酶催化杂Diels-Alder反应

doi:10.12211/2096-8280.2023-015

合成生物学 ›› 2024, Vol. 5 ›› Issue (1): 107-125.DOI: 10.12211/2096-8280.2023-015

酶催化杂Diels-Alder反应

王翠珍¹, 陈窕¹, 王健博¹^,²

^1.湖南师范大学化学化工学院，化学生物学及中药分析教育部重点实验室，植化单体开发与利用湖南省重点实验室，湖南长沙 410081
^2.浙江大学基础医学院药物生物技术研究所，浙江大学医学院附属第二医院综合ICU科室，浙江杭州 310030

收稿日期:2023-02-21 修回日期:2023-05-29 出版日期:2024-02-29 发布日期:2024-03-20
通讯作者: 王健博
作者简介:王翠珍（1998—），女，硕士研究生。研究方向为酶催化碳氟键断裂以及活化。 E-mail：wangcuizhen1998@163.com
陈窕（2000—），女，硕士研究生。研究方向为糖基转移酶催化机理的研究。 E-mail：chentiao1208@163.com
王健博（1982—），男，博士，研究员，博士生导师。研究方向为酶的催化机理以及按需定制。 E-mail：jwang2023@zju.edu.cn
基金资助:
国家自然科学基金(22077029);湖南省自然科学基金杰出青年项目(2021JJ10034)

Enzyme-catalyzed Hetero-Diels-Alder reactions

Cuizhen WANG¹, Tiao CHEN¹, Jianbo WANG¹^,²

^1.Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research （Ministry of Education），Key Laboratory of Phytochemical R & D of Human Province，College of Chemistry and Chemical Engineering，Hunan Normal University，Changsha 410081，Hunan，China
^2.Institute of Pharmaceutical Biotechnology，School of Basic Medical Sciences，Zhejiang University and Department of Integrated ICU，The Second Hospital Affiliated to Zhejiang University School of Medicine，Hangzhou 310030，Zhejiang，China

Received:2023-02-21 Revised:2023-05-29 Online:2024-02-29 Published:2024-03-20
Contact: Jianbo WANG

摘要/Abstract

摘要：

Diels-Alder反应被认为是合成复杂天然产物的最有效的方法之一，一直以来都深受化学家的关注。而杂原子参与的HDA（Hetero-Diels-Alder）反应是合成各种天然杂环的重要工具，其中以氧杂DA反应和氮杂DA反应最为常见。酶催化HDA反应以其绿色温和、高效、高选择性等优势受到人们广泛关注。随着杂环天然产物中酶催化HDA反应的不断发现，对HDA相关酶的立体选择性、底物特异性的研究也不断深入，有效促进了人们对这一类酶序列与功能关系的了解，为其挖掘和改造奠定了基础。本文集中对目前已知的酶催化HDA反应合成杂环天然产物的成果进行概述，主要包括吡喃类化合物和吲哚生物碱生物合成中涉及的酶促HDA反应，以期通过对途径和催化机理的分析，为发展新的相关生物催化剂用于合成非天然的杂环产物提供思路。

关键词: Hetero-Diels-Alder反应, 酶, 杂原子, 吡喃类化合物, 吲哚生物碱

Abstract:

The Diels-Alder reaction is a chemical process where a conjugated diene reacts with a dienophile to form cyclohexene. This reaction can generate up to four adjacent chiral centers and two carbon-carbon bonds simultaneously, making it an effective method to form C—C bonds. Therefore, it has attracted wide attention. Hetero-Diels-Alder (HDA) reactions, which involve heteroatoms, are an important tool for synthesizing natural heterocyclic rings. HAD reaction types are classified according to the heteroatoms involved, with the most common types being oxa Diels-Alder reaction and aza Diels-Alder reaction. At present, non-enzyme catalysts have been successfully applied to catalyze HDA reactions, which are catalyzed by chemical catalysts such as Lewis acids, metal ions, and organic molecules can do. However, compared to chemical catalysis, enzyme-catalyzed HDA reactions are favored due to their green, mild, efficient, and highly selective properties. With the discovery of enzyme-catalyzed HDA reactions in natural product biosynthetic pathways, uncovering the stereoselectivity and substrate specificity of HDA-related enzymes promotes our understandings of the relationship between sequences and functions. Additionally, it lays the foundation for further mining and modification of enzymes. However, there are several challenges need to be tackled. Firstly, although a few HDA enzymes have been studied, the vast majority are remained to be isolated and characterized. Secondly, the catalytic mechanisms of most reported HDA enzymes are not clear, and more information about their structures, key residues and catalytic processes remains to be uncovered. Thirdly, all reported cases present rather narrow substrate spectra, and the stereoselectivity is rather poor. Here, we summarize the currently known enzyme-catalyzed HDA reactions in heterocyclic natural product biosynthetic pathways, focusing mainly on those involved in the biosynthesis of pyridines and indole alkaloids. By summarizing and analyzing the entire biocatalytic pathways and catalytic mechanisms, we expect to guide further research and engineering of HAD enzymes to improve their activity and selectivity. We also hope to inspire the development of new biocatalysts for the synthesis of non-natural heterocyclic products.

Key words: Hetero-Diels-Alder reaction, enzyme, heteroatom, pyranoids, indole alkaloids

中图分类号:

王翠珍, 陈窕, 王健博. 酶催化杂Diels-Alder反应[J]. 合成生物学, 2024, 5(1): 107-125.

Cuizhen WANG, Tiao CHEN, Jianbo WANG. Enzyme-catalyzed Hetero-Diels-Alder reactions[J]. Synthetic Biology Journal, 2024, 5(1): 107-125.

图/表 15

图1 吡喃类化合物

Fig. 1 Pyran compounds

图2 含有双环［2.2.2］重氮辛烷的产物

Fig. 2 Products containing bicyclo[2.2.2] diazaoctane rings

图3 Diels-Alder反应的分类EDG—给电子基团；EWG—吸电子基团

Fig. 3 Classification of Diels-Alder reactionsEDG—Electron donating group; EWG—Electron withdrawing group

图4 Leporin B（1）的生物合成途径

Fig. 4 Biosynthetic pathway of Leporin B (1)

图5 Neosetophomone B（3）与Epolone B（4）的生物合成途径

Fig. 5 Biosynthetic pathway of Neosetophomone B (3) and Epolone B (4)

图6 Fusaricide（10）前体Asperpyridone A（9）的生物合成途径

Fig. 6 Pathway for synthesizing the precursor Asperpyridone A (9) of Fusaricide (10)

图7 人工锌金属酶DA7催化HDA反应

Fig. 7 HDA reaction catalyzed by the artificial zinc metalloenzyme DA7

图8 6 -癸氨基-2-氟-3-氧己酸甲酯（47）

Fig. 8 Methyl 6-decanamido-2-fluoro-3-oxohexanoate (47)

图9 Tetronasin（13）的生物合成途径

Fig. 9 Biosynthetic pathway of Tetronasin (13)

图10 Tetromadurin（14）的生物合成途径

Fig. 10 Biosynthetic pathway of Tetromadurin (14)

图11 吲哚生物碱Malbrancheamides（17）的生物合成途径

Fig. 11 Biosynthetic pathway of indole alkaloid malbrancheamides (17)

图12 MalC/Phq催化Diels-Alder反应的催化机理

Fig. 12 Catalytic mechanism underlying the MalC/PhqE-catalysed Diels-Alder reaction

图13 吲哚生物碱（+）-Precitrinadin A（19）的生物合成途径

Fig. 13 Biosynthetic pathway of indole alkaloid (+)-Precitrinadin A (19)

图14 CtdP催化的IEDDA反应的催化机理

Fig. 14 Catalytic mechanism underlying the CtdP-catalysed IEDDA reaction

表1 HDA酶及其产物

Table 1 HDA enzymes and products

HDA酶基因簇	来源	HDA产物	晶体结构	催化机理
lep	Aspergillus flavus	1, 2	[56-59]	[54,56-57,59]
eupf	Penicillium janthinellum	3, 4, 5	－	[61]
pyc	Leptobacillium sp.	6, 36	－	[65]
epi	Epicoccum sorghinum FT1062^[66]	9, 10, 41	－	－
upi	Uncinocarpus reesii^[68]	9, 10, 41	－	－
hpi	Hymenoscyphus scutula^[68]	9, 10, 41	[68]	[68]
tsn	Streptomyces longisporoflavus	13	[85]	[85]
mad	Actinomadura verrucosospora^[86]	14	－	－
mal	Malbranchea aurantiaca^[89]	17, 18	[29,95]	[29,95]
ctd	Penicillium citrinum ATCC 9849^[97]	19, 20	[45,97]	[45,97-98]

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酶催化杂Diels-Alder反应

Enzyme-catalyzed Hetero-Diels-Alder reactions

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