微生物发酵法合成虾青素的研究进展

doi:10.12211/2096-8280.2023-065

合成生物学 ›› 2024, Vol. 5 ›› Issue (1): 126-143.DOI: 10.12211/2096-8280.2023-065

微生物发酵法合成虾青素的研究进展

周强¹, 周大伟¹, 孙敬翔¹, 王靖楠¹, 姜万奎¹, 章文明¹^,², 蒋羽佳¹^,², 信丰学¹^,², 姜岷¹^,²

^1.南京工业大学生物与制药工程学院，材料化学工程国家重点实验室，江苏南京 211816
^2.南京工业大学，江苏先进生物与化学制造协同创新中心（SICAM），江苏南京 210009

收稿日期:2023-09-14 修回日期:2023-11-20 出版日期:2024-02-29 发布日期:2024-03-20
通讯作者: 蒋羽佳,信丰学
作者简介:周强（2000—），男，硕士。研究方向为代谢工程及合成生物学。 E-mail：2278766279@qq.com
蒋羽佳（1991—），女，博士，副教授，硕士生导师。研究方向为可再生生物能源底盘细胞的开发与利用，低劣生物质高值化利用的人工多细胞体系构建及菌株间互作机制解析。 E-mail：jiangyujia@njtech.edu.cn
信丰学（1982—），男，博士，教授，博士生导师。研究方向为：①木质纤维素、厨余垃圾等废弃碳资源的生物降解与大宗化学品、生物燃料的合成；②CBP和精细化学品合成人工混菌体系的设计、构建与功能调控；③GRAS级安全酵母的开发和细胞工厂构建，尤其针对功能脂肪酸、胡萝卜素、虾青素等医药营养品。 E-mail：xinfengxue@njtech.edu.cn
基金资助:
国家自然科学基金面上项目(22178169);江苏省杰出青年基金(BK20220052);山东省泰山产业领军人才工程(202306155)

Research progress in synthesis of astaxanthin by microbial fermentation

Qiang ZHOU¹, Dawei ZHOU¹, Jingxiang SUN¹, Jingnan WANG¹, Wankui JIANG¹, Wenming ZHANG¹^,², Yujia JIANG¹^,², Fengxue XIN¹^,², Min JIANG¹^,²

^1.State key Laboratory of Materials Chemical Engineering，College of Biological and Pharmaceutical Engineering，Nanjing Tech University，Nanjing 211816，Jiangsu，China
^2.Jiangsu Advanced Biological and Chemical Manufacturing Collaborative Innovation Center （SICAM），Nanjing Tech University，Nanjing 210009，Jiangsu，China

Received:2023-09-14 Revised:2023-11-20 Online:2024-02-29 Published:2024-03-20
Contact: Yujia JIANG, Fengxue XIN

摘要/Abstract

摘要：

虾青素是一种高附加值的抗氧化萜类物质，具有很强的抗氧化活性，同时还具有抗癌、预防炎症、护眼等诸多功效。随着合成生物学技术的不断发展，利用微生物发酵法合成虾青素是实现虾青素工业化生产最有效的途径之一，也更能满足消费者对天然化合物的需求。目前，生产虾青素的微生物包括细菌、真菌、藻类等。本文系统介绍了虾青素的结构性质和生产方法，重点讲述了虾青素天然合成以及外源构建的合成路径，总结了不同微生物如雨生红球藻、酵母和大肠杆菌生产虾青素的最新进展，分析了利用基因工程和发酵过程调控手段提高虾青素产量的方法。未来，通过代谢工程等手段（如虾青素合成基因过表达、使用高强度启动子、代谢途径优化等）可提高虾青素产量，以进一步增加虾青素在食品、医疗、化妆品和饲料等产业的应用。

关键词: 微生物, 虾青素, 萜类物质, 生物合成

Abstract:

Astaxanthin is a value-added terpene with strong antioxidant activity as well as other physiological functions, such as anti-cancer, enhancing immunity, eye protection, and cardio-cerebrovascular protection. Natural astaxanthin mainly comes from algae and aquatic crustaceans such as lobster shell. Astaxanthin presents with stereoisomerism and geometric isomerism, which have different biological activities and applications. Currently, astaxanthin in the market is obtained primarily through natural extraction from Haematococcus pluvialis or Xanthophyllomyces dendrorhous and chemical synthesis as well. While H. pluvialis has a long growth cycle and high light demand, leading to low biomass productivity and extraction rate for high production cost of astaxanthin, X. dendrorhous has a low astaxanthin yield and is easy to degenerate, making them challenging for the large-scale commercial production. The chemical synthesis of astaxanthin involves multiple reactions with complicated processes, producing mixed isomers and various byproducts, which consequently compromises its antioxidant capacity. Moreover, the assimilation and utilization of chemically synthesized astaxanthin in vivo is poor compared to its natural product, making it not suitable for being used by human being. With the continuous development of synthetic biology, microbial fermentation has been developed as an effective way for the commercial production of astaxanthin to better meet consumer demand. At present, astaxanthin-producing microorganisms include bacteria, fungi, and algae. This review introduces astaxanthin's structure, properties, production methods, and processes for its extraction and purification, with an emphasis on natural and engineered biosynthetic pathways. The latest progress in the production of astaxanthin by different microorganisms such as H. pluvialis, Yarrowia lipolytica and Escherichia coli is summarized, along with strategies for increasing astaxanthin production through genetic engineering and fermentation process optimization. Future metabolic engineering strategies are proposed, such as over-expression of astaxanthin synthesis genes, promoters with higher substitution intensity, subcellular localization, metabolic pathway optimization, etc, to increase astaxanthin yield for wide usage in food, medical, cosmetic and feed industries.

Key words: microorganisms, astaxanthin, terpenoids, biosynthesis

中图分类号:

TQ929

周强, 周大伟, 孙敬翔, 王靖楠, 姜万奎, 章文明, 蒋羽佳, 信丰学, 姜岷. 微生物发酵法合成虾青素的研究进展[J]. 合成生物学, 2024, 5(1): 126-143.

Qiang ZHOU, Dawei ZHOU, Jingxiang SUN, Jingnan WANG, Wankui JIANG, Wenming ZHANG, Yujia JIANG, Fengxue XIN, Min JIANG. Research progress in synthesis of astaxanthin by microbial fermentation[J]. Synthetic Biology Journal, 2024, 5(1): 126-143.

图/表 8

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菌株	碳源	菌株类型	浓度/产量	发酵模式	参考文献
X. dendrorhous	葡萄糖	野生菌	27.05 mg/L	30L发酵罐	[37]
X. dendrorhous	葡萄糖	诱变菌	85.02 mg/L	5L发酵罐	[38]
X. dendrorhous	甜高粱蔗渣	野生菌	48.9 mg/L	分批补料发酵	[39]
X. dendrorhous	葡萄糖	诱变菌	9.7 mg/g	1.3L发酵罐	[40]
X. dendrorhous	葡萄糖	野生菌	67.9 mg/L	分批补料发酵	[41]

菌株	碳源	菌株类型	浓度/产量	发酵模式	参考文献
X. dendrorhous	葡萄糖	野生菌	27.05 mg/L	30L发酵罐	[37]
X. dendrorhous	葡萄糖	诱变菌	85.02 mg/L	5L发酵罐	[38]
X. dendrorhous	甜高粱蔗渣	野生菌	48.9 mg/L	分批补料发酵	[39]
X. dendrorhous	葡萄糖	诱变菌	9.7 mg/g	1.3L发酵罐	[40]
X. dendrorhous	葡萄糖	野生菌	67.9 mg/L	分批补料发酵	[41]

菌株	碳源	菌株类型	浓度/产量	发酵模式	参考文献
S. cerevisiae	葡萄糖	表达不同来源的crtW和crtZ，替换不同强度的启动子	81 mg/L	5L发酵罐	[45]
S. cerevisiae	葡萄糖	定向协同进化获得关键基因的突变体，借助温度调节响应系统	235 mg/L	5L发酵罐	[46]
S. cerevisiae	葡萄糖	适度调节脂质代谢的相关基因，平衡crtW和crtZ的表达	446.4 mg/L	5L发酵罐	[47]
S. cerevisiae	葡萄糖	组成型启动子表达crtW，诱导型启动子表达crtZ	464.09 mg/L		[48]

菌株	碳源	菌株类型	浓度/产量	发酵模式	参考文献
S. cerevisiae	葡萄糖	表达不同来源的crtW和crtZ，替换不同强度的启动子	81 mg/L	5L发酵罐	[45]
S. cerevisiae	葡萄糖	定向协同进化获得关键基因的突变体，借助温度调节响应系统	235 mg/L	5L发酵罐	[46]
S. cerevisiae	葡萄糖	适度调节脂质代谢的相关基因，平衡crtW和crtZ的表达	446.4 mg/L	5L发酵罐	[47]
S. cerevisiae	葡萄糖	组成型启动子表达crtW，诱导型启动子表达crtZ	464.09 mg/L		[48]

菌株	碳源	改造策略	浓度/产量	发酵模式	参考文献
Y. lipolytica	葡萄糖	表达不同来源的crtW和crtZ，增加关键基因拷贝数	54.6 mg/L	96深孔板培养	[59]
Y. lipolytica	葡萄糖	定位于不同的亚细胞器	858 mg/L	3L发酵罐	[60]
Y. lipolytica	蔗糖	加入外源油相，模块化工程途径融合关键基因	973.4 mg/L	3L发酵罐	[61]
Y. lipolytica	葡萄糖	表达来自雨生红球藻的关键基因，通过短肽连接，增加融合酶的拷贝数	3.3 g/L	分批补料发酵	[62]
Y. lipolytica	葡萄糖	表达来自夏侧金盏花的关键基因，引入crtX基因	3.46 mg/L	摇瓶发酵	[63]
Y. lipolytica		组合表达不同来源的crtW和crtZ	99 mg/L	摇瓶发酵	[64]

微生物发酵法合成虾青素的研究进展

Research progress in synthesis of astaxanthin by microbial fermentation

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菌株	碳源	改造策略	浓度/产量	发酵模式	参考文献
E. coli	酵母粉	表达伴侣基因ApcpnA和ApcpnB	890 μg/g	摇瓶发酵	[74]
E. coli	酵母粉	表达MEP途径关键基因与MVA途径共表达	1100 μg/g	摇瓶发酵	[75]
E. coli	酵母粉	表达类异戊二烯途径关键基因与MVA途径共表达	1200 μg/g	摇瓶发酵	[76]
E. coli	葡萄糖	通过γ-Red重组技术将虾青素合成途径的基因整合到大肠杆菌染色体中	1.4 mg/g	摇瓶发酵	[77]
E. coli	蔗糖	表达不同来源的crtW和crtZ，平衡相关基因的活性	7.4 mg/g	摇瓶发酵	[78]
E. coli	葡萄糖	表达不同来源的crtW和crtZ，通过短肽连接关键基因	5.18 mg/g	摇瓶发酵	[79]
E. coli	葡萄糖	表达不同来源的crtW和crtZ，表达不同强度的启动子	4.3 mg/g	摇瓶发酵	[80]
E. coli	酵母粉	删除形态、膜、氧化应激相关基因，建立温度敏感质粒互补表达系统	11.92 mg/g	摇瓶发酵	[81]
E. coli	甘油	对crtW进行随机突变，通过Cre-loxP平衡增加基因拷贝数	5.88 mg/g	7L发酵罐	[82]
E. coli	甘油	增加crtYB的拷贝数，调节操纵子的表达水平	6.17 mg/g	5L发酵罐	[20]
E. coli	甘油	筛选不同来源的crtZ并对这些不同底物偏好的酶进行联合利用	11.5 mg/g	5L发酵罐	[83]

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