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

汤志军; 胡友财; 刘文

doi:10.12211/2096-8280.2023-081

您当前的位置：

首页 >

文章列表页 >

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

评论 | 更新时间：2025-03-19

- 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
- Enzymatic （4+2）- and （2+2）-cycloaddition reactions: fundamentals and applications of regio- and stereoselectivity
- 合成生物学 2024年5卷第3期页码：401-407
- 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：
  
  [ "汤志军（1990—），男，副研究员。研究方向为复杂天然天然产物的发现、生物合成，蛋白质定向进化与生物催化。E-mail：tangzj@sioc.ac.cn" ]
  [ "胡友财（1978—），男，研究员，博士生导师，中国医学科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副主任。研究方向为药用天然产物生物合成与新药创制。E-mail：huyoucai@imm.ac.cn" ]
  [ "刘文（1971—），男，教授，博士生导师，中国科学院上海有机化学研究所副所长。研究方向为复杂天然产物的生物合成（遗传学、生物化学和化学），以产量提高和结构多样性为目的组合生物合成，以基因组扫描为手段的新型天然产物发现。E-mail：wliu@sioc.ac.cn" ]
- 基金信息：
  
  国家自然科学基金(32030002;22193070;22207116;82225042)
- DOI：10.12211/2096-8280.2023-081
  中图分类号： Q816
- 收稿：2023-11-20，
  
  修回：2023-12-11，
  
  纸质出版：2024-06-30
- 稿件说明：
移动端阅览
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.

关键词

Keywords

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 .

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

卤化酶在生物催化中的应用：机制解析、定向进化和绿色制造的进展

AI+定向进化赋能蛋白改造及优化

合成生物学视角下的基因功能探索与酵母工程菌株文库构建

化学原理驱动的光生物不对称催化研究进展