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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志  2023, Vol. 43 Issue (1): 127-138    DOI: 10.13523/j.cb.2207046
综述     
酵母合成2'-岩藻糖基乳糖的研究进展*
杨洋,姚明东,王颖,肖文海**()
天津大学化工学院 系统生物工程教育部重点实验室 天津 300072
Research Progress of Synthesis of 2'-Fucosyllactose by Yeast
YANG Yang,YAO Ming-dong,WANG Ying,XIAO Wen-hai**()
Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
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摘要:

2'-岩藻糖基乳糖(2'-fucosyllactose,2'-FL)是人乳寡糖中含量最高的岩藻糖基化寡糖,具有促进双歧杆菌增殖和调节肠道菌群等作用,已被广泛用于婴幼儿食品行业。目前,2'-FL已经成功在大肠杆菌、酿酒酵母、解脂耶氏酵母、枯草芽孢杆菌和谷氨酸棒杆菌中实现从头合成。考虑到食品安全、消费者认知和接受程度,酵母作为GRAS(generally recognized as safe)菌株,在2'-FL的生物合成中更具工业应用前景和商业价值。概述2'-FL的生物合成路径和现状,对2'-FL生物合成常用的底盘细胞进行比较,从底物转运、前体GDP-L-岩藻糖供应、α-1, 2-岩藻糖基转移酶、产物外排和拓宽底物谱等方面综述酵母合成2'-FL的工程化策略,提出酵母合成2'-FL的限制性因素,并对未来研究进行展望。

关键词: 2'-岩藻糖基乳糖酵母α-1, 2-岩藻糖基转移酶合成生物学    
Abstract:

2'-Fucosyllactose is the richest fucosylated oligosaccharide in human milk oligosaccharides, which has been widely used in infant food industry due to its beneficial effect on promoting the proliferation of Bifidobacterium and regulating the balance of intestinal flora. At present, 2'-fucosyllactose has been successfully synthesized in several hosts, such as Escherichia coli, Saccharomyces cerevisiae, Yarrowia lipolytica, Bacillus subtilis and Corynebacterium glutamicum. Previous studies on the biosynthesis of 2'-fucosyllactose in Escherichia coli have been reviewed. In consideration of food safety, consumers’ cognition and acceptance, yeast, as a GRAS strain, has more industrial and commercial prospects for the biosynthesis of 2'-fucosyllactose. However, there are few reviews on the biosynthesis of 2'-fucosyllactose in yeast. Firstly, the current situation and several common hosts of biosynthesis of 2'-fucosyllactose are introduced and compared. Then, some engineering strategies of biosynthesis of 2'-fucosyllactose by yeast are introduced from five aspects, such as substrate transport, the supply of precursor GDP-L-fucose, α-1,2-fucosyltransferase, product efflux and broadening of the substrate spectrum. Finally, several limiting factors of yeast in the biosynthesis of 2'-fucosyllactose are put forward and the future development trends and prospects are discussed.

Key words: 2'-Fucosyllactose    Yeast    α-1,2-Fucosyltransferase    Synthetic biology
收稿日期: 2022-07-21 出版日期: 2023-02-14
ZTFLH:  Q819  
基金资助: *国家自然科学基金(22178261)
通讯作者: **肖文海 电子信箱:wenhai.xiao@tju.edu.cn   
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引用本文:

杨洋, 姚明东, 王颖, 肖文海. 酵母合成2'-岩藻糖基乳糖的研究进展*[J]. 中国生物工程杂志, 2023, 43(1): 127-138.

YANG Yang, YAO Ming-dong, WANG Ying, XIAO Wen-hai. Research Progress of Synthesis of 2'-Fucosyllactose by Yeast. China Biotechnology, 2023, 43(1): 127-138.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2207046        https://manu60.magtech.com.cn/biotech/CN/Y2023/V43/I1/127

图1  2'-岩藻糖基乳糖的功能和主要合成方法
图2  酵母合成2'-岩藻糖基乳糖的路径
底盘 优势 不足 产量现状 利用率 产率
/(g·L-1·
h-1)
参考文献
大肠
杆菌
代谢工程和合成生物学中应用最广泛的原核底盘;具有内源GDP-L-岩藻糖合成相关基因 可能的噬菌体和内毒素感染;GDP-L-岩藻糖是可拉酸的前体;存在乳糖代谢路径 100 g/L, 3 L
fed batch
- - [14-16,30]
枯草
芽孢
杆菌
GRAS;与真核表达系统相比,培养条件更简单,传代时间更短;目前未发现岩藻糖降解路径 代谢修饰导致生长较慢,产胞期影响发酵和蛋白酶分泌;相比大肠杆菌,可用的遗传元件和动态调控工具较少 5.01 g/L,
3 L fed batch
0.27 mol 2'-FL/
mol lactose,
0.85 mol 2'-FL/
mol fucose
0.1 [21-23]
谷氨
酸棒
杆菌
GRAS;具有内源基因manBmanC;较高的NADPH再生能力;GMP和GDP的含量高 基因编辑工具效率低;基因组中超过40%的基因功能未知 8.1 g/L,
2.5 L fed batch
0.42 mol 2'-FL/
mol lactose
0.07 [24-27]
酿酒
酵母
GRAS;代谢工程和合成生物学中应用最广泛的真核底盘;对苛刻的工业发酵条件有良好的耐受性;相对丰富的GDP-甘露糖胞内池 Crabtree effect;蛋白质的过度糖基化和低蛋白得率 26.63 g/L,
5 L fed batch
0.85 mol 2'-FL/
mol lactose
0.44 [13,28,30,33,37-38]
解脂
耶氏
酵母
GRAS;已用于类胡萝卜素、糖醇和核黄素等营养食品生产;在多种疏水性底物、碳源、pH和盐浓度条件下均可生长;高活性的三羧酸循环和磷酸戊糖途径 相比酿酒酵母,在代谢调控、遗传背景和生理特性等方面更复杂,可用的合成生物学工具较少 24 g/L, 2 L
fed batch
- 0.71 [29,38-39,42-43]
表1  2'-岩藻糖基乳糖生物合成常用底盘比较及实例
底盘 外源基因 策略 产量 产率/效率 参考文献
S.cerevisiae
D452-2
FKP-Bacteroides fragilis 9343、FucT2-Helicobacter pylori
Lac12-Kluyveromyces lactics
补救合成;筛选三种不同来源的FKP 0.503 g/L,125 mL fed batch 0.3 mol 2'-FL/mol lactose,0.63 mol 2'-FL/mol fucose [47]
S.cerevisiae
D452-2
Gmd,WcaG-E. coli K-12、
FucT2-Helicobacter pylori
Lac12-Kluyveromyces lactics
从头合成;优化乳糖浓度 0.51 g/L,125 mL fed batch 0.229 mol 2'-FL/mol lactose [44]
S.cerevisiae
PNY1500
GmdGMER-E. coli K-12、
FutC-Helicobacter pylori 26695、
Lac12-Kluyveromyces lactics
从头合成;筛选四种来源的Gmd-Gmer基因对;筛选四种来源的α-1, 2-岩藻糖基转移酶;增加α-1, 2-岩藻糖基转移酶的可溶性-N端融合SUMOstar标签;增加α-1, 2-岩藻糖基转移酶的拷贝数(双拷贝) 15 g/L,2 L fed batch 0.44 g/(L·h) [29]
底盘 外源基因 策略 产量 产率/效率 参考文献
Y.lipolytica
Y2224
Lac12-Kluyveromyces lactics
GmdGMER-Mortierella alpineFutC-Helicobacter pylori 26695
从头合成;增加Lac12GmdGMERFutC的拷贝数(双拷贝);增加α-1, 2-岩藻糖基转移酶的可溶性-N端融合;SUMOstar标签 24 g/L,2 L fed batch 0.71 g/(L·h) [29]
S.cerevisiae
D452-2
Lac12-Kluyveromyces lactics
GmdWcaG-E. coli K-12、
WbgL- E. coli O126
从头合成;木糖作为主要碳源;增加GmdWcaGWbgL的拷贝数(双拷贝) 25.5 g/L,1 L fed batch 0.35 g/(L·h),
0.82 mol 2'-
FL/mol lactose
[45]
S.cerevisiae
W303-1a
Lac12-Kluyveromyces lactics
GmdWcaG-E. coli K-12
从头合成;筛选不同来源的α-1, 2-岩藻糖基转移酶;过表达Sec53Psa1,增加GDP-甘露糖含量;删除gal80 26.63 g/L,5 L fed batch 0.44 g/(L·h),
0.85 mol 2'-
FL/mol lactose
[28]
表2  酵母生物合成2'-岩藻糖基乳糖的实例
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