Synthetic Biology Journal

   

Recent research progress in non-canonical biosynthesis of terpenoids

Xiaolei CHENG, Tiangang LIU, Hui TAO   

  1. School of Pharmacy,Wuhan University,Key Laboratory of Combinatorial Biosynthesis and New Drug Discovery,Ministry of Education,Wuhan 430071,Hubei,China
  • Received:2021-01-10 Revised:2024-04-09 Published:2024-04-25
  • Contact: Tiangang LIU, Hui TAO

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   

  1. 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
  • 通讯作者: 刘天罡,陶慧
  • 作者简介:程晓雷(1999—),女,在读硕士研究生。研究方向为真菌来源萜类合酶的功能研究。 E-mail:2021206500005@whu.edu.cn
    刘天罡(1979—),男,武汉大学药学院教授,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,武汉大学药学院教授,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。入选国家级青年人才项目、国家重点研发计划青年科学家项目、湖北省百人计划。 E-mail:thui@whu.edu.cn
  • 基金资助:
    国家重点研发计划(2023YFA0916200)

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 terpenoids for clinical drug development.

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

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。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,有助于我们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

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