从化学合成到生物合成——天然产物全合成新趋势

doi:10.12211/2096-8280.2021-039

合成生物学 ›› 2021, Vol. 2 ›› Issue (5): 674-696.DOI: 10.12211/2096-8280.2021-039

从化学合成到生物合成——天然产物全合成新趋势

张发光¹, 曲戈², 孙周通², 马军安¹

^1.天津大学理学院化学系，合成生物学前沿科学中心，天津 300072
^2.中国科学院天津工业生物技术研究所，天津 300308

收稿日期:2021-04-01 修回日期:2021-06-19 出版日期:2021-11-19 发布日期:2021-11-19
通讯作者: 孙周通,马军安
作者简介:张发光（1987—），男，博士，副教授。研究方向为有机氟化学、不对称合成、合成生物学。E-mail：zhangfg1987@tju.edu.cn
曲戈（1985—），男，博士，副研究员。研究方向为酶分子理性设计与生物催化。E-mail：qug@tib.cas.cn曲戈（1985—），男，博士，副研究员。研究方向为酶分子理性设计与生物催化。E-mail：qug@tib.cas.cn
孙周通（1982—），男，博士，研究员。研究方向为酶分子工程与工业生物催化。E-mail：sunzht@tib.cas.cn
马军安（1968—），男，博士，教授，合成生物学前沿科学中心PI。研究方向为有机合成与合成生物学。E-mail：majun_an68@tju.edu.cn
基金资助:
国家重点研发计划(2019YFA0905100);广东省重点领域研发计划(2020B0303070002)

From chemical synthesis to biosynthesis: trends toward total synthesis of natural products

Faguang ZHANG¹, Ge QU², Zhoutong SUN², Jun′an MA¹

^1.Department of Chemistry，School of Science，Frontiers Science Center for Synthetic Biology （Ministry of Education），Tianjin University，Tianjin 300072，China
^2.Tianjin Institute of Industrial Biotechnology，Chinese Academy of Sciences，Tianjin 300308，China

Received:2021-04-01 Revised:2021-06-19 Online:2021-11-19 Published:2021-11-19
Contact: Zhoutong SUN, Jun′an MA

摘要/Abstract

摘要：

结构复杂而多样的天然产物是药物发现和创制的重要宝库。为了克服有限的自然资源，来自学术界和工业界的科学家近两个世纪一直不断尝试人工合成天然产物。化学全合成已经取得了巨大成就，众多高度复杂的天然产物已经被有机化学家成功制备；但本领域仍存在诸多挑战性问题，例如化学反应中涉及昂贵的化学试剂、苛刻的反应条件、难控的立体选择性、冗长的合成路线以及较低的总收率等。随着合成生物学的发展，越来越多天然产物可通过生物细胞工厂实现人工制备，从而提供全新而互补的全合成策略。本文简要概括天然产物化学全合成，围绕几种药物活性天然产物的生物合成介绍其相关进展，以青霉素、红霉素、阿维菌素为例分析总结了天然产物同源途径的改造与优化；以维生素B₁₂、莨菪烷碱为例概括评述了天然产物的异源表达与生物制造；并以人源胰岛素、青蒿素、沙弗拉霉素、嗜氮酮、卡英酸、鬼臼毒素为例重点介绍了生物与化学交叉融合策略在天然产物全合成中的应用。尽管在类天然产物新分子、立体复杂天然产物等的全合成中仍面临诸多挑战，但生物全合成对这些天然产物分子的构建将发挥越来越显著的作用；通过化学合成与生物合成优势互补，并借助当今蓬勃发展的人工智能技术，实现生物全合成的智能化、自动化、高效化将是本领域发展的新趋势。

关键词: 天然产物, 全合成, 合成生物学, 生物催化, 化学-酶法合成

Abstract:

The complexity and diversity of natural products have made them a rich source for drug and agrochemical discovery. To overcome the supplying limitation of natural resources, tremendous effort has been made by the academic and industrial communities during the past two centuries for the total artificial synthesis of natural products. In this regard, total chemical synthesis has achieved significant progress, and numerous highly complex natural products have been synthesized through different chemical processes. Despite these great achievements in total chemical synthesis, there are still many challenges including expensive chemical reagents, harsh reaction conditions, difficult control on stereoselectivity, long synthetic route, and low product yield. Notably, the development of synthetic biology has allowed more and more natural products to be produced through biological cell factories, which provides a new and complementary strategy for the synthesis of natural products at a large scale. This review critically comments on the representative advances in total chemical synthesis of natural products (Section 1), and then highlight major progress and trends in the biosynthesis of pharmaceutically important natural products (Sections 2 and 3). In Section 2.1, we selected the production of penicillin, erythromycin, and avermectin as examples to analyze the modification and optimization of natural product biosynthetic pathways. The discovery and utilization of secondary metabolites from microorganisms has been a continuous driving force in the field of natural products. Notably, significant progress has been made in the total biosynthesis of natural products from secondary metabolism via the genetic manipulation of microbial cells. In Section 2.2, we selected Vitamin B₁₂ and Tropane alkaloids as examples to demonstrate the use of heterologous expression and biological production for natural product synthesis. In recent years, on the basis of analyzing the structure of natural products in animals, plants, and microorganisms, great advances have emerged in exploring their biochemical reaction mechanisms and synthetic routes. More importantly, expressing and regulating the relative genes in heterologous microbial cells have enabled the complete biosynthesis of many natural products. Furthermore, in Section 3, human insulin, artemisinin, saframycin, azaphilone, kainic acid, and podophyllotoxin were selected as examples to showcase the power of merging chemical and biological processes for the total synthesis of natural products. Although there are still many challenges in the total synthesis of new and complex natural products, biosynthesis will ultimately play a significant role in the construction of natural molecules and their relative analogues. By taking advantage of the merits with organic chemistry, synthetic biology, and artificial intelligence, the development of highly efficient and automatic biosynthesis could be a trend in this field.

Key words: natural products, total synthesis, synthetic biology, biocatalysis, chemoenzymatic synthesis

中图分类号:

张发光, 曲戈, 孙周通, 马军安. 从化学合成到生物合成——天然产物全合成新趋势[J]. 合成生物学, 2021, 2(5): 674-696.

Faguang ZHANG, Ge QU, Zhoutong SUN, Jun′an MA. From chemical synthesis to biosynthesis: trends toward total synthesis of natural products[J]. Synthetic Biology Journal, 2021, 2(5): 674-696.

图/表 15

图1 吗啡、水杨苷、水杨酸及乙酰水杨酸化学结构

Fig. 1 Chemical structures of morphine, salicin, salicylic acid, and acetylsalicylic acid

图2 天然产物中的部分明星药物分子结构

Fig. 2 Molecular structures of several star natural products as pharmaceuticals

图3 广谱抗癌活性天然产物紫杉醇Robert Holton全合成(a)及Pierre Potier半合成路线(b)

Fig. 3 Total synthesis of the anti-cancer natural product paclitaxel by Robert Holton (a) and its semi-synthesis by the Pierre Potier route (b)

图4 青霉素生物合成途径

Fig. 4 Biosynthetic pathway of penicillin

图5 红霉素A生物体内全合成路线

Fig. 5 Biosynthetic pathway of erythromycin A

图6 阿维菌素生物合成途径

Fig. 6 Biosynthetic pathway of avermectin

图7 维生素B12从头生物合成

Fig. 7 De novo biosynthesis of vitamin B12

图8 莨菪烷碱的生物合成机制解析

Fig. 8 Biosynthetic pathway of tropane alkaloids

图9 莨菪烷碱的酵母异源生物合成途径

Fig. 9 Heterologous biosynthesis of tropane alkaloids in yeast

图10 人源胰岛素分子A和B链的生物合成及化学连接

Fig. 10 Biosynthesis of human insulin A and B chains, as well as their chemical linkage

图11 青蒿素的生物-化学交叉全合成

Fig. 11 Total synthesis of artemisin via combining bio-synthesis and chemical synthesis

图12 沙弗拉霉素的化学-酶法全合成

Fig. 12 Syntheses of saframycins through the chemo-enzymatic catalysis

图13 嗜氮酮天然产物的化学-酶法立体多样性全合成

Fig. 13 Stereodivergent and chemoenzymatic synthesis of azaphilone natural products

图14 卡英酸的化学-酶法全合成

Fig. 14 Chemoenzymatic synthesis of kainic acid

图15 鬼臼毒素的两种化学-酶法合成途径

Fig. 15 Two chemoenzymatic synthesis pathways of podophyllotoxin

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从化学合成到生物合成——天然产物全合成新趋势

From chemical synthesis to biosynthesis: trends toward total synthesis of natural products

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