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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2023, Vol. 43 Issue (8): 100-110    DOI: 10.13523/j.cb.2302037
综述     
中链脂肪酸毒性机制及耐受性菌株构建研究进展*
刘梦晓1,2,郝雪雁1,2,韩紫依1,2,房立霞1,2,**(),曹英秀1,2,**()
1 天津大学化工学院 天津 300072
2 天津大学合成生物学前沿科学中心和系统生物工程教育部重点实验室 天津 300072
Advances in Mechanism of Medium-chain Fatty Acid Toxicity and Construction of Tolerant Strains
LIU Meng-xiao1,2,HAO Xue-yan1,2,HAN Zi-yi1,2,FANG Li-xia1,2,**(),CAO Ying-xiu1,2,**()
1 School of Chemical Engineering and Technology,Tianjin University,Tianjin 300072,China
2 Frontier Science Center for Synthetic Biology, Key Laboratory of Systems Bioengineering (Ministry of Education),Tianjin 300072,China
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摘要：

中链脂肪酸(medium-chain fatty acids,MCFAs)作为一种重要的平台化学品,被广泛应用到能源、食品和医药等行业。工业微生物发酵生产MCFAs是一条绿色环保的路线,但MCFAs会对微生物细胞膜造成损伤,并导致细胞pH、渗透压失衡及氧化应激,从而严重抑制细胞的生长速率和生产能力。因此,构建MCFAs耐受性工业微生物菌株,有助于进一步提高MCFAs的生产效率。以大肠杆菌和酿酒酵母等工业微生物为例,首先简介了MCFAs对微生物细胞的毒性机制。其次综述了运用膜改造、转运体筛选等理性代谢工程手段构建MCFAs耐受性菌株的相关研究进展,并概括了运用适应性进化、代谢通量分析等方法系统性挖掘MCFAs耐受靶点进而增强菌株耐受性的研究进展。最后对后续提高工业微生物MCFAs耐受性和生产能力的研究方向进行了展望。
关键词： 工业微生物;  中链脂肪酸;  膜损伤;  耐受性;  转运体    
Abstract:

As important platform chemicals, medium-chain fatty acids (MCFAs) are widely used in industries such as energy, food and medicine. The production of MCFAs by industrial microbial fermentation provides a green and environmentally-friendly route, but MCFAs can cause membrane damage, cell pH and osmotic pressure imbalance and oxidative stress, resulting in inhibition of cell growth rate and production capacity. Hence, the construction of MCFA-tolerant industrial microbial strains will improve the production efficiency of MCFAs. In this paper, taking industrial microorganisms such as Escherichia coli and Saccharomyces cerevisiae as examples, the toxicity mechanism of MCFAs to microbial cells is first introduced. Second, the relevant research on using rational metabolic engineering methods such as membrane modification and transporter screening to construct MCFA-tolerant strains is reviewed. Meanwhile, the paper reviews the research progress on the use of such methods as adaptive evolution and metabolic flux analysis to systematically mine MCFA-tolerant targets and improve strain tolerance. Finally, the future research directions for improving the tolerance and production capacity of MCFAs in industrial microorganisms are discussed.
Key words: Industrial microbes    Medium-chain fatty acids(MCFA)    Membrane damage    Tolerance    Transporter
收稿日期: 2023-02-21 出版日期: 2023-09-05
ZTFLH:  Q819  
基金资助: 国家重点研发计划(2021YFC2104400);国家自然科学基金(NSFC22078240)
通讯作者: **电子信箱:caoyingxiu@tju.edu.cn; lxfang@tju.edu.cn   
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引用本文:

刘梦晓, 郝雪雁, 韩紫依, 房立霞, 曹英秀. 中链脂肪酸毒性机制及耐受性菌株构建研究进展*[J]. 中国生物工程杂志, 2023, 43(8): 100-110.

LIU Meng-xiao, HAO Xue-yan, HAN Zi-yi, FANG Li-xia, CAO Ying-xiu. Advances in Mechanism of Medium-chain Fatty Acid Toxicity and Construction of Tolerant Strains. China Biotechnology, 2023, 43(8): 100-110.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2302037    或    https://manu60.magtech.com.cn/biotech/CN/Y2023/V43/I8/100

图1  MCFAs对微生物的毒性机制
策略 菌株 方法 胁迫条件 耐受表型及产量 参考文献
膜改造 E.coli MG1655 过表达地芽孢杆菌的硫酯酶GeoTE 细胞存活率比对照菌高33.1%,MCFAs产量比对照菌高41%,653 mg/L [35]
E.coli JW1794 敲除酰基-ACP合成酶基因aas 5 mmol/L月桂酸 细胞存活率提高1倍,MCFAs产量比对照菌高20%,690 mg/L [36]
E.coli MG1655 过表达铜绿假单胞菌的顺反异构酶基因cti 20 mmol/L辛酸 比生长速率提高13%,辛酸产量比对照菌高41%,43.7 mg/L [37]
E.coli MG1655 过表达磷脂酰丝氨酸合酶基因pssA 20 mmol/L辛酸 比生长速率比对照菌高29%,辛酸产量比对照菌高46%,220 mg/L [38]
S. cerevisiae 组合调控膜不对称调节因子Lem3和Sfk1表达水平 0.25 mmol/L癸酸 细胞存活率提高57.5%,MCFAs产量比对照菌高13.3%,273.5 mg/L [39]
E.coli MG1655 敲除多重抗逆性外膜蛋白基因bhsA 10 mmol/L辛酸 比生长速率提高36.3% [40]
S. cerevisiae 过表达突变的乙酰辅酶A羧化酶(1 157位丝氨酸替换为丙氨酸) 0.9 mmol/L辛酸 细胞存活率比对照菌高10倍 [41]
转运体筛选 E.coli MG1655 筛选获得转运体ArcAB并过表达 29 mmol/L 癸酸 癸酸的最小抑制浓度由0.5 g/L提高至5 g/L [42]
E.coli JM109 筛选获得转运体AcrE、MdtE和MdtC并组合过表达 MCFAs产量提高2倍,1.6 g/L [43]
Synechococcus
elongatus PCC 7942		 筛选获得转运体RndA1B1并过表达 100 μmol/L月桂酸 工程菌在胁迫条件下生长,对照菌未生长 [44]
S. cerevisiae 转运体Tpo1定向进化 0.47 mmol/L癸酸 最大OD600从3.2提高至4.0,MCFAs产量提高0.8~3.2倍 [13]
E.coli MG1655 过表达外膜蛋白FadL并敲除OmpF 10 mmol/L辛酸 比生长速率比对照菌高18% [18]
E.coli BL21 过表达膜蛋白CAV1 5 mmol/L壬酸 细胞存活率比对照菌高50% [45]
E.coli BL21 筛选获得异源转运蛋白AcrE和AcrF并过表达 MCFAs产量提高2.5倍,2.0 g/L [46]
应激响应调控 S.cerevisiae 动态调控肌动蛋白细胞骨架表达水平 0.20 mmol/L癸酸 最大OD600比对照菌高36%,MCFAs产量比对照菌高37.3%,692.3 mg/L [47]
E.coli BL21 过表达rcsB和dsrA基因激活GDAR耐酸系统 5 mmol/L庚酸 细胞存活率比对照菌高28% [48]
表1  理性代谢工程构建MCFAs耐受性菌株策略
图2  膜改造示意图
策略 菌株 方法 胁迫条件 耐受表型及产量 参考文献
适应性进化 E.coli MG1655 基因waaG突变恢复、rpoC、basR突变组合表达 20 mmol/L辛酸 比生长速率比对照菌高2.2倍,MCFAs产量提高近10倍,780 mg/L [59- 60]
S.cerevisiae 敲除基因pdr1和osh2 2.77 mmol/L辛酸 比生长速率提高近5倍,MCFAs产量提高0.3~2.2倍 [13]
E.coli MG1655 敲除基因fadD 19 mmol/L壬酸 能够耐受胁迫条件,并以壬酸为碳源 [61]
E.coli 自然恶劣环境进化 10 mmol/L辛酸 MCFAs产量比对照菌高约5倍,251 mg/L [62]
代谢通量分析 E.coli MG1655 外源补充丙酮酸 25 mmol/L辛酸 生长速率提高25.8% [63]
E.coli MG1655 过表达fabZ并敲除fadE、fumAC、ackA 辛酸产量提高82%,500 mg/L [64]
组学分析 S.cerevisiae 外源补充油酸 1 mmol/L辛酸 比生长速率比对照菌高6.9倍 [19]
S.cerevisiae 过表达基因RPL40B 辛酸产量提高40%,50.4 mg/L [65]
E.coli MG1655 敲除基因ompF 15 mmol/L辛酸 耐受前后OD600最大差值从3.1降低至2.7 [66]
S.cerevisiae 挖掘出MCFAs响应型启动子pPDR12、pTDH1和pPHO3 1 mmol/L己酸
或月桂酸		 能够响应MCFAs上调基因表达 [67]
表2  系统性靶点挖掘增强MCFAs耐受性策略
图3  适应性进化示意图
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