Applications of the multienzyme-catalyzed tandem strategy in the synthesis of complex natural products

doi:10.12211/2096-8280.2020-010

Abstract

Abstract:

Structurally diverse natural products and their derivatives have been an indispensable source for the discovery of new drugs. However, the traditional extraction, isolation and characterization of natural products from animals, plants and microorganisms often have challenges such as low efficiency, time-consuming and expensive cost, which greatly hinder their development as new drugs. The complete synthesis of natural products mainly includes chemical synthesis and biosynthesis. Among them, In vitro enzymatic synthesis has the advantages of high catalytic efficiency, high chemo-, stereo- and regio-selectivity, specific product spectrum, simple and mild reaction conditions and environmental friendly, which make it an effective strategy for the synthesis of complex natural products. This paper reviews recent research advances in the synthesis of complex natural products by in vitro enzymatic methods, especially the applications of the multienzyme-catalyzed tandem strategy for synthesis of complex natural products including polyketides, alkaloids, terpenoids, steroids, macrolides and nucleosides. Furthermore, the bottlenecks, corresponding solutions and the perspective of this strategy are discussed.

Key words: natural products, biosynthesis, enzymatic catalysis, multienzyme-catalyzed tandem strategy

摘要：

结构新颖、复杂多样的天然产物及其衍生物一直是新药发现的重要源泉。然而，传统的从动植物及微生物中提取分离天然产物的方法往往存在效率低、耗时长、成本高等问题，极大地制约了新型药物的研发。天然产物的全合成主要包括化学合成和生物合成，其中体外酶催化合成因其具有催化效率高、反应选择性强、目标产物专一、反应条件简单温和、绿色环保等优点，为复杂天然产物的合成提供了有效策略。本文总结了近年来采用体外酶催化方法合成复杂天然产物的研究进展，着重介绍了多酶催化串联方法在聚酮类、生物碱类、萜类、甾体类、大环内酰胺类、核苷类等复杂天然产物合成中的应用，并对其目前存在的问题以及解决对策进行了讨论，同时对其未来发展也进行了展望。

关键词: 天然产物, 生物合成, 酶催化, 串联

CLC Number:

Q814.9

Junbin HE, Song MENG, Haixue PAN, Gongli TANG. Applications of the multienzyme-catalyzed tandem strategy in the synthesis of complex natural products[J]. Synthetic Biology Journal, 2020, 1(2): 226-246.

贺俊斌, 孟松, 潘海学, 唐功利. 多酶催化串联策略在复杂天然产物合成中的应用[J]. 合成生物学, 2020, 1(2): 226-246.

Figures/Tables 14

Fig. 1 Multienzyme-catalyzed tandem synthesis of enterocin (1) and wailupemycins

Fig. 2 Chemical structures of gilvocarcin V and steffimycin and the multienzyme-catalyzed tandem synthesis of rabelomycin (5), defucogilvocarcin M (6) and presteffimycinone (7)

Fig. 3 Multienzyme-catalyzed tandem synthesis of psilocybin (8)

Fig. 4 Multienzyme-catalyzed tandem synthesis of benzylisoquinoline alkaloids [(9)～(16)]

Fig. 5 Biosynthetic pathway of thaxtomins

Fig. 6 Biosynthetic pathway (a) and in vitro multienzyme-catalyzed synthesis (b) of bicyclomycin (22)

Fig. 7 Multienzyme-catalyzed tandem synthesis of gibberellin A4 (23)

Fig. 8 Multienzyme-catalyzed tandem synthesis of ursodeoxycholic acid (24)

Fig. 9 Biosynthetic pathway of ikarugamycin (25)

Fig. 10 Multienzyme-catalyzed tandem synthesis of UK-2A analogues

Fig. 11 Multienzyme-catalyzed tandem synthesis of islatravir (41)

Fig. 12 Enzymatic tandem synthesis of other compounds 45～57

Fig. 13 Chemoenzymatic synthesis of spinosyn A (58)

Fig. 14 Chemoenzymatic synthesis of ultralow molecular weight heparins （68） and （69）

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