合成生物制造进展

doi:10.12211/2096-8280.2020-052

合成生物学 ›› 2021, Vol. 2 ›› Issue (2): 145-160.DOI: 10.12211/2096-8280.2020-052

合成生物制造进展

张媛媛¹, 曾艳², 王钦宏¹

^1.中国科学院天津工业生物技术研究所，中国科学院系统微生物工程重点实验室，天津 300308
^2.中国科学院科技促进发展局，北京 100864

收稿日期:2020-06-07 修回日期:2021-02-04 出版日期:2021-04-29 发布日期:2021-04-30
通讯作者: 王钦宏
作者简介:张媛媛（1985—），女，硕士，助理研究员。研究方向为进化与代谢工程。E-mail：zhang_yy@tib.cas.cn
王钦宏（1974—），男，博士，研究员。研究方向为化学品代谢途径构建，发展基因组水平编辑和进化策略以及液滴微流控高通量筛选系统，进行生产重要化学品的细胞工厂优化改造，获得实用高性能微生物细胞工厂。E-mail：wang_qh@tib.cas.cn
基金资助:
国家新药创制重大专项(2018ZX09711001-006-003);中国科学院科技服务网络计划（STS计划）(KFJ-STS-ZDTP-065)

Advances in synthetic biomanufacturing

Yuanyuan ZHANG¹, Yan ZENG², Qinhong WANG¹

^1.Tianjin Institute of Industrial Biotechnology，CAS Key Laboratory of Systems Microbial Biotechnology，Chinese Academy of Sciences，Tianjin 300308，China
^2.Bureau of Science and Technology for Development，Chinese Academy of Sciences，Beijing 100864，China

Received:2020-06-07 Revised:2021-02-04 Online:2021-04-29 Published:2021-04-30
Contact: Qinhong WANG

摘要/Abstract

摘要：

合成生物制造是以合成生物为工具进行物质加工与合成的生产方式，有望彻底变革未来医药、化工、食品、能源、材料、农业等传统模式，触发新的产业变革，引领新的产业模式和经济形态，重塑碳基物质文明。合成生物制造具有清洁、高效、可再生等特点，能够减少工业经济对生态环境的影响。本文综述了近年来合成生物制造在大宗发酵产品、精细与医药化学品、可再生化学品与聚合材料、天然产物、未来农产品以及一碳原料利用方面的重要进展，对各领域代表性重大产品的技术进展及产业应用状况与潜力进行了探讨。未来，随着合成生物学发展，以及与人工智能、大数据等新技术的融合，通过合成生物制造可以获得更多的生物基产品，促进生物经济形成，更好地服务于人类社会的可持续发展。

关键词: 合成生物学, 生物制造, 可再生原料, 生物基产品, 生物经济

Abstract:

Synthetic biomanufacturing is a paradigm for material processing and synthesis via synthetic biology. It is expected to completely transform the traditional production mode for medicines, chemicals, food, energy, materials and agriculture in the future, trigger new industrial revolution, lead to new economic growth and reshape carbon-based civilization. In particular, the COVID-19 global spread that has accelerated the reshaping process of the world's economic and social development. In the foreseeable future, human life and production patterns will undergo profound changes in medicines and healthcare, food and agriculture, energy and materials, etc., during which demands for new technologies will promote evolution in the field of biotechnology, and the biomanufacturing industry in the post COVID-19 era is facing unprecedented opportunities for revitalization and new challenges. According to the analysis of the research report from the Ministry of Economy, Trade and Industry of Japan, engineered biological cells and their combination with information & artificial intelligence technologies will become the main driving force for the "post-fourth industrial revolution".Synthetic biomanufacturing has the characteristics of cleanliness, efficiency and renewableness that can reduce the impact of industrial economy on the ecological environment. Here, in this review, we summarize the progress of synthetic biomanufacturing with respect to bulk fermentation products, fine and pharmaceutical chemicals, renewable chemicals and bio-based polymeric materials, natural products, foods and the utilization of C₁ raw materials. The technological progress, status and potential of industrial applications of many important bio-based products via synthetic biomanufacturing are analyzed and discussed. The development of synthetic biomanufacturing shows great potentials for building up the ecological route of industrial economy and addressing current issues of economic sustainability in terms of limited substrate, high cost, and poor viability, and to form whole new industry chain with sustainable growth. In the future, with the development of synthetic biology, and the integration of new technologies such as artificial intelligence and big data, more and more bio-based products can be produced via synthetic biomanufacturing. The formation of bioeconomy can be promoted, and the sustainable development of human society will be better served.

Key words: synthetic biology, biomanufacturing, renewable feedstock, bio-based product, bioeconomy

中图分类号:

张媛媛, 曾艳, 王钦宏. 合成生物制造进展[J]. 合成生物学, 2021, 2(2): 145-160.

Yuanyuan ZHANG, Yan ZENG, Qinhong WANG. Advances in synthetic biomanufacturing[J]. Synthetic Biology Journal, 2021, 2(2): 145-160.

图/表 4

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芳香族化合物	宿主细胞	发酵时间	发酵方式	产量	参考文献
左旋多巴	E. coli	60 h	分批补料发酵	57 g/L	[63]
羟基酪醇	E. coli	48 h	摇瓶发酵	169.2 g /L	[64]
没食子酸	E. coli	48 h	摇瓶发酵	1266.39 mg /L	[65]
水杨酸	E. coli	48 h	分批补料发酵	11. 5 g /L	[66]
L-苯丙氨酸	E. coli	48 h	分批补料发酵	72.9 g /L	[67]
苯乙醇	E. coli	72 h	摇瓶发酵	3.59 g /L	[68]
肉桂酸	E. coli	80 h	摇瓶发酵	1.7 g /L	[69]
L-色氨酸	E. coli	42 h	分批补料发酵	39.7 g /L	[70]
香草醇	E. coli	36 h	摇瓶发酵	240.69 mg /L	[71]
顺，顺黏康酸	E. coli	72 h	分批补料发酵	64.5 g /L	[72]

芳香族化合物	宿主细胞	发酵时间	发酵方式	产量	参考文献
左旋多巴	E. coli	60 h	分批补料发酵	57 g/L	[63]
羟基酪醇	E. coli	48 h	摇瓶发酵	169.2 g /L	[64]
没食子酸	E. coli	48 h	摇瓶发酵	1266.39 mg /L	[65]
水杨酸	E. coli	48 h	分批补料发酵	11. 5 g /L	[66]
L-苯丙氨酸	E. coli	48 h	分批补料发酵	72.9 g /L	[67]
苯乙醇	E. coli	72 h	摇瓶发酵	3.59 g /L	[68]
肉桂酸	E. coli	80 h	摇瓶发酵	1.7 g /L	[69]
L-色氨酸	E. coli	42 h	分批补料发酵	39.7 g /L	[70]
香草醇	E. coli	36 h	摇瓶发酵	240.69 mg /L	[71]
顺，顺黏康酸	E. coli	72 h	分批补料发酵	64.5 g /L	[72]

种类	天然产物	功效	改造策略	参考文献
萜类化合物	β-胡萝卜素	抗氧化，免疫调节，抗癌等	通过导入β-胡萝卜素外源合成途径，并进行物质代谢、能量代谢、细胞生理调节优化改造，将其产量提高至2.1 g/L	[93]
	番茄红素	抗氧化，保护心脑血管，增强免疫力	通过物质代谢、能量代谢、细胞生理调节等综合手段协同控制构建人工细胞，优化发酵过程，实现3.52 g/L或50.6 mg/g(以DCW计)的产量，正在进行产业化应用	[94]
	丹参酮	抗氧化，抗菌，抗肿瘤等	通过构建含有关键基因CYP76AH1的铁锈醇高产酵母工程菌株，结合次丹参酮二烯合成功能酶以及P450基因，获得可同时生产多类型丹参酮化合物酵母工程菌株	[95-96]
	齐墩果酸	抗菌药	对酿酒酵母进行分子改造等提升齐墩果酸的生物合成效率，结合发酵过程优化，最终实现产物浓度（606.9±9.1） mg/L及得率（16.0±0.8） mg/g (以DCW计），高出之前报道7.6倍	[97]
	甘草次酸	抗炎及抗免疫等	在酿酒酵母中构建新型甘草次酸合成途径，实现产物甘草次酸浓度(18.9±2.0) mg/L，前体物11-氧代-β-糊精浓度(108.1±4.6) mg/L	[98]
苯丙素类	天麻素	神经衰弱及神经衰弱综合征	在国际上首次获得以葡萄糖为原料合成天麻素的高产人工细胞，发酵72 h，产量可达10 g/L，成本低于植物提取的1/200、化学合成的1/2，可替代化学合成	[99]
	红景天苷	抗缺氧、抗寒冷、抗病毒等	首次创建了红景天苷微生物异源高效合成新途径，以葡萄糖为原料，生产成本是植物提取的1/40、化学合成的1/10，具备了工业化应用潜力	[100]
	灯盏乙素	治疗心脑血管疾病	理性设计灯盏乙素合成途径，筛选关键基因，以酿酒酵母为底盘细胞构建人工细胞，结合代谢调控、发酵过程优化，产量可达百毫克级，具有较好产业前景	[101]
	丹参素	改善心血管疾病症状	构建了全新的生物合成途径，后期增强外源途径关键酶与底物的特异性提升丹参素产量，可达7 g/L，具有产业化应用前景	[102]

种类	天然产物	功效	改造策略	参考文献
萜类化合物	β-胡萝卜素	抗氧化，免疫调节，抗癌等	通过导入β-胡萝卜素外源合成途径，并进行物质代谢、能量代谢、细胞生理调节优化改造，将其产量提高至2.1 g/L	[93]
	番茄红素	抗氧化，保护心脑血管，增强免疫力	通过物质代谢、能量代谢、细胞生理调节等综合手段协同控制构建人工细胞，优化发酵过程，实现3.52 g/L或50.6 mg/g(以DCW计)的产量，正在进行产业化应用	[94]
	丹参酮	抗氧化，抗菌，抗肿瘤等	通过构建含有关键基因CYP76AH1的铁锈醇高产酵母工程菌株，结合次丹参酮二烯合成功能酶以及P450基因，获得可同时生产多类型丹参酮化合物酵母工程菌株	[95-96]
	齐墩果酸	抗菌药	对酿酒酵母进行分子改造等提升齐墩果酸的生物合成效率，结合发酵过程优化，最终实现产物浓度（606.9±9.1） mg/L及得率（16.0±0.8） mg/g (以DCW计），高出之前报道7.6倍	[97]
	甘草次酸	抗炎及抗免疫等	在酿酒酵母中构建新型甘草次酸合成途径，实现产物甘草次酸浓度(18.9±2.0) mg/L，前体物11-氧代-β-糊精浓度(108.1±4.6) mg/L	[98]
苯丙素类	天麻素	神经衰弱及神经衰弱综合征	在国际上首次获得以葡萄糖为原料合成天麻素的高产人工细胞，发酵72 h，产量可达10 g/L，成本低于植物提取的1/200、化学合成的1/2，可替代化学合成	[99]
	红景天苷	抗缺氧、抗寒冷、抗病毒等	首次创建了红景天苷微生物异源高效合成新途径，以葡萄糖为原料，生产成本是植物提取的1/40、化学合成的1/10，具备了工业化应用潜力	[100]
	灯盏乙素	治疗心脑血管疾病	理性设计灯盏乙素合成途径，筛选关键基因，以酿酒酵母为底盘细胞构建人工细胞，结合代谢调控、发酵过程优化，产量可达百毫克级，具有较好产业前景	[101]
	丹参素	改善心血管疾病症状	构建了全新的生物合成途径，后期增强外源途径关键酶与底物的特异性提升丹参素产量，可达7 g/L，具有产业化应用前景	[102]

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合成生物制造进展

Advances in synthetic biomanufacturing

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