小分子生物农药及其生物合成研究进展

doi:10.12211/2096-8280.2024-078

合成生物学

• 特约评述 •

小分子生物农药及其生物合成研究进展

宋开南¹, 张礼文¹, 王超², 田平芳³, 李广悦⁴, 潘国辉⁵, 徐玉泉¹

^1.中国农业科学院生物技术研究所，北京 100081
^2.国家粮食和物资储备局科学研究院，北京 100035
^3.北京化工大学生命科学与技术学院 100029
^4.中国农业科学院植物保护研究所，北京 100081
^5.中国科学院微生物研究所 100101

收稿日期:2024-10-30 修回日期:2024-12-18 出版日期:2024-12-19
通讯作者: 徐玉泉
作者简介:宋开南（1996—），男，博士研究生。研究方向为真菌次级代谢产物的挖掘与生物合成研究。E-mail：s15850653283@126.com
徐玉泉（1971—），男，研究员，博士生导师，主要从事发明新技术发现在临床和农业生产中有重要应用价值的微生物天然产物、阐明聚酮和非核糖体多肽天然产物生物合成和合成后修饰机制、利用合成生物学技术合成“非天然”聚酮化合物和非核糖体多肽的研究。E-mail：xuyuquan@caas.cn
基金资助:
国家重点研发计划“合成生物学”重点专项项目“生物农药微生物细胞工厂的设计构建”(2023YFA0914700)

Advances in small-molecule biopesticides and their biosynthesis

Kainan SONG¹, Liwen ZHANG¹, Chao WANG², Pingfang TIAN³, Guangyue LI⁴, Guohui PAN⁵, Yuquan XU¹

^1.Biotechnology Research Institute，Chinese Academy of Agricultural Sciences，Beijing 100081，China
^2.Academy of State Administration of Grain，Beijing 100035，China
^3.College of Life Science and Technology，Beijing University of Chemical Technology，Beijing 100029，China
^4.Institute of Plant Protection，Chinese Academy of Agricultural Sciences，Beijing 100081，China
^5.Institute of Microbiology，Chinese Academy of Sciences，Beijing 100101，China

Received:2024-10-30 Revised:2024-12-18 Online:2024-12-19
Contact: Yuquan XU

摘要/Abstract

摘要：

利用对环境和非靶标生物友好的小分子生物农药防治病虫害，是一种可持续保障农作物安全生产的管理方法。然而，小分子生物农药的研发和应用也面临一些挑战，比如种类少、产量低等。通过合成生物学和代谢工程等方法，构建高产特定生物农药的微生物细胞工厂可以克服这些瓶颈问题。本文总结了2000年以来在我国新登记的小分子生物农药及部分半合成农药的化学结构与作用对象，并对代表性生物农药的生物合成机制与细胞工厂构建，如多杀霉素、白藜芦醇等进行了综述。对这些小分子生物农药的深入理解可为解析其生物合成途径与提高产量提供理论依据，并对新型生物农药的发现和应用提供借鉴。随着合成生物学与代谢工程等学科的不断发展，可以预见未来将设计和构建出更多高效、环保小分子生物农药的细胞工厂，并将其广泛应用于生产。

关键词: 小分子生物农药, 合成生物学, 生物合成, 微生物细胞工厂。

Abstract:

Small-molecule biopesticides, as opposed to chemically synthesized pesticides, exhibit enhanced degradability within the natural environment and exert a reduced adverse effect on non-target organisms and overall ecosystems. Consequently, the evolution of small-molecule biopesticides represents a pivotal shift for the pesticide industry towards more sustainable and environmentally benign practices, with their significance projected to escalate in the realm of agricultural production in the years ahead. Despite their potential, these pesticides are currently constrained by a limited variety and suboptimal production yields, primarily attributable to the intricate research and manufacturing processes that demand substantial time and resource investments. Moreover, the biosynthetic pathways of the majority of these small molecules remain enigmatic, posing a significant challenge to their industrial application. However, the advent of synthetic biology and metabolic engineering offers promising solutions to these impediments. This progress is not merely instrumental in deepening our understanding of the intricate synthetic mechanisms of these bioactive compounds within biological systems, but it also paves the way for augmenting their production yields. By employing microbial cell factories, these technologies enable the efficient and targeted biosynthesis of specific biopesticides, thereby overcoming the limitations associated with traditional extraction and purification methods from natural sources. Microbial cell factories not only facilitate the cost-effective and environmentally friendly large-scale production of small-molecule biopesticides but also foster the innovation of novel biopesticide varieties. This review aims to summarize the small-molecule biopesticides and some semi-synthetic pesticides derived from natural products that have been registered in China from January 2000 to December 2024, including eight polyketides, twelve terpenes, four alkaloids, and five other small-molecule biopesticides. Depending on their specific uses in agricultural practices, they can be classified into insecticides, microbicide, plant growth regulators, and so on. Furthermore, this review provides a succinct overview of the representative biosynthetic pathways and the corresponding microbial cell factories that are pivotal to the production of these biopesticides. We expect that an in-depth understanding of the biosynthesis of small-molecule biopesticides will pave solid ways for further elucidation of biosynthesis pathways, yield improvement, and the discovery and application of novel biopesticides.

Key words: small-molecule biopesticides, synthetic biology, biosynthesis, microbial cell factory

中图分类号:

Q816

宋开南, 张礼文, 王超, 田平芳, 李广悦, 潘国辉, 徐玉泉. 小分子生物农药及其生物合成研究进展[J]. 合成生物学, DOI: 10.12211/2096-8280.2024-078.

Kainan SONG, Liwen ZHANG, Chao WANG, Pingfang TIAN, Guangyue LI, Guohui PAN, Yuquan XU. Advances in small-molecule biopesticides and their biosynthesis[J]. Synthetic Biology Journal, DOI: 10.12211/2096-8280.2024-078.

图/表 10

表1 2000年以来我国新登记的小分子生物农药

Tab. 1 Summary of small molecule biological pesticides registered in China between 2000 and 2024

农药名称	主要来源	结构分类	用途	原药有效成分含量	登记证号*
聚酮类
多杀霉素	刺糖多孢菌 Saccharopolyspora spinosa	大环内酯类	杀虫	92.5%	PD20241953 LS20042235；
乙基多杀菌素	刺糖多孢菌-半合成 Saccharopolyspora spinosa	大环内酯类	杀虫	81.2%	PD20181527； LS20091058
伊维菌素	阿维链霉菌-半合成 Streptomyces avermitilis	大环内酯类	杀虫	95%	PD20211308； PD20120410
甲氨基阿维菌素苯甲酸盐	阿维链霉菌-半合成 Streptomyces avermitilis	大环内酯类	杀虫	90%	PD20182180； LS20021924
大黄素甲醚	掌叶大黄 Rheum palmatum	蒽醌类	杀菌	8.5%	PD20190139； LS20080104
狼毒素	狼毒 Stellera chamaejasme	黄酮类	杀虫	9.5%	PD20120876； LS20053042
蛇床子素	蛇床花 Cnidium monnieri	香豆素类	杀菌/杀虫	2%	PD20183068； LS20030489
白藜芦醇	藜芦 Veratrum sp.	芪类	杀菌	10%	PD20212931

萜烯类
苦皮藤素	苦皮藤 Celastrus angulatus	倍半萜类	杀虫	6%	PD20182273； LS20030503
甾烯醇	锦葵 Malva sp.	甾体类	抗病毒	0.66%	PD20181615； LS20150137
螺威	油茶 Camellia oleifera	三萜皂苷类	杀虫	50%	PD20131346; LS20080123
莪术醇	姜黄 Curcuma zedoaria	倍半萜类	杀鼠	92%	PD20101276； LS20053774
桉油精	蓝桉 Eucalyptus globulus	单萜类	杀虫	90%	PD20101270； LS20040664
d-柠檬烯	柠檬 Citrus limon	单萜类	杀虫/杀菌	92%	PD20220205； LS20160240
香芹酚	丁香 Syzygium aromaticum	单萜类	杀虫/杀菌	16%	PD20200138； LS20011820
24-表芸苔素内酯	油菜 Brassica campestris	甾醇类	植物生长调节剂	95%	PD20240892； PD20100303
28-高芸苔素内酯	油菜 Brassica campestris	甾醇类	植物生长调节剂	95%	PD20241931； PD20080444
28-表高芸苔素内酯	油菜 Brassica campestris	甾醇类	植物生长调节剂	90%	PD20241668； PD20082793
14-羟基芸苔素甾醇	油菜 Brassica campestris	甾醇类	植物生长调节剂	80%	PD20242107； PD20070289
丙酰芸苔素内酯	油菜 Brassica campestris	甾醇类	植物生长调节剂	80%	PD20242339； LS20011797

生物碱类
申嗪霉素	荧光假单胞菌 Pseudomonas fluorescens	吩嗪类	杀菌	95%	PD20131515； LS20031381
小檗碱	黄连 Coptis chinensis	喹啉生物碱类	杀菌	75%	PD20230660； LS20170288
吲哚乙酸		吲哚生物碱类	植物生长调节剂	97%	PD20241437； PD20081124
吲哚丁酸		吲哚生物碱类	植物生长调节剂	95%	PD20230592； LS20050293

其他类
冠菌素	丁香假单胞菌 Pseudomonas syringae	聚酮-非核糖体肽类	植物生长调节剂	98%	PD20211351
除虫菊素	除虫菊 Tanacetum cinerariifolium	杂萜类	杀虫	60%	WP20210184； WL2001279
谷维菌素	链霉菌 Streptomyces sp. NEAU6	核苷类	植物生长调节剂	94%	PD20241925； PD20212929
异硫氰酸烯丙酯	羽衣甘蓝 Brassica oleracea	有机硫类	杀菌/杀线虫	70%	PD20190037； PD20181601
大蒜素	大蒜 Allium sativum	有机硫类	杀菌	50%	PD20161252

表1 2000年以来我国新登记的小分子生物农药

Tab. 1 Summary of small molecule biological pesticides registered in China between 2000 and 2024

农药名称	主要来源	结构分类	用途	原药有效成分含量	登记证号*
聚酮类
多杀霉素	刺糖多孢菌 Saccharopolyspora spinosa	大环内酯类	杀虫	92.5%	PD20241953 LS20042235；
乙基多杀菌素	刺糖多孢菌-半合成 Saccharopolyspora spinosa	大环内酯类	杀虫	81.2%	PD20181527； LS20091058
伊维菌素	阿维链霉菌-半合成 Streptomyces avermitilis	大环内酯类	杀虫	95%	PD20211308； PD20120410
甲氨基阿维菌素苯甲酸盐	阿维链霉菌-半合成 Streptomyces avermitilis	大环内酯类	杀虫	90%	PD20182180； LS20021924
大黄素甲醚	掌叶大黄 Rheum palmatum	蒽醌类	杀菌	8.5%	PD20190139； LS20080104
狼毒素	狼毒 Stellera chamaejasme	黄酮类	杀虫	9.5%	PD20120876； LS20053042
蛇床子素	蛇床花 Cnidium monnieri	香豆素类	杀菌/杀虫	2%	PD20183068； LS20030489
白藜芦醇	藜芦 Veratrum sp.	芪类	杀菌	10%	PD20212931

萜烯类
苦皮藤素	苦皮藤 Celastrus angulatus	倍半萜类	杀虫	6%	PD20182273； LS20030503
甾烯醇	锦葵 Malva sp.	甾体类	抗病毒	0.66%	PD20181615； LS20150137
螺威	油茶 Camellia oleifera	三萜皂苷类	杀虫	50%	PD20131346; LS20080123
莪术醇	姜黄 Curcuma zedoaria	倍半萜类	杀鼠	92%	PD20101276； LS20053774
桉油精	蓝桉 Eucalyptus globulus	单萜类	杀虫	90%	PD20101270； LS20040664
d-柠檬烯	柠檬 Citrus limon	单萜类	杀虫/杀菌	92%	PD20220205； LS20160240
香芹酚	丁香 Syzygium aromaticum	单萜类	杀虫/杀菌	16%	PD20200138； LS20011820
24-表芸苔素内酯	油菜 Brassica campestris	甾醇类	植物生长调节剂	95%	PD20240892； PD20100303
28-高芸苔素内酯	油菜 Brassica campestris	甾醇类	植物生长调节剂	95%	PD20241931； PD20080444
28-表高芸苔素内酯	油菜 Brassica campestris	甾醇类	植物生长调节剂	90%	PD20241668； PD20082793
14-羟基芸苔素甾醇	油菜 Brassica campestris	甾醇类	植物生长调节剂	80%	PD20242107； PD20070289
丙酰芸苔素内酯	油菜 Brassica campestris	甾醇类	植物生长调节剂	80%	PD20242339； LS20011797

生物碱类
申嗪霉素	荧光假单胞菌 Pseudomonas fluorescens	吩嗪类	杀菌	95%	PD20131515； LS20031381
小檗碱	黄连 Coptis chinensis	喹啉生物碱类	杀菌	75%	PD20230660； LS20170288
吲哚乙酸		吲哚生物碱类	植物生长调节剂	97%	PD20241437； PD20081124
吲哚丁酸		吲哚生物碱类	植物生长调节剂	95%	PD20230592； LS20050293

其他类
冠菌素	丁香假单胞菌 Pseudomonas syringae	聚酮-非核糖体肽类	植物生长调节剂	98%	PD20211351
除虫菊素	除虫菊 Tanacetum cinerariifolium	杂萜类	杀虫	60%	WP20210184； WL2001279
谷维菌素	链霉菌 Streptomyces sp. NEAU6	核苷类	植物生长调节剂	94%	PD20241925； PD20212929
异硫氰酸烯丙酯	羽衣甘蓝 Brassica oleracea	有机硫类	杀菌/杀线虫	70%	PD20190037； PD20181601
大蒜素	大蒜 Allium sativum	有机硫类	杀菌	50%	PD20161252

图1 聚酮类生物农药的化学结构

Fig. 1 Chemical structures of polyketide biopesticides

图2 萜烯类生物农药的化学结构

Fig. 2 Chemical structures of terpene biopesticides

图3 生物碱类和其他小分子生物农药的化学结构

Fig. 3 Chemical structures of alkaloid and other small-molecule biopesticides

图4 多杀霉素类杀虫剂的生物合成通路

Fig. 4 Biosynthetic pathway of spinosyn

图5 白藜芦醇的生物合成通路PAH—苯丙氨酸羟化酶；PAL—苯丙氨酸氨解酶；C4H—肉桂酸-4-羟化酶；TAL—酪氨酸氨解酶； 4CL—对香豆酰辅酶A连接酶；STS—芪合酶

Fig. 5 Biosynthetic pathway of resveratrolPAH—phenylalanine hydroxylase; PAL—phenylalanine ammonia lyase; C4H—cinnamate-4-hydroxylase; TAL—tyrosine ammonia lyase; 4CL—4-coumarate coA ligase; STS—stilbene synthase

图6 萜烯类农药A萜烯类生物农药的生物合成 B香芹酚的生物合成通路TPS—γ-萜品烯合酶；CYP71D180等—P450单加氧酶；TvSDR1—短链还原酶1

Fig. 6 Terpenes-based biopesticides. (A)Biosynthesis of terpene-based biopesticides; (B)Biosynthetic pathway of carvacrolTPS—γ-terpinene synthase; CYP71D180, etc—cytochrome P450 monooxygenase; TvSDR1—short-chain dehydrogenase/reductase 1

图7 申嗪霉素的生物合成途径PhzE—2-氨基脱氧分支酸合酶；PhzD—异分支酸酶；PhzF—DHHA异构酶；PhzB—3-类固醇异构酶； PhzG—FMN依赖氧化酶

Fig. 7 Biosynthetic pathway of shenqinmycinPhzE—2-amino-2-desoxyisochorismate synthase; PhzD—isochorismatase; PhzF—DHHA isomerase; PhzB—Δ5-3-ketosteroid isomerase; PhzG—FMN-dependent oxidase

图8 小檗碱的生物合成途径NCS—去甲乌药碱合酶；6-OMT—去甲乌药碱-6-O-甲基转移酶；CNMT—乌药碱-N-甲基转移酶；CYP80B3—N-甲基乌药碱-3'-羟化酶；4'-OMT—3'-羟基-N-甲基乌药碱-4'-O-甲基转移酶；BBE—小檗碱桥酶；SMT—金黄紫堇碱-9-O-甲基转移酶；CYP719A1—氢化小檗碱合酶；THBO—四氢小檗碱氧化酶

Fig. 8 Biosynthetic pathway of berberineNCS—noraconitine synthase; 6-OMT—noraconitine 6-O-h; CNMT 2—alcohol dehydrogenase 2; CYP80B3—aldehyde dehydrogenase 1; 4'-OMT—10-carboxychrysanthemic acid 10-methyltransferase; BBE —berberine bridge enzyme; SMT—scoulerine-9-O-methyltransferase; CYP719A1—canadine synthase; THBO—tetrahydroberberine oxidase

图9 除虫菊素的生物合成途径CDS—菊基二磷酸合成酶；CHH—chrysanthemol 羟化酶；ADH2—乙醇脱氢酶2；ALDH1—醛脱氢酶1； CCMT—10-羧酸菊酸10-甲基转移酶；CL—辅酶A连接酶；JMH—茉莉酮羟化酶；PYS—除虫菊醇酮合酶；GLIP—GDSL脂肪酶

Fig. 9 Biosynthetic pathway of pyrethrinsCDS—chrysanthemyl diphosphate synthase; CHH—chrysanthemol 10-hydroxylase; ADH2—alcohol dehydrogenase 2; ALDH1—aldehyde dehydrogenase 1;CCMT—10-carboxychrysanthemic acid 10-methyltransferase; CL —CoA ligase; JMH—jasmone hydroxylase; PYS—pyrethrolone synthase; GLIP—GDSL lipase-like protein

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小分子生物农药及其生物合成研究进展

Advances in small-molecule biopesticides and their biosynthesis

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