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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 (4): 112-122    DOI: 10.13523/j.cb.2211030
综述     
微生物辅因子工程研究进展*
张鸿伟,王鹏超()
东北林业大学生命科学学院 哈尔滨 150040
Research Progress of Microbial Cofactor Engineering
ZHANG Hong-wei,WANG Peng-chao()
School of Life Sciences, Northeast Forestry University, Harbin 150040, China
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摘要：

微生物细胞中的大部分酶促反应都需要各种辅因子的参与,辅因子平衡对维持细胞内的生化反应稳态非常重要,辅因子供应不足会导致细胞生长和化合物生产的紊乱。近年来,辅因子在生化反应过程中的关键作用备受关注,但由于其价格较昂贵、稳定性差,因此限制了辅因子工程的发展。合成生物学和代谢工程的发展为辅因子的可持续供应提供了可行的解决方案,多种加强辅因子供应的策略有效地推动了目标化合物的生物合成。其中,烟酰胺类辅因子NAD(P)+、NAD(P)H是微生物代谢过程中最常见的氧化还原辅因子,它们在所有生物体内作为重要的电子受体或供体推动合成与分解代谢反应,对维持胞内氧化还原动态平衡起着决定性作用。从NAD(P)H的主要来源和NAD(P)+/NAD(P)H的平衡对天然产物生物合成中的影响出发,重点从三个不同维度讨论辅因子工程策略,综述代谢途径调节、外源氧化还原酶的引入、蛋白质工程等多种辅因子再生策略的最新研究进展及应用,展望辅因子代谢工程在生物合成中的未来发展方向。
关键词： 辅因子工程;  NAD(P)H/NAD(P)+;  氧化还原平衡;  代谢工程    
Abstract:

Various cofactors are required in the process of most enzyme-catalyzed reaction of cells. Cofactor balance is very important to maintain the homeostasis of biochemical reaction in cells. However, insufficient supply of cofactors will lead to the disorder of cell growth and compound production. In recent years, the key role of cofactors in the biochemical reaction process has attracted the attention of researchers, but most cofactors are expensive and have poor stability. These disadvantages have limited the potential application of cofactor engineering. The development of synthetic biology and metabolic engineering provides feasible solutions for the sustainable supply of cofactors, and multiple strategies to strengthen the supply of cofactors effectively promote the biosynthesis of target compounds. Among them, nicotinamide cofactors NAD(P)+ and NAD(P)H are the most common redox cofactors in the process of microbial metabolism. They are important electron receptors or donors in all organisms, promote synthesis and catabolism reactions, and play a decisive role in maintaining the dynamic balance of intracellular redox. Starting from the main sources of NAD(P)H and the influence of NAD(P)+/NAD(P)H balance in the synthesis of natural products, cofactor engineering strategies were reviewed from three different dimensions. This paper introduces the latest research progress and application of multiple cofactor regeneration strategies through metabolic pathway regulation, introduction of exogenous oxidoreductase, and protein engineering. The future development prospects of cofactor metabolic engineering in biosynthesis is also discussed.
Key words: Cofactor engineering    NAD(P)H/NAD(P)+    Redox balance    Metabolic engineering
收稿日期: 2022-11-14 出版日期: 2023-05-04
ZTFLH:  Q939  
基金资助: 中央高校基本科研业务费专项(2572022BD03);国家自然科学基金(31900064)
通讯作者: **电子信箱:pengchaowang1990@nefu.edu.cn   
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引用本文:

张鸿伟, 王鹏超. 微生物辅因子工程研究进展*[J]. 中国生物工程杂志, 2023, 43(4): 112-122.

ZHANG Hong-wei, WANG Peng-chao. Research Progress of Microbial Cofactor Engineering. China Biotechnology, 2023, 43(4): 112-122.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2211030    或    https://manu60.magtech.com.cn/biotech/CN/Y2023/V43/I4/112

图1  辅酶NAD(P)H和NAD(P)+的结构式
图2  微生物中辅因子NAD(P)H代谢的相关途径
优化方向 酶或因子 来源 辅因子 代谢产物 策略 结果 参考文献
内源基因
-敲除		 pgi Escherichia coli NADPH/
NADP+		 甲羟戊酸 敲除了竞争途径的关键基因pgi Δpgi株的NADPH/NADP+比野生株高约7倍,从20 g/L葡萄糖中产出8.0 g/L的甲羟戊酸 [46]
pfkA、pfkB Escherichia coli NADPH/
NADP+		 木糖醇 组合敲除sthA、pgi、pfkA和pfkB 基因,引入木糖还原酶(xylose reductase,XR)基因 利用15 L生物反应器从半纤维素水解液中产出131.6 g/L木糖醇 [47]
yahK Escherichia coli NADPH/
NADP+		 四氢叶酸(4-hydroxyphenylacetic acid,4HPAA) 经过CRISPRi筛选,将NADPH消耗酶编码基因yahK敲除 使4HPAA的产量从6.32 g/L增加到7.76 g/L [48]
内源基因
-过表达		 G6PDH Lactococcus
lactis		 NADPH/
NADP+		 L-5-甲基四氢叶酸(5-methyltetrahydrofolic acid,5-MTHF) 过表达G6PDH以加强生成NADPH NADPH浓度增加60%,5-MTHF产量增加35%(97 μg/L) [49]
ZWF1、GND1 Yarrowia
lipolytica		 NADPH/
NADP+		 赤藓糖醇 过表达ZWF1和GND1 以葡萄糖为碳源,在摇瓶中产出190 g/L的赤藓糖醇,比野生型菌株高23.5% [50]
Zwf1、Gnd1 Saccharomyces
cerevisiae		 NADPH/
NADP+		 咖啡酸 过表达zwf1和gnd1 将咖啡酸合成量提高到5.5 g/L,远高于已报道的0.8 g/L [51]
G6PD2、苹果酸酶(malic enzyme,ME2) Mortierella
alpina		 NADPH/
NADP+		 花生四烯酸 G6PD2和ME2共同过表达 产量达1.9 g/(L·d),比对照组高7.2倍 [52]
POS5 Saccharomyces
cerevisiae		 NADPH/
NADH		 角鲨烯 POS5和tHMG1共同过表达 共表达菌株的角鲨烯产量达58.6 mg/g细胞干重,与对照组相比增加27.5倍 [53]
内源基因
-调节因子		 Anr Pseudomonas
xtremaustralis		 NADPH/
NADP+		 - Anr的缺失,降低对氧化应激的耐受性 可降低NADPH/NADP+比率 [54]
Stb5 Saccharomyces
cerevisiae		 NADPH - STB5的缺失 NADPH水平显著降低 [55]
外源基因
-级联反应		 环己酮单加氧酶(cyclohexanone
monooxygenase,CHMO)、乙醇脱氢酶(alcohol dehydrogenase,ADH)、脂肪酶(lipase,CAL-A)		 Acinetobacter
calcoaceticus,
Candida
antarctica		 NADPH/
NADP+		 寡聚-ε-己内酯 外源三酶级联的引入,并对核糖体结合位点进行工程改造 20 mmol/L环己醇在16 h催化后几乎完全转化,对照组仅为20% [56]
膜结合转氢酶(membrane-bound transhydrogenase,PntAB)、NAD+激酶(NAD+ kinase,PpnK) Escherichia
coli,
Corynebacterium
lutamicum		 NADPH/
NADP+/
NAD+		 L-精氨酸 将外源膜结合转氢酶和NAD+激酶进行共表达 在5 L生物反应器中生成67.01 g/L的L-精氨酸,比原始菌株提高53.45% [57]
外源基因-过表达 甲酸脱氢酶(formate dehydrogenase,FDH) Mycobacterium
vaccae		 NADPH/
NADP+		 (2R, 5R)-二氢香芹酮 过表达外源FDH (R)-香芹酮转化率高达96.0%~99.2% [58]
谷氨酸脱氢酶(glutamate dehydrogenase,EcGDH) Escherichia coli NADPH/
NADP+		 2-苯乙醇 将EcGDH与外源转氨酶、乙醇脱氢酶在大肠杆菌中偶联过表达 生物催化效率提高3.8倍,获得43.6 mmol/L 2-苯乙醇 [59]
预苯酸脱氢酶(prephenate dehydrogenase,TyrAfbr) Escherichia coli NADH/
NAD+		 羟基酪醇 外源引入TyrAfbr 与基础菌株相比,最终产物羟基酪醇产量提高了36.9%,达到1.12 g/L [60]
GAPDH、谷氨酸脱氢酶(glutamate dehydrogenase,ROCDH) Clostridium acetobutylicum,Bacillus subtilis NAD(P)H L-鸟氨酸 将不同的外源脱氢酶基因过表达 产生14.84 g/L的L-鸟氨酸,产量增加52.83% [26]
表1  NAD(P)H相关内源和外源基因在辅因子调控中的策略
图3  辅因子再生策略
酶 来源 突变位点 功能 参考文献
SH Ralstonia eutropha E341A、S342R 使偏好从NAD+转变为NADP+ [64]
XR Pichia stipitis R276H 使偏好从NADPH转变为NADH [14]
CcIDH Campylobacter concisus Leu580、Leu591、Ala640 使偏好从NAD+转变为NADP+ [19]
GAPDH、MDH Corynebacterium glutamicum S9114 N208R、E47G、A51S 使GlcNAc的产量提高6.15倍 [3]
BstFDH Burkholderia stabilis G146M、A287G 与NADP+结合活性提高, K m N A D P +降低至0.09 mmol/L [66]
KpADH Kluyveromyces polysporus V84I、Y127M 提高了对NADP+的亲和力,kcat/Km比WTKpADH
高11.6倍		 [67]
CbADH Clostridium beijerinckii S24P、G182A、G196A、H222D、S250E、S254R 可溶性和高表达活性分别是野生型的16倍和3倍,进行产物转化时6 h内转化率达100% [68]
BsGDH、LkCR Lactobacillus kefir、Bacillus subtilis - 利用ER/K-10 nm连接肽融合表达,大幅消耗
1.2 mol的底物		 [69]
表2  蛋白质工程在辅因子调控中的策略
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