萜类化合物的非常规生物合成研究进展

doi:10.12211/2096-8280.2024-006

合成生物学 ›› 2024, Vol. 5 ›› Issue (5): 1050-1071.DOI: 10.12211/2096-8280.2024-006

萜类化合物的非常规生物合成研究进展

程晓雷, 刘天罡, 陶慧

武汉大学药学院，组合生物合成与新药发现教育部重点实验室，湖北武汉 430071

收稿日期:2024-01-10 修回日期:2024-04-09 出版日期:2024-10-31 发布日期:2024-11-20
通讯作者: 刘天罡,陶慧
作者简介:程晓雷（1999—），女，硕士研究生。研究方向为真菌来源萜类合酶的功能。 E-mail：2021206500005@whu.edu.cn
刘天罡（1979—），男，教授，博士生导师。研究方向为萜类等天然产物的高效合成与创新发现；基于底盘细胞和自动化平台的天然产物基因组挖掘；微生物与人体的代谢互作。 E-mail：liutg@whu.edu.cn
陶慧（1990—），女，教授，博士生导师。研究方向为复杂微生物来源天然产物的生物合成机制解析与绿色生物制造。 E-mail：thui@whu.edu.cn
基金资助:
国家重点研发计划(2023YFA0916200)

Recent research progress in non-canonical biosynthesis of terpenoids

Xiaolei CHENG, Tiangang LIU, Hui TAO

Key Laboratory of Combinatorial Biosynthesis and New Drug Discovery，Ministry of Education and School of Pharmacy，Wuhan University，Wuhan 430071，Hubei，China

Received:2024-01-10 Revised:2024-04-09 Online:2024-10-31 Published:2024-11-20
Contact: Tiangang LIU, Hui TAO

摘要/Abstract

摘要：

萜类化合物是自然界中广泛存在的一类具有重要生理功能和显著生物活性的天然产物，在食品、医疗及日化行业有着广泛的应用。在萜类化合物的生物合成途径中，萜类合酶往往决定了萜类碳骨架的种类和结构新颖性，细胞色素P450酶等后修饰酶则可对碳骨架进行多种修饰，最终形成结构和功能都具有丰富多样性的萜类化合物。近年来，随着基因测序技术与合成生物学的发展，大量植物和微生物来源的萜类生物合成酶被表征，令人兴奋的是，其中包含一些与经典萜类合酶不同的非常规萜类合酶，它们亦可催化生成独特的环化萜类骨架。与此同时，利用组合生物合成等策略，人们创造了许多新颖的非天然萜类化合物，进一步丰富了萜类资源库。本文综述了近5年在非常规萜类环化酶与组合生物合成途径等方面取得的最新研究进展，以期为未来新型萜类化合物的发现和生物合成提供启示。本文首先综述了新发现的具有萜类环化功能的新酶，包含Ⅰ型萜类合酶新亚族、非角鲨烯来源三萜合酶、UbiA型萜类环化酶、细胞色素P450氧化酶、甲基转移酶、钒依赖卤素过氧化物酶、卤代酸脱卤酶等，同时还对其序列、功能和可能的环化机制进行了介绍，有助于理解自然界中萜类生物合成酶的进化起源和发现新颖萜类化合物。然后，本文介绍了非常规萜类衍生物的组合生物合成，通过将萜类合酶与甲基转移酶、天然或人工细胞色素P450氧化酶进行组合，产生了一系列包含非常规C₁₁、C₁₆骨架以及具有不同氧化形式的非天然萜类化合物，可为往后萜类化合物的结构创新研究带来启发。这些新颖酶元件的挖掘与新型组合生物合成途径的构建，将进一步拓宽萜类化合物的结构多样性和化学空间，有望为临床萜类药物研发提供更多的潜在小分子。

关键词: 萜类化合物, 非常规萜类合酶, 细胞色素P450酶, 组合生物合成, C₁₆萜类

Abstract:

Terpenoids are a class of natural products with important physiological functions and significant biological activities that are widely found in nature and have a wide range of applications in the food, medical, and daily chemical industries. In the biosynthetic pathway of terpenoids, terpene synthases often determine the type and novelty of the terpene carbon skeleton, and tailoring enzymes, such as cytochrome P450 enzymes, can carry out a variety of post-modifications, ultimately resulting in terpenoids with a rich diversity of structures and functions. In recent years, with the development of genome-sequencing technology and synthetic biology, a large number of terpene biosynthetic enzymes of plant and microbial origin have been characterized, which, excitingly, include non-canonical terpene synthases that can also catalyze the generation of unique cyclized skeletons. Meanwhile, the use of combinatorial biosynthetic strategies has led to the creation of many novel and unnatural terpenoids, further enriching the kingdom of terpenoids. Here, we review the recent advances in non-canonical terpene cyclases and combinatorial biosynthetic pathways over the past five years, with a view to shedding light on the discovery and biosynthesis of novel terpenes in the future. Firstly, the newly discovered novel enzymes with terpene cyclization functions are reviewed, containing a new subclass of type Ⅰ terpene synthases, non-squalene triterpene synthases, UbiA-type terpene cyclases, cytochrome P450 oxygenases, methyltransferases, vanadium-dependent haloperoxidases, and haloacid dehalogenase, along with their sequences, functions, and possible cyclization mechanisms, which can contribute to our understanding of terpenoid biosynthetic enzymes and the discovery of novel terpenoids. This review then describes the combinatorial biosynthesis of non-canonical terpenoids. By combining terpene synthases with methyltransferases or natural/artificial cytochrome P450 oxygenases, a series of unnatural terpenoids containing non-canonical C₁₁ and C₁₆ backbones, or with unusual structural modifications, were produced. This could inspire the structural innovation studies of terpenoids in the future. The discovery of novel enzymes and the construction of novel combinatorial biosynthetic pathways will further broaden the structural diversity and chemical space of terpenoids, which is expected to provide more potential novel terpenoids for clinical drug development.

Key words: terpenoid, non-canonical terpene synthase, cytochrome P450 oxygenase, combinatorial biosynthesis, C₁₆ terpenoid

中图分类号:

Q819

程晓雷, 刘天罡, 陶慧. 萜类化合物的非常规生物合成研究进展[J]. 合成生物学, 2024, 5(5): 1050-1071.

Xiaolei CHENG, Tiangang LIU, Hui TAO. Recent research progress in non-canonical biosynthesis of terpenoids[J]. Synthetic Biology Journal, 2024, 5(5): 1050-1071.

图/表 13

图1 萜类化合物的生物合成途径

Fig. 1 The biosynthetic pathway of terpenoids

图2 Ⅰ型和Ⅱ型TS

Fig. 2 Type Ⅰ and Type Ⅱ TS

表1 非常规萜类合酶

Table 1 Non-canonical terpene synthases

酶家族	成员	GenBank/UniProt ID	生物合成途径	富含 Asp 的基序	PDB ID	参考文献
TypeⅠsubunit	VenA	AAB81504.1	venezuelaene A	DxxxxD	7Y9H	[35]
Chimeric typeⅠTS	TvTS	P9WER5.1	talaropentaene	DDxxD NSE	7VTB	[36]
UbiA-type cyclase	Tps1A	KAI0942648.1	(+)-(S,Z)-α-bisabolene	Nxxx(G/A)xxxD QDxxDxxxD	—	[37]
Cytochrome P450	SdnB	A0A1B4XBJ9.1	sordarinane	—	—	[38]
Cytochrome P450	AriF	WP_092528764.1	aridacins A-C	—	—	[39]
Methyltransferase	SodC	A0A7U3Z1M0	sodorifen	—	—	[40-41]
Methyltransferase	PchlO6_6045	EIM17055.1	chlororaphen	—	—	[42]
Vanadium haloperoxidase	LoVBPO2a	BCK50960.1	snyderol	—	—	[43]
Haloacid dehalogenase	AncA	THU99223.1	monocyclofarnesol	—	—	[44]
Haloacid dehalogenase	AncC	THU99223.1	antrocin	—	—	[44]

图3 二萜合酶VenA

Fig. 3 Diterpene synthase VenA

图4 非角鲨烯来源三萜的生物合成

Fig. 4 The biosynthesis of non-squalene triterpenes

图5 （+）-（S，Z）-α-红没药烯

Fig. 5 (+)-(S,Z)-α-bisabolene

图6 索达啉类的生物合成途径

Fig. 6 Biosynthetic pathways of sordaricin

图7 Aridacins的生物合成途径

Fig. 7 Biosynthetic pathway of aridacins

图8 C16萜类化合物

Fig. 8 C16 terpenoids

图 9 chlororaphen的生物合成途径

Fig. 9 Biosynthetic pathway of chlororaphen

图10 推测VBPO催化橙花醇合成橙花醇异构体的机理

Fig. 10 Possible catalytic mechanism of VBPO for the biosynthesis of β-snyderol from nerolidol

图11 （-）-antrocin的生物合成途径（a）与AncC与AncA可能的环化机制（b）

Fig. 11 Biosynthetic pathway of (-)-antrocin (a) and possible cyclization mechanism of AncC and AncA (b)

图12 由SpSodMT 及其变体合成的C16前体（a）与结合FPP和SAH的SpSodMT模型（b）［90］

Fig. 12 C16 building blocks synthesized by SpSodMT and its variants (a) and SpSodMT model with FPP and SAH (b)[90]

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萜类化合物的非常规生物合成研究进展

Recent research progress in non-canonical biosynthesis of terpenoids

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