天然产物生物合成与微生物制造的挑战<sup>*</sup>

doi:10.13523/j.cb.2312106

中国生物工程杂志

2024, Vol. 44

Issue (1): 72-87 DOI: 10.13523/j.cb.2312106

生物经济核心产业专题

天然产物生物合成与微生物制造的挑战^*

李秋阳^1,²,孙文涛^2,³,秦磊^2,⁴,吕波^1,^4,^**(

),李春^1,^2,^4,^**(

)

1 北京理工大学医药分子科学与制剂工程工信部重点实验室化学与化工学院生物化工研究所北京 100081
2 清华大学化学工程系北京 100084
3 中国医学科学院药物研究所天然药物活性物质与功能国家重点实验室北京 100050
4 清华大学工业生物催化教育部重点实验室北京 100084

Challenges in the Biosynthesis of Natural Products and Microbial Manufacturing

Qiuyang LI^1,²,Wentao SUN^2,³,Lei QIN^2,⁴,Bo LV^1,^4,^**(

),Chun LI^1,^2,^4,^**(

)

1 Key Laboratory of Medicinal Molecule Science and Pharmaceutical Engineering (Ministry of Industry and Information Technology), Institute of Biochemical Engineering, School of Chemistry and Chemical Engineering,Beijing Institute of Technology, Beijing 100081, China
2 Department of Chemical Engineering, Tsinghua University, Beijing 100084, China
3 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica,Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
4 Key Lab for Industrial Biocatalysis (Ministry of Education), Tsinghua University, Beijing 100084, China

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摘要：

天然产物是大自然赐予人类的资源宝库,与人类的生活质量和健康息息相关。利用传统方式获取天然产物存在含量低、提取工艺复杂耗时以及资源不可持续等问题,而化学合成步骤繁琐、成本高,这些都严重制约了天然产物的广泛应用。合成生物学赋能的微生物细胞工厂通过变革天然产物的传统获取方式,实现高效、绿色及可持续的生物制造。分析天然产物传统获取方式面临的挑战,总结不同类型微生物细胞工厂的特点及天然产物合成案例。基于天然产物代谢通路的复杂性、底盘细胞的稳定性可能导致产物的结构和性质难以预测以及纯度和收率低等问题,从催化元件的局限、途径组装调控及底盘网络重塑的角度分析设计微生物细胞工厂的应对策略,并针对微生物制造产品的发展与应用提出政策建议。

关键词： 天然产物; 生物制造; 微生物细胞工厂; 底盘细胞; 生物安全

Abstract:

Natural products are a treasure trove given to mankind by nature and are intimately linked to human quality of life and health. Traditional methods of obtaining natural products face challenges such as low natural biocontent, complex and time-consuming extraction processes, and unsustainable resource utilization. The intricate structures of natural products also severely impede the commercialization of chemical total synthesis. Microbial cell factories, empowered by synthetic biology, have the potential to revolutionize the current approaches to natural product extraction, with the goal of efficient, eco-friendly, and controllable biomanufacturing. This review discusses the challenges posed by traditional methods of obtaining natural products and summarizes the characteristics of different types of cell factories along with examples of natural product synthesis. Considering the complexity of natural product metabolic pathways and issues such as unpredictable product structure and properties, low purity, and low yield due to the stability of chassis cells, the article analyzes the challenges in designing microbial cell factories from the perspective of catalytic component limitations, pathway assembly regulation, and chassis cell network remodeling. Strategies and countermeasures are discussed. Moreover, recommendations are proposed to address the current regulatory constraints in microbial manufacturing.

Key words: Natural products Biomanufacturing Microbial cell factories Chassis cells Biosafety

收稿日期: 2024-01-11 出版日期: 2024-02-04

ZTFLH:

Q819

基金资助: *国家重点研发计划(2018YFA0901800)

通讯作者: ** 电子信箱: lv-b@bit.edu.cn; lichun@tsinghua.edu.cn

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引用本文:

李秋阳, 孙文涛, 秦磊, 吕波, 李春. 天然产物生物合成与微生物制造的挑战^*[J]. 中国生物工程杂志, 2024, 44(1): 72-87.

Qiuyang LI, Wentao SUN, Lei QIN, Bo LV, Chun LI. Challenges in the Biosynthesis of Natural Products and Microbial Manufacturing. China Biotechnology, 2024, 44(1): 72-87.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2312106 或 https://manu60.magtech.com.cn/biotech/CN/Y2024/V44/I1/72

图1 微生物细胞工厂制造天然产物发展历程

类型	分类	名称	天然来源	功效	参考文献
萜烯类	单萜	柠檬烯	柑橘属果皮	抗炎、抗菌、镇静、促进消化、减肥	[11]
		香叶醇	玫瑰	抗氧化、抗菌、保肝、神经保护	[12]
	倍半萜	青蒿素	青蒿	抗疟疾	[13]
		红没药烯	香柠檬	抗痒、消炎、抗癌	[11]
	二萜	紫杉醇	红豆杉	抗肿瘤	[14]
		香紫苏醇	抹香鲸/香紫苏	抗菌消炎、利胆、抗癌	[15]
	三萜	甘草酸	甘草	免疫调节、抗肿瘤、抗病毒、保肝	[16]
		原人参二醇	人参	镇静、促进细胞分化增殖、抗肿瘤、降血糖	[17]
		齐墩果酸	丁香/女贞子、三七	抗HIV、抗菌、抗癌、抗溃疡、治疗骨质疏松	[18]
	四萜	虾青素	雨生红球藻/红发夫酵母	抗氧化、抗炎、伤口愈合、保护心脏、保肝、抗糖尿病、神经保护、抗癌	[19]
		番茄红素	番茄	抗氧化、保护心血管	[20]
黄酮类	黄酮	黄芩素	黄芩	保肝、镇静、抗过敏、抗炎	[21]
	二氢黄酮	柚皮素	葡萄柚	抗氧化、抗雄激素、消炎、抗癌	[22]
	黄酮醇	淫羊藿素	淫羊藿	抗肿瘤、神经保护、心血管保护、免疫调节、骨保护	[23]
生物碱	异喹啉类	吗啡	罂粟	治疗急性和慢性中度至重度疼痛	[24]
	四氢异喹啉类	海鞘素	加勒比海鞘	抗肿瘤	[25]
	单萜吲哚类	长春碱	长春花	抗肿瘤	[26]
酚酸	单羟基苯甲酸	水杨酸	柳树	缓解疼痛和发热、消炎、治疗痤疮	[27]
	二羟基苯甲酸	原儿茶酸	乌蕨/冬青	抗氧化、抗肿瘤、神经保护	[28]
	三羟基苯甲酸	没食子酸	五倍子/金缕梅	抗氧化、抗癌、抗菌、保护软骨、碳酸酐酶抑制剂、抗糖尿病、抗溃疡、组织蛋白酶D抑制剂	[29]
抗生素	聚酮类	四环素	链霉菌	治疗呼吸道、胃肠道和泌尿生殖道感染	[30]
	大环内酯类	红霉素	糖多孢红霉菌	治疗呼吸道、皮肤和衣原体菌感染,治疗梅毒	[31]

表1 部分经典天然产物的功效

表2 部分植物天然产物的传统获取方式

图2 微生物细胞工厂类型

表3 酵母细胞工厂合成的部分天然产物

表4 大肠杆菌细胞工厂合成的部分天然产物

表5 谷氨酸棒杆菌细胞工厂生产非必需氨基酸类的部分天然产物

图3 催化元件的挖掘和改造策略

图4 通过底盘细胞改造优化与代谢平衡调控构建高效细胞工厂

图5 生物逆合成途径预测流程

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