生物燃料高效生产微生物细胞工厂构建研究进展

doi:10.12211/2096-8280.2023-047

合成生物学 ›› 2023, Vol. 4 ›› Issue (6): 1082-1121.DOI: 10.12211/2096-8280.2023-047

生物燃料高效生产微生物细胞工厂构建研究进展

晏雄鹰, 王振, 娄吉芸, 张皓瑜, 黄星宇, 王霞, 杨世辉

湖北大学生命科学学院，省部共建生物催化与酶工程国家重点实验室，湖北武汉 430062

收稿日期:2023-07-02 修回日期:2023-08-30 出版日期:2023-12-31 发布日期:2024-01-19
通讯作者: 王霞,杨世辉
作者简介:晏雄鹰（1998—），男，博士研究生。研究方向为微生物代谢工程与合成生物学。E-mail：xiongying.Yan@stu.hubu.edu.cn
王霞（1988—），女，博士，讲师。研究方向为合成生物学与微生物代谢工程。E-mail：xxwang@hubu.edu.cn
杨世辉（1971—），男，博士，教授，“省部共建生物催化与酶工程国家重点实验室”副主任。研究方向为微生物代谢工程、合成生物学以及生物能源与绿色生物制造等。E-mail：Shihui.Yang@hubu.edu.cn
基金资助:
国家重点研发计划(2022YFA0911800);国家自然科学基金(22108064);湖北省科技厅重大科技创新计划(2021BAD001)

Progress in the construction of microbial cell factories for efficient biofuel production

Xiongying YAN, Zhen WANG, Jiyun LOU, Haoyu ZHANG, Xingyu HUANG, Xia WANG, Shihui YANG

State Key Laboratory of Biocatalysis and Enzyme Engineering，School of Life Sciences，Hubei University，Wuhan 430062，Hubei，China

Received:2023-07-02 Revised:2023-08-30 Online:2023-12-31 Published:2024-01-19
Contact: Xia WANG, Shihui YANG

摘要/Abstract

摘要：

生物燃料替代化石燃料可解决当前全球正面临的能源危机和环境危机。通过筛选、改造微生物，利用可再生资源高效生产具有经济效益和社会效益的生物燃料已成为可持续生物制造的重大发展方向。基于系统生物学理解并设计细胞工厂生物燃料的合成途径与调控网络，利用合成生物学手段开发高产稳产微生物细胞工厂是实现生物燃料经济生产的重要手段。本文概述了当前生物燃料的主要种类及对应的代谢途径，并总结了当前主要生物燃料的生产情况。重点介绍从微生物物质代谢、能量代谢、生理代谢和信息代谢四个方面去认识、改造、开发微生物底盘细胞使其成为高产稳产的生物能源细胞工厂。此外，本文也对当前生物能源的生产瓶颈和挑战进行了总结，并从酶元件库的挖掘、合成途径的创建与优化、底盘细胞的理解和性能改善、发酵工艺的智能控制等方面提出了未来的发展方向和目标任务，强调了在未来的研究中，信息技术（IT）和生物技术（BT）交叉融合是能源细胞工厂构建的发展趋势，可为高效生物燃料细胞工厂的构建提供工具和资源，加速生物能源的产业化进程。

关键词: 合成生物学, 生物燃料, 微生物细胞工厂, 代谢工程, 信息技术, 生物技术

Abstract:

Biofuels are important supplements and alternatives to fossil fuels, which can alleviate the current global energy crisis and environmental pollution. Using microbes mined from nature or engineered in the lab to produce biofuels from renewable biomass of both economic and social benefits has become a major direction of sustainable biomanufacturing. It is necessary to develop robust microbial cell factories through synthetic biology for efficient and economic biofuel production, combining the strategy of systems biology to understand and design the synthetic pathways for biofuels and regulatory networks in microbes. This review discussed the major types of biofuels, the corresponding metabolic pathways, and current progress for producing these biofuels, including bioethanol, higher alcohols, biodiesel, fatty acid derivatives and isoprenoid derivatives. The strategies to understand, construct, and engineer synthetic microbial chassis as cell factories for diverse biofuel production were summarized, especially from substance metabolism, energy balance, physiological modification, and information regulation. In addition, current status and challenges for microbial biofuel production were analyzed. The insufficient understanding of natural biosynthetic pathways and the functions of biological components, lack of genetic manipulation tools for non-model biofuel chassis cells, low efficiency of gene editing, incompatibility between different heterologous pathways and chassis cells, toxicity of heterologous products and metabolic intermediates to cell factories, inhibition of many stress factors when using cheap renewable resources as raw materials, and engineering obstacles in industrial scale-up are the barriers and challenges to the industrial biofuel production. However, the rapid development of artificial intelligence and bioinformatics provides new solutions to these challenges. Finally, this review proposed future directions and key tasks based on the need for biofuel commercialization, emphasizing the combination of information technology and biotechnology as the trend in developing biofuel cell factories, which can provide tools and resources for strain engineering and accelerate the industrialization process of biofuels.

Key words: synthetic biology, biofuels, microbial cell factories, metabolic engineering, information technology, biotechnology

中图分类号:

Q939.97

晏雄鹰, 王振, 娄吉芸, 张皓瑜, 黄星宇, 王霞, 杨世辉. 生物燃料高效生产微生物细胞工厂构建研究进展[J]. 合成生物学, 2023, 4(6): 1082-1121.

Xiongying YAN, Zhen WANG, Jiyun LOU, Haoyu ZHANG, Xingyu HUANG, Xia WANG, Shihui YANG. Progress in the construction of microbial cell factories for efficient biofuel production[J]. Synthetic Biology Journal, 2023, 4(6): 1082-1121.

图/表 8

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产物 Product	价格 Price /（元/t）	宿主 Host	发酵方式 Fermentation	原料 Substrate	滴度 Titer /(g/L)	参考文献 Reference
Propanol	7000～7400	E. coli	Fed-batch	Glucose or glycerol	10.3	[16]
Propanol	7000～7400	E. coli	Shake flask	Glucose	3.5	[17]
Isopropanol	6500～7500	E. coli	Fed-batch with gas stripping	Glucose	143	[18]
Isopropanol	6500～7500	E. coli	Shake flask	Glucose	13.6	[19]
1-Butanol	8550	C. acetobutylicum	Bioreactor	Glucose	20.3	[20]
		E. coli	Bioreactor with gas stripping	Glucose	30	[21]
		C. tyrobutyricum	Bioreactor	Mannitol	20.5	[22]
Isobutanol	8100	E. coli	Capped flask	Glucose	22	[23]
		E. coli	Bioreactor	Glucose	56	[24]
		Z. mobilis	Shake flask	Glucose	4	[25]
		C. thermocellum	Consolidated bioprocessing	Cellulose	5.4	[26]
		C. glutamicum	Shake flask	Glucose	20.8	[27]
		S. cerevisiae	NA	Glucose	5.8	[28]
2,3-Butanediol	10 000	S. marcescens	Shake flask	Glucose	42.5	[29]
		S. marcescens	Fed-batch	Sucrose	152	[30]
		Z. mobilis	Shake flask	Glucose	13.3	[31]
2-Methy-1-butanol	15 500	B. flavum	Shake flash	Glucose; duckweed	19.5/17.5	[32]
		E. coli	Shake flask	Glucose	1.25	[33]
		C. crenatum	Shake flask	Glucose	5.26	[34]
3-Methy-1-butanol	22 000	E. coli	Shake flask; two-phase fermentation	Glucose	9.5	[35]
		B. flavum	Shake flask	Glucose; duckweed	0.79/0.78	[32]
		C. crenatum	Shake flask	Glucose	3.78	[34]

产物 Product	价格 Price /（元/t）	宿主 Host	发酵方式 Fermentation	原料 Substrate	滴度 Titer /(g/L)	参考文献 Reference
Propanol	7000～7400	E. coli	Fed-batch	Glucose or glycerol	10.3	[16]
Propanol	7000～7400	E. coli	Shake flask	Glucose	3.5	[17]
Isopropanol	6500～7500	E. coli	Fed-batch with gas stripping	Glucose	143	[18]
Isopropanol	6500～7500	E. coli	Shake flask	Glucose	13.6	[19]
1-Butanol	8550	C. acetobutylicum	Bioreactor	Glucose	20.3	[20]
		E. coli	Bioreactor with gas stripping	Glucose	30	[21]
		C. tyrobutyricum	Bioreactor	Mannitol	20.5	[22]
Isobutanol	8100	E. coli	Capped flask	Glucose	22	[23]
		E. coli	Bioreactor	Glucose	56	[24]
		Z. mobilis	Shake flask	Glucose	4	[25]
		C. thermocellum	Consolidated bioprocessing	Cellulose	5.4	[26]
		C. glutamicum	Shake flask	Glucose	20.8	[27]
		S. cerevisiae	NA	Glucose	5.8	[28]
2,3-Butanediol	10 000	S. marcescens	Shake flask	Glucose	42.5	[29]
		S. marcescens	Fed-batch	Sucrose	152	[30]
		Z. mobilis	Shake flask	Glucose	13.3	[31]
2-Methy-1-butanol	15 500	B. flavum	Shake flash	Glucose; duckweed	19.5/17.5	[32]
		E. coli	Shake flask	Glucose	1.25	[33]
		C. crenatum	Shake flask	Glucose	5.26	[34]
3-Methy-1-butanol	22 000	E. coli	Shake flask; two-phase fermentation	Glucose	9.5	[35]
		B. flavum	Shake flask	Glucose; duckweed	0.79/0.78	[32]
		C. crenatum	Shake flask	Glucose	3.78	[34]

类别 Class	产物 Product	宿主 Host	发酵方式 Fermentation	底物 Substrate	产量 Titer/(g/L)	参考文献 Reference
Fatty acids	Lipid	Y. lipolytica	3-L bioreactor	Glucose	90.00	[66]
			Shake flask	Fructose	5.51	[67]
			Shake flask	Sucrose	9.15	[67]
			2-L bioreactor	Galactose	3.22	[68]
			3-L, fed-batch	Hydrolysate	16.50	[69]
		E. coli	0.45-L, fed-batch	Glucose	21.50	[70]
		L. starkeyi	Shake flask	Glucose and xylose	12.60	[71]
		Thraustochytrid T18	7-L, fed-batch	Glucose and xylose	87.00	[72]
	Fatty acid	S. cerevisiae	1-L bioreactor, fed-batch	Glucose	33.40	[73]
		R. opacus	6.6-L, fed-batch	Glucose	50.20	[74]
		C. glutamicum	Shake flask	Glucose	1.07	[75]
	Fatty acid ethyl esters	Y. lipolytica	Shake flash	Glucose	0.137	[76]
	Fatty acid ethyl esters	R. toruloides	1-L, fed-batch	Glucose	9.97	[77]
	Wax ester	A. baylyi	Shake flask	Glucose	1.82	[78]
	Methyl ketone	E. coli	2-L, fed-batch	Glucose	3.40	[79]
	Methyl ketone	P. putida	Test tube	Glucose	1.10	[80]
	Heavy oils	A. melanogenum	10-L bioreactor	Glucose	43.00	[81]
Alkanes	Short chain alkane (C₂～C₅)	E. coli	Bioreactor	Glycerol	0.11～0.14	[82]
	Medium chain alkane (C₆～C₁₂)	Synechocystis sp. PCC6803	Bioreactor	CO₂	0.026	[83]
		E. coli	5-L, fed-batch	Glucose	1.01	[84]
			6.6-L, fed-batch	Glucose	0.58	[85]
			5-L, fed-batch	Glucose	2.5	[86]
			Shake flask	Glucose	0.26	[87]
	Long chain alkane (C₁₃～C₂₂)	R. opacus	6.6-L, fed-batch	Glucose	5.2	[74]
		A. melanogenum	10-L bioreactor	Glucose	32.5	[88]
		S. cerevisiae	NA	Glucose	86 μg/g	[89]

类别 Class	产物 Product	宿主 Host	发酵方式 Fermentation	底物 Substrate	产量 Titer/(g/L)	参考文献 Reference
Fatty acids	Lipid	Y. lipolytica	3-L bioreactor	Glucose	90.00	[66]
			Shake flask	Fructose	5.51	[67]
			Shake flask	Sucrose	9.15	[67]
			2-L bioreactor	Galactose	3.22	[68]
			3-L, fed-batch	Hydrolysate	16.50	[69]
		E. coli	0.45-L, fed-batch	Glucose	21.50	[70]
		L. starkeyi	Shake flask	Glucose and xylose	12.60	[71]
		Thraustochytrid T18	7-L, fed-batch	Glucose and xylose	87.00	[72]
	Fatty acid	S. cerevisiae	1-L bioreactor, fed-batch	Glucose	33.40	[73]
		R. opacus	6.6-L, fed-batch	Glucose	50.20	[74]
		C. glutamicum	Shake flask	Glucose	1.07	[75]
	Fatty acid ethyl esters	Y. lipolytica	Shake flash	Glucose	0.137	[76]
	Fatty acid ethyl esters	R. toruloides	1-L, fed-batch	Glucose	9.97	[77]
	Wax ester	A. baylyi	Shake flask	Glucose	1.82	[78]
	Methyl ketone	E. coli	2-L, fed-batch	Glucose	3.40	[79]
	Methyl ketone	P. putida	Test tube	Glucose	1.10	[80]
	Heavy oils	A. melanogenum	10-L bioreactor	Glucose	43.00	[81]
Alkanes	Short chain alkane (C₂～C₅)	E. coli	Bioreactor	Glycerol	0.11～0.14	[82]
	Medium chain alkane (C₆～C₁₂)	Synechocystis sp. PCC6803	Bioreactor	CO₂	0.026	[83]
		E. coli	5-L, fed-batch	Glucose	1.01	[84]
			6.6-L, fed-batch	Glucose	0.58	[85]
			5-L, fed-batch	Glucose	2.5	[86]
			Shake flask	Glucose	0.26	[87]
	Long chain alkane (C₁₃～C₂₂)	R. opacus	6.6-L, fed-batch	Glucose	5.2	[74]
		A. melanogenum	10-L bioreactor	Glucose	32.5	[88]
		S. cerevisiae	NA	Glucose	86 μg/g	[89]

产物 Product	宿主 Host	发酵方式 Fermentation	底物 Substrate	产量 Titer/(g/L)	参考文献 Reference
Pinene	E. coli	Shake flask	Glucose	0.14	[129]
	Y. lipolytica	Shake flask	Hydrolysate	0.036	[130]
	C. glutamicum	Shake flask	Glucose	27 μg/g	[131]
	R. sphaeroides	Shake flask	CO₂	0.54 mg/L	[132]
Sabinene	E. coli	5-L bioreactor	Glycerol	2.65	[133]
Sabinene	S. cerevisiae	Shake flask	Glucose	0.018	[134]
Limonene	E. coli	Shake flask	Glucose	1.29	[135]
	E. coli	3.1-L，two-phase	Glycerol	3.6	[136]
	Y. lipolytica	1.5-L；fed-batch	Glycerol	0.17	[137]
	S. cerevisiae	Shake flask	Glucose	0.92	[138]
Farnesene	E. coli	Shake flask	Glycerol	8.74	[139]
	S. cerevisiae	NA	NA	104.3	Amyris
	P. pastoris	Shake flask	Oleic acid; sorbitol	2.56	[140]
	Y. lipolytica	1-L；fed-batch	Glucose	2.56	[141]
	Y. lipolytica	200 t；fed-batch	Cane syrup	130	[142]
Bisabolene	E. coli	Shake flask	Glucose	0.91	[143]
	S. cerevisiae	Shake flask	Mannose; glucose	0.99	[4]
	R. capsulatus	Shake flask	Glucose	1.08	[144]

生物燃料高效生产微生物细胞工厂构建研究进展

Progress in the construction of microbial cell factories for efficient biofuel production

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类别 Class	菌株 Strain	生长条件 Growth condition	安全性 Safety status	基因组大小 Genome size /Mb	底物 Substrates	基因组修饰工具 Genome manipulation tools	产物 Products
Model microbes	E. coli	Facultative aerobic	Not GRAS	4.64	Pentose, hexose, glycerol, starch	Various tools	Alcohols, fatty acids and terpenoids
	S. cerevisiae	Facultative aerobic	GRAS	11.8 16 chromosomes	Starch, sucrose, hexose	Various tools	Terpenoids, nature products
	C. glutamicum	Facultative aerobic	GRAS	3.28	Sugars, alcohols, organic acid	HR, CRISPR-Cas9 CRISPR-Cpf1/dCpf1	Alcohols, aminol acid
Non-model microbes	Y. lipolytica	Facultative aerobic	GRAS	20.5 6 chromosomes	Glucose, glycerol, sucrose, starch, inulin, cellobiose	NHEJ, ZFN, TALEN CRISPR-Cas9 (CRISPRi/CRISPRa)	Lipid, FAAE, terpenoids, Alkanes
	Z. mobilis	Facultative anaerobic	GRAS	2.2 4 plasmids	Glucose, sucrose, fructose	HR, CRISPR-Cas9, CRISPR-Cas 12a, Endogenous Type-Ⅰ-F CRISPR-Cas system	Ethanol, isobutanol, 2,3-butanediol, PHB
	C. thermocellum	Strictly anaerobic	Not GRAS	3.56	Hydrolysate	Endogenous Ⅰ-B CRISPR system; Heterologous Ⅱ CRISPR system	Ethanol, isobutanol
	C. acetobutylicum	Strictly anaerobic	Not GRAS	4.1	Glucose	CRISPR-Cas9/dCas9	Acetone, ethanol, butanol

菌株 Strain	模型 Model	基因、反应与代谢物 Genes, reactions and metabolites	时间 Time	应用 Applications	参考文献 Reference
E. coli	iJE660	660、627、438	2000	NR	[295]
	iJR904	904、931、625	2003	1,4-BDO production	[296]
	iAF1260	1260、2077、1039	2007	Fatty acid production	[297]
	iJO1366	1366、2251、1136	2011	NR	[298]
	iML1515	1515、2719、1192	2017	NR	[299]
B. subtilis	iBsu1103	1103、1437、1138	2009	NR	[300]
	iBsu1103V2	1147、1742、1456	2013	NR	[301]
	iBsu1147	1147、1742、1456	2013	Riboflavin, cellulase, 2,3-butanediol and isobutanol production	[48]
	iBsu1144	1144、1955、1103	2017	Serine alkaline protease production	[302]
	ec-iY0844	844、1020、988	2019	Poly-γ-glutamic acid production	[303]
C. glutamicum	iCW773	773、1207、950	2017	L-lysine and hyaluronic acid production	[304-305]
C. glutamicum	iJM658	658、1065、984	2016	NR	[306]
S. cerevisiae	iFF708	708、1175、584	2003	Ethanol production	[307]
	iND750	750、1149、646	2004	NR	[308]
	iLL672	672、1038、636	2005	NR	[309]
	iLN800	800、1446、1013	2008	NR	[310]
	iMM904	904、1412、1228	2009	2,3-BDO production	[311]
	Yeast1	832、962、813	2008	NR	[312]
	Yeast8	1133、3949、2680	2019	NR	[313]

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