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中国生物工程杂志

China Biotechnology
China Biotechnology
China Biotechnology  2023, Vol. 43 Issue (1): 127-138    DOI: 10.13523/j.cb.2207046
    
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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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     
Received: 21 July 2022      Published: 14 February 2023
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Yang YANG
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Cite this article:

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.

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

Fig.1 Functions and main synthetic methods of 2'-fucosyllactose
Fig.2 The biosynthetic pathway of 2'-fucosyllactose in yeast Lac12: Lactose permease; Pmi40: Mannose-6-phosphate isomerase; Sec53: Phosphomannomutase; Psa1: GDP-mannose pyrophosphorylase; CDT2: Cellodextrin transporter
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manB和manC;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]
Table 1 Comparison of common hosts for the biosynthesis of 2'-fucosyllactose and examples
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		 Gmd、GMER-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、
Gmd、GMER-Mortierella alpine、FutC-Helicobacter pylori 26695		 从头合成;增加Lac12、Gmd、GMER、FutC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、
Gmd、WcaG-E. coli K-12、
WbgL- E. coli O126		 从头合成;木糖作为主要碳源;增加Gmd、WcaG、WbgL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、
Gmd、WcaG-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Sec53和Psa1,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]
Table 2 Examples of biosynthesis of 2'-fucosyllactose by yeast
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