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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  2022, Vol. 42 Issue (7): 79-89    DOI: 10.13523/j.cb.2203042
综述     
辅因子在微生物细胞工厂中的代谢调控与应用*
贾男1,臧国伟1,李春1,2,**(),王颖1,**()
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 北京理工大学化学与化工学院 生物化工研究所 北京 100081
2. 清华大学化学工程系 北京 100084
Metabolic Regulations and Applications of Cofactors in Microbial Cell Factories
Nan JIA1,Guo-wei ZANG1,Chun LI1,2,**(),Ying WANG1,**()
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
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摘要：

生物体中大部分酶催化反应都需要辅因子参与,辅因子平衡对维持正常的细胞代谢至关重要,而辅因子失衡则会导致细胞生长和生产的紊乱。在微生物细胞工厂的构建中,通过调节辅因子代谢平衡来提高产物合成途径的效率,从而调控细胞生长与产物生产,使代谢流能够最大限度地流向目标产物,已经成为代谢调控的重要手段。目前常见的用于代谢调控的辅因子有NAD(P)H/NAD(P)+、辅酶、ATP/ADP等。围绕这几种辅因子的代谢途径及功能分类进行了综述,并总结了微生物中不同产物利用辅因子平衡策略进行合成调控的研究,以期为各类化合物的高效生物合成提供参考。
关键词： 辅因子工程;  微生物细胞工厂;  代谢工程;  生物制造    
Abstract:

Most of the enzyme-catalyzed reactions in organisms require the participation of cofactors. The balance of cofactors is essential to maintain normal cellular metabolism, and the imbalance of cofactors can lead to the inhibition of cell growth and production. In the construction of microbial cell factories, it has been considered to be an important strategy to regulate the balance of cofactor metabolism since the cofactor regulation could be employed to improve the efficiency of synthetic pathway of products and thus balance the cell growth and products synthesis, achieving the maximum metabolic flux towards the target products. Common cofactors currently used for metabolic regulation include NAD(P)H/NAD(P)+, coenzyme, and ATP/ADP. The metabolic pathways and functional classifications of these cofactors are reviewed, and the studies on the synthesis regulation of different products in microorganisms using cofactor balancing strategies are summarized. This paper will provide references for the efficient biosynthesis of various compounds.
Key words: Cofactor engineering    Microbial cell factory    Metabolic engineering    Biological manufacturing
收稿日期: 2022-03-18 出版日期: 2022-08-03
ZTFLH:  Q819  
基金资助: *国家重点研发计划(2019YFA0905700);国家重点研发计划(2019YFA0901800);国家自然科学基金(22078020)
通讯作者: 李春,王颖     E-mail: wy2015@bit.edu.cn;lichun@tsinghua.edu.cn
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贾男
臧国伟
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引用本文:

贾男,臧国伟,李春,王颖. 辅因子在微生物细胞工厂中的代谢调控与应用*[J]. 中国生物工程杂志, 2022, 42(7): 79-89.

Nan JIA,Guo-wei ZANG,Chun LI,Ying WANG. Metabolic Regulations and Applications of Cofactors in Microbial Cell Factories. China Biotechnology, 2022, 42(7): 79-89.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2203042    或    https://manu60.magtech.com.cn/biotech/CN/Y2022/V42/I7/79

图1  辅因子的关键代谢途径
代谢产物 辅因子 底盘细胞 调控优化策略 效果
异戊二烯 NADPH Escherichia coli 引入1,3-丙二醇合成途径,使过量的NADPH被利用 异戊二烯和1,3-丙二醇产量分别提升3.3倍和4.3倍[44]
2,3-丁二醇 NADH Saccharomyces
cerevisiae		 过表达乳酸乳球菌Lactococcus lactis来源的NADH氧化酶基因noxE,消耗过量的NADH 2,3-丁二醇产量提高1.3倍[31]
2,3-丁二醇 NADH Bacillus subtilis 过表达可溶性转氢酶基因udhA,促进NADH再生;敲除乳酸脱氢酶基因ldh,减少NADH的消耗 2,3-丁二醇产量提高22.82%[46]
异丁醇 NAD(P)H Shimwellia blattae 引入NADH依赖性乙醇脱氢酶AdhA来降低对NADPH的依赖;过表达转氢酶PntAB,增加NADPH水平 AdhA和PntAB的表达分别将异丁醇收率从11.9%提高到14.4%和16.4%[42]
异丁醇 NADPH Bacillus
licheniformis		 过表达来自苏云金芽孢杆菌B. thuringiensis的NADP+依赖性甘油醛-3-磷酸脱氢酶的基因gapN,促进NADPH再生 异丁醇产量从7.52 g/L增加到7.81 g/L,胞内NADPH/NADP+值比出发菌株提高了1.3倍[43]
7-脱氢胆固醇 NADH Saccharomyces
cerevisiae		 过表达来自肺炎链球菌Streptococcus pneumoniae的NADH氧化酶NOX和荚膜组织胞浆菌Histoplasma capsulatum的交替氧化酶AOX1,消耗过量的NADH 7-脱氢胆固醇产量增加了74.4%[41]
乙偶姻 NADH Candida glabrata 过表达乳酸乳球菌Lactococcus lactis来源的NADH氧化酶NOX,消耗过量的NADH 乙偶姻产量提高2.3倍[39]
D-葡糖二酸 NADH Escherichia coli 过表达戊糖乳杆菌Lactobacillus pentosus来源的NADH氧化酶,消耗过量的NADH D-葡糖二酸产量从4.56g/L提高到5.12 g/L[40]
聚-γ-谷氨酸 NAD(P)H Bacillus
licheniformis		 获得谷氨酸脱氢酶突变体RocGD276E,辅因子偏好性从NADPH转变为NADH 产量增加了40.50%,副产物乙偶姻和2,3-丁二醇产率分别下降21.70%和16.53%[38]
赖氨酸 NADH Corynebacterium
glutamicum		 鉴定了四种NADH脱氢酶:PaASPDH、TmASADH、EcDHDPR和PtDAPDH,赖氨酸合成可利用NADH 在菌株LC298中分别过表四种NADH脱氢酶,赖氨酸的产量分别增加了30.7%、32.4%、17.4%和36.8%[47]
2-苯乙醇 NAD(P)H Escherichia coli 将谷氨酸脱氢酶与转氨酶和乙醇脱氢酶偶联,开发辅因子自给自足系统 2-苯乙醇生物催化效率提高了3.8倍[48]
1,3-丙二醇 NADH Pseudomonas
denitrificans		 敲除编码NADH脱氢酶I的nuo操纵子基因和NADH脱氢酶II的ndh基因,降低NADH的氧化 1,3-丙二醇的产率达到0.89 mol/mol甘油[35]
丙酮酸 NADH Saccharomyces
cerevisiae		 过表达来自大肠杆菌的可溶性转氢酶基因udhA,促进NADH生成 丙酮酸产量达到75.1 g/L,与原始菌株相比增加了21%[49]
丁醇 NAD(P)H Clostridium sp. 在培养基中添加不同剂量L-色氨酸,作为辅因子NAD(P)H生产途径的前体 细胞内NADH和NADPH的水平增加了67%[45]
ω-羟基棕
榈酸		 NADH Escherichia coli 过表达念珠菌Candida boidinii的NAD+依赖性甲酸脱氢酶FDH,敲除乙醇脱氢酶ADH,促进NADH再生 NADH的量达到610 mg/L,与对照相比产量几乎增加了3倍[50]
白桦酸 NAD(P)H Yarrowia lipolytica 过表达外源苹果酸酶EMC、EMT、Rtme和3-磷酸甘油醛脱氢酶Gapc,增强NAD(P)H的供应 桦木酸的最终产量达到51.87 mg/L[51]
L-缬氨酸 NAD(P)H Escherichia coli 乙酰羟酸异构还原酶被偏好NADH的突变体取代,支链氨基酸氨基转移酶被枯草芽孢杆菌Bacillus subtilis的亮氨酸脱氢酶取代,重新平衡NAD(P)H/NAD(P)+ L-缬氨酸产量由1.63 g/L提高到10.77 g/L[33]
表1  NAD(P)H辅因子调控策略
代谢产物 辅因子 底盘细胞 调控优化策略 效果
4-羟基苯
乙酸		 NADPH Escherichia coli 通过CRISPRi抑制消耗NADPH酶编码基因的表达 敲除NADPH依赖性醛还原酶基因yahK,4-羟基苯乙酸产量提高了67.1%[34]
N-乙酰葡
糖胺		 NAD(P)H Corynebacterium
glutamicum		 通过定点诱变将NAD+依赖性的3-磷酸甘油醛脱氢酶和苹果酸脱氢酶的转变为NADP+依赖性的酶 摇瓶中N-乙酰葡糖胺的产量从27.5 g/L提高到36.9 g/L[37]
甲羟戊酸 NAD(P)H Escherichia coli 敲除磷酸葡萄糖异构酶基因pgi,使碳通量更多地流向戊糖磷酸途径以生成更多NADPH 胞内NADPH/NADP+值比野生型高约7倍[36]
表1  续
代谢产物 底盘细胞 调控优化策略 效果
香叶醇 Saccharomyces
cerevisiae		 将线粒体中的乙酰辅酶A作为底物,靶向香叶醇生物合成途径至线粒体 香叶醇产量提高6倍[57]
1-十六烷醇 Saccharomyces
cerevisiae		 过表达拟南芥来源的柠檬酸裂解酶ACL,促进乙酰辅酶A的合成 将1-十六烷醇产量从140 mg/L增加到217 mg/L[71]
正丁醇 Saccharomyces
cerevisiae		 过表达胺氧化酶Fms1编码基因,提高胞内前体辅酶A的含量 正丁醇产量从165 mg/L提高到243 mg/L[72]
游离脂肪酸 Saccharomyces
cerevisiae		 使3-磷酸甘油脱氢酶失活,碳通量重定向到丙酮酸和乙醛;过表达来源于解脂耶氏酵母的柠檬酸裂解酶ACL,促进乙酰辅酶A合成 两种代谢调控策略分别使游离脂肪酸产量提高23%和26%[73]
1-丁醇 Saccharomyces
cerevisiae		 过表达乙醛脱氢酶ALD6和乙醇脱氢酶ADH2,过表达肠沙门菌Salmonella enterica来源的乙酰辅酶A合酶突变体ACSL641P,促进乙酰辅酶A合成 将1-丁醇产量从2 mg/L增加到10.3 mg/L[60]
三乙酸内酯 Saccharomyces
cerevisiae		 引入大肠杆菌PDH旁路基因,促进乙酰辅酶A的合成 乙酰辅酶A水平提高2倍,三乙酸内酯产量提高30%[74]
β-香树脂醇 Saccharomyces
cerevisiae		 敲除柠檬酸合酶CIT2编码基因,减少乙酰辅酶A的消耗 β-香树脂醇产量提高了近330%[59]
α-葎草烯 Saccharomyces
cerevisiae		 以过氧化物酶体乙酰辅酶A为底物,将α-葎草烯生物合成途径重新定位至过氧化物酶体 α-葎草烯产量提高2.5倍[58]
(2S)-柚皮素 Saccharomyces
cerevisiae		 过表达过氧化物酶体增殖蛋白PEX11编码基因,增强脂肪酸的β氧化,增加乙酰辅酶A供应 (2S)-柚皮素产量提高了30.26%[75]
聚-β-羟丁酸 Escherichia coli 对糖酵解途径进行改造,过表达磷酸丙酮异构酶基因tpiA和果糖二磷酸醛缩酶基因fbaA 聚-β-羟丁酸产量从0.4 g/L提高到1.6 g/L[68]
丙二酰辅酶A Escherichia coli 改造三羧酸循环途径,敲除延胡索酸酶基因fumB/C或琥珀酰辅酶A合成酶基因sucC 丙二酰辅酶A产量为4.43 μmol/g DW,提高了近4倍[69]
3-羟基丙酸 Escherichia coli 改造β氧化途径,敲除脂肪酸氧化调节因子基因fadR,过表达脂酰辅酶A脱氢酶基因fadE、脂酰辅酶A合酶基因fadD、脂肪酸氧化酶基因fadBA、脂肪酸外膜孔蛋白基因fadL 3-羟基丙酸产量最终达到52 g/L[70]
香草醛 Escherichia coli 改造乙醛酸途径,敲除异柠檬酸脱氢酶IDH,增加乙酰辅酶A通量 香草醛的产量从0.79 g/L提高到了2.06 g/L[76]
表2  酿酒酵母和大肠杆菌中乙酰辅酶A调控策略
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