosynthesis [J ] . Cell Chemical Biology , 2018 , 25 ( 6 ): 718 - 727.e3 .

ZOU Y K , YANG S , SANDERS J N , et al . Computational investigation of the mechanism of Diels-Alderase PyrI4 [J ] . Journal of the American Chemical Society , 2020 , 142 ( 47 ): 20232 - 20239 .

LI B , GUAN X Y , YANG S , et al . Mechanism of the stereoselective catalysis of Diels-Alderase PyrE3 involved in pyrroindomycin biosynthesis [J ] . Journal of the American Chemical Society , 2022 , 144 ( 11 ): 5099 - 5107 .

HASHIMOTO T , HASHIMOTO J , TERUYA K , et al . Biosynthesis of versipelostatin: identification of an enzyme-catalyzed [4+2]-cycloaddition required for macrocyclization of spirotetronate-containing polyketides [J ] . Journal of the American Chemical Society , 2015 , 137 ( 2 ): 572 - 575 .

OHASHI M , LIU F , HAI Y , et al . SAM-dependent enzyme-catalysed pericyclic reactions in natural product biosynthesis [J ] . Nature , 2017 , 549 ( 7673 ): 502 - 506 .

ZHANG B , WANG K B , WANG W , et al . Enzyme-catalysed[6+4] cycloadditions in the biosynthesis of natural products [J ] . Nature , 2019 , 568 ( 7750 ): 122 - 126 .

GAO L , SU C , DU X X , et al . FAD-dependent enzyme-catalysed intermolecular [4+2] cycloaddition in natural product biosynthesis [J ] . Nature Chemistry , 2020 , 12 ( 7 ): 620 - 628 .

LITTLE R , PAIVA F C R , JENKINS R , et al . Unexpected enzyme-catalysed [4+2] cycloaddition and rearrangement in polyether antibiotic biosynthesis [J ] . Nature Catalysis , 2019 , 2 ( 11 ): 1045 - 1054 .

SATO M , KISHIMOTO S , YOKOYAMA M , et al . Catalytic mechanism and endo -to- exo selectivity reversion of an octalin-forming natural Diels-Alderase [J ] . Nature Catalysis , 2021 , 4 ( 3 ): 223 - 232 .

OHASHI M , TAN D , LU J Y , et al . Enzymatic cis- decalin formation in natural product biosynthesis [J ] . Journal of the American Chemical Society , 2023 , 145 ( 6 ): 3301 - 3305 .

LIU Z W , RIVERA S , NEWMISTER S A , et al . An NmrA-like enzyme-catalysed redox-mediated Diels-Alder cycloaddition with anti -selectivity [J ] . Nature Chemistry , 2023 , 15 ( 4 ): 526 - 534 .

LIU J W , LU J Y , ZHANG C , et al . Tandem intermolecular[4+2] cycloadditions are catalysed by glycosylated enzymes for natural product biosynthesis [J ] . Nature Chemistry , 2023 , 15 ( 8 ): 1083 - 1090 .

CHEN Q B , GAO J , JAMIESON C , et al . Enzymatic intermolecular Hetero-Diels-Alder reaction in the biosynthesis of tropolonic sesquiterpenes [J ] . Journal of the American Chemical Society , 2019 , 141 ( 36 ): 14052 - 14056 .

SUN N N , HUANG J J , QIAN J Y , et al . Enantioselective[2+2]-cycloadditions with triplet photoenzymes [J ] . Nature , 2022 , 611 ( 7937 ): 715 - 720 .

TRIMBLE J S , CRAWSHAW R , HARDY F J , et al . A designed photoenzyme for enantioselective [2+2] cycloadditions [J ] . Nature , 2022 , 611 ( 7937 ): 709 - 714 .

WANG H B , ZOU Y K , LI M , et al . A cyclase that catalyses competing 2+2 and 4+2 cycloadditions [J ] . Nature Chemistry , 2023 , 15 ( 2 ): 177 - 184 .

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