生物合成红景天苷的研究进展

doi:10.12211/2096-8280.2024-076

合成生物学 ›› 2025, Vol. 6 ›› Issue (2): 391-407.DOI: 10.12211/2096-8280.2024-076

生物合成红景天苷的研究进展

黄姝涵¹, 马赫¹, 罗云孜¹^,²^,³^,⁴

^1.天津大学化工学院，教育部合成生物学前沿科学中心，天津 300072
^2.天津大学合成生物技术全国重点实验室，天津 300072
^3.物质绿色创造与制造海河实验室，天津 300192
^4.天津大学佐治亚理工大学深圳学院，广东深圳 518071

收稿日期:2024-10-18 修回日期:2025-03-09 出版日期:2025-04-30 发布日期:2025-05-20
通讯作者: 罗云孜
作者简介:黄姝涵（2002—），女，硕士研究生。研究方向为天然产物的生物合成。E-mail：huangshuhan@tju.edu.cn
马赫（1999—），男，博士研究生。研究方向为天然产物的生物合成。E-mail：2021207667@tju.edu.cn
罗云孜（1985—），女，博士，教授，博士生导师。研究方向为合成生物学。E-mail：yunzi.luo@tju.edu.cn
第一联系人：黄姝涵、马赫为共同第一作者
基金资助:
国家自然科学基金(32471492);物质绿色创造与制造海河实验室(24HHWCSS00006);广东省重点研发计划(2020B0303070002)

Research progress in the biosynthesis of salidroside

HUANG Shuhan¹, MA He¹, LUO Yunzi¹^,²^,³^,⁴

^1.Frontiers Science Center for Synthetic Biology （Ministry of Education），School of Chemical Engineering and Technology，Tianjin University，Tianjin 300072，China
^2.State Key Laboratory of Synthetic Biology，Tianjin University，Tianjin 300072，China
^3.Haihe Laboratory of Sustainable Chemical Transformations，Tianjin 300192，China
^4.Georgia Tech Shenzhen Institute，Tianjin University，Shenzhen 518071，Guangdong，China

Received:2024-10-18 Revised:2025-03-09 Online:2025-04-30 Published:2025-05-20
Contact: LUO Yunzi

摘要/Abstract

摘要：

红景天苷是一种具有抗缺氧、抗氧化、抗衰老和抗肿瘤等活性的天然产物，被广泛应用于化妆品与医药领域。目前获取红景天苷的主要方式是从红景天属植物的根茎和块茎中提取，由于其含量稀少，日益增长的市场需求导致植物资源逐渐匮乏。因此，开发新的合成方法成为了研究热点。红景天苷的天然生物合成路径已被解析，随着合成生物学的发展，采用合成生物技术构建微生物细胞工厂合成红景天苷成为缓解当前供需失衡和资源紧缺状况的有效途径。本文针对红景天苷的药理活性、植物合成路径、途径酶的挖掘与筛选、大肠杆菌和酿酒酵母的生物合成现状等相关研究进展进行系统性的综述，探讨了红景天苷的分离提纯方法以及它作为合成中间体在制备其他化合物方面的应用潜力，以期助力对红景天苷合成路径与相关工程改造策略的理解，并推动红景天苷绿色、高效的生物合成。

关键词: 红景天苷, 微生物合成, 合成生物学, 代谢工程, 化妆品

Abstract:

Salidroside, a natural product known for its anti-hypoxia, anti-oxidation, anti-inflammatory, anti-aging, and anti-tumor properties, is extensively utilized in the food, cosmetics and pharmaceutical industries. Traditionally, salidroside has been obtained through the extraction from the rhizomes and tubers of Rhodiola species, including water extraction, two-phase aqueous extraction, supercritical CO₂ extraction and microwave assisted extraction. However, its low natural abundance (with the salidroside content in rhizomes and tubers of Rhodiola species ranging from 0.5% to 0.8%), coupled with escalating demand, has led to a progressive depletion of these plant resources. Given the broad application potential of salidroside, the rapid growth of market demand, and the increasing scarcity of natural resources, there is an urgent need to develop innovative synthetic approaches for this valuable compound. Chemical synthesis of salidroside is characterized by its efficiency and rapid processing time. However, the use of strong acids, bases, and catalysts with heavy metal ions in the synthesis process poses challenges for the separation of salidroside with environmental risks. In recent years, with the advancements in synthetic biology, the construction of microbial cell factories for the biosynthesis of salidroside has become a viable strategy for addressing the current supply-demand imbalance and resource scarcity associated with the natural biosynthetic pathway of salidroside. To enhance the production of salidroside biosynthesis, two major strategies can be employed. First, metabolic engineering approaches can be used to overexpress key genes in the synthesis pathways while knocking out or downregulating the expression of genes related to the bypass routes, thereby increasing precursor accumulation and enhancing the metabolic flux. Second, enzyme engineering can be applied to improve the catalytic efficiency and regioselectivity of natural glycosyltransferases, which often exhibit low activity and poor selectivity. Sequence alignment techniques can be used to identify and screen potential glycosyltransferases from various biological genomes. Additionally, protein engineering combined with computational approaches can be utilized to optimize these enzymes to meet specific requirements, ultimately improving the production of salidroside. In this comprehensive review, we systematically assess the pharmacological activities of salidroside, the plant biosynthetic pathway, the mining and screening of the enzymes, and the biosynthetic advancements in Escherichia coli and Saccharomyces cerevisiae. Additionally, we discuss the separation and purification methods of salidroside and its application potential as a synthetic intermediate in the preparation of other compounds, such as hydroxysalidroside, verbascoside and echinacoside. This review aims to enhance the understanding of the biosynthetic pathway of salidroside, thereby promoting a greener and more efficient biosynthetic approach to salidroside production.

Key words: salidroside, microbial synthesis, synthetic biology, metabolic engineering, cosmetics

中图分类号:

Q819

黄姝涵, 马赫, 罗云孜. 生物合成红景天苷的研究进展[J]. 合成生物学, 2025, 6(2): 391-407.

HUANG Shuhan, MA He, LUO Yunzi. Research progress in the biosynthesis of salidroside[J]. Synthetic Biology Journal, 2025, 6(2): 391-407.

图/表 6

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酶的名称	酶的来源植物	酶的功能	红景天苷产量（mg/L）、干重（mg/g DW）或酶活K_cat/K_m[L/（mmol·s）]	参考文献
Rr4HPAAS	蔷薇红景天	4-羟基苯乙醛合酶	11.71 L/（mmol·s）	[60]
RrUGT29	蔷薇红景天	糖基转移酶	316.04 L/（mmol·s）	[60]
RrUGT32	蔷薇红景天	糖基转移酶	NA	[60]
RrUGT33	蔷薇红景天	糖基转移酶	420.60 L/（mmol·s）	[60]
AtUGT73C5	拟南芥	糖基转移酶	NA	[61]
AtUGT73C6	拟南芥	糖基转移酶	NA	[61]
AtUGT85A1	拟南芥	糖基转移酶	288.00 mg/L	[61]
RsUGT73B6	库页红景天	糖基转移酶	8.76 mg/g DW	[62]
RsUGT72B14	库页红景天	糖基转移酶	19.81 mg/g DW	[62]
RsUGT74R1	库页红景天	糖基转移酶	5.72 mg/g DW	[62]

酶的名称	酶的来源植物	酶的功能	红景天苷产量（mg/L）、干重（mg/g DW）或酶活K_cat/K_m[L/（mmol·s）]	参考文献
Rr4HPAAS	蔷薇红景天	4-羟基苯乙醛合酶	11.71 L/（mmol·s）	[60]
RrUGT29	蔷薇红景天	糖基转移酶	316.04 L/（mmol·s）	[60]
RrUGT32	蔷薇红景天	糖基转移酶	NA	[60]
RrUGT33	蔷薇红景天	糖基转移酶	420.60 L/（mmol·s）	[60]
AtUGT73C5	拟南芥	糖基转移酶	NA	[61]
AtUGT73C6	拟南芥	糖基转移酶	NA	[61]
AtUGT85A1	拟南芥	糖基转移酶	288.00 mg/L	[61]
RsUGT73B6	库页红景天	糖基转移酶	8.76 mg/g DW	[62]
RsUGT72B14	库页红景天	糖基转移酶	19.81 mg/g DW	[62]
RsUGT74R1	库页红景天	糖基转移酶	5.72 mg/g DW	[62]

名称	优点	缺点
大肠杆菌	应用广泛、适宜天然产物生产^[65]	致病性大肠杆菌可能含有毒素^[70]
	成熟的高密度细胞培养技术^[66]	缺乏对部分植物来源酶的转录和翻译功能^[71]
	生长速率快，具有多种系统代谢工程工具和策略^[67]
	可以结合和转导转移DNA，遗传物质可以水平转移^[68]
	开发了各种蛋白质表达系统，可以通过质粒大规模生产重组蛋白^[69]
酿酒酵母	易于基因操作，营养需求简单，无细胞内毒素，安全性高^[72]	特征明确的启动子数量不足，动态范围差^[76]
	高分泌能力，在多种碳源上的高生长速率^[73]	异源蛋白表达量较少^[77]
	具有翻译后修饰能力，对噬菌体等传染性病原体不敏感^[74]
	遗传易处理性和整体易用性^[75]

名称	优点	缺点
大肠杆菌	应用广泛、适宜天然产物生产^[65]	致病性大肠杆菌可能含有毒素^[70]
	成熟的高密度细胞培养技术^[66]	缺乏对部分植物来源酶的转录和翻译功能^[71]
	生长速率快，具有多种系统代谢工程工具和策略^[67]
	可以结合和转导转移DNA，遗传物质可以水平转移^[68]
	开发了各种蛋白质表达系统，可以通过质粒大规模生产重组蛋白^[69]
酿酒酵母	易于基因操作，营养需求简单，无细胞内毒素，安全性高^[72]	特征明确的启动子数量不足，动态范围差^[76]
	高分泌能力，在多种碳源上的高生长速率^[73]	异源蛋白表达量较少^[77]
	具有翻译后修饰能力，对噬菌体等传染性病原体不敏感^[74]
	遗传易处理性和整体易用性^[75]

微生物类别	产量	发酵方式	改造策略	参考文献
大肠杆菌	6.70 mg/L	摇瓶培养	高效表达UGT72B14	[82]
	56.90 mg/L	摇瓶培养	异源表达红景天来源的UGT73B6、酵母的ARO10，构建共养大肠杆菌，过表达tyrA（tyrA^syn* ）、aroG（aroG^syn* ）等酪醇内源合成途径基因，敲除tyrR、pykA等旁路基因	[83]
	288.00 mg/L	摇瓶培养	异源表达AtUGT85A1和PcAAS	[61]
	1.04 g/L	摇瓶培养	异源表达地衣芽孢杆菌ZSP01来源的UGT_BL1	[84]
	8.17 g/L	5 L发酵罐	构建了UDP-葡萄糖循环再生系统，整合糖基转移酶基因UGT33	[85]
	9.48 g/L	5 L发酵罐	增加大肠杆菌中UGT85A1的拷贝数	[86]
	7.50 g/L	摇瓶发酵	过表达UDP-葡萄糖合成路径中的基因pgm和galU，并利用酶工程策略对糖基转移酶UGT85A1进行改造，整合突变体基因UGT85A1^A21G	[87]
	16.80 g/L	5 L发酵罐		[87]
酿酒酵母	640.00 mg/L	摇瓶培养	整合ARO4^K229L 和ARO7^T266I 到酵母菌上，过表达TYR1和ARO10，异源表达OsUGT13	[88]
	732.50 mg/L	5 L发酵罐	过表达ARO4^K229L 、ARO7^G141S 、aroL，而后引入PcAAS^syn 和AtUGT85A1^syn	[14]
	1575.45 mg/L	摇瓶培养	过表达RKI1、TKL1、ARO3^K222L 、ARO4^K229L 、ARO7^G141S 突变体、分支酸合成酶ARO2与苯丙氨酸脱羧酶ARO10并敲除酪醇竞争路径中的PDC1、PHA2，整合RrU8GT33	[89]
	26.55 g /L	5 L发酵罐		[89]
	1.82 g/L	3 L发酵罐	敲除PDC1、PHA2和TRP3，异源表达PcAAS、EcTyrA^M53I/A354V，异源表达Xfpk、UGT85A1	[90]
	2.40 g/L	摇瓶培养	将突变体ARO3^D154N 整合到酿酒酵母工程菌中	[91]
植物内生菌	2.34 mg/L	摇瓶培养	筛选了347种内生菌，最终获得目标菌株Phialocephala fortinii Rac56，并在此基础上优化了其发酵条件	[92]
混菌培养	3.80 g/L	摇瓶培养	酿酒酵母中共表达GmSUS和RrUGT33，大肠杆菌中异源表达AAS，建立共培养体系并优化发酵条件	[93]
混菌培养	6.03 g/L	5 L发酵罐	在两株大肠杆菌中分别表达KDC4和UGT85A1构建酪醇生产菌株与红景天苷生产菌株，并对两种菌株的碳源利用进行优化	[94]

生物合成红景天苷的研究进展

Research progress in the biosynthesis of salidroside

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