生物合成法生产α-熊果苷的研究进展

doi:10.12211/2096-8280.2024-054

合成生物学 ›› 2025, Vol. 6 ›› Issue (1): 118-135.DOI: 10.12211/2096-8280.2024-054

• 特约评述 • 上一篇

生物合成法生产α-熊果苷的研究进展

仲泉周¹^,², 单依怡¹^,², 裴清云¹^,², 金艳芸¹^,², 王艺涵¹^,², 孟璐远¹, 王歆韵¹, 张雨鑫¹, 刘坤媛¹, 王慧中¹^,², 冯尚国¹^,²

^1.杭州师范大学生命与环境科学学院，浙江杭州 311121
^2.浙江省药用植物种质改良和质量监控重点实验室，浙江杭州 311121

收稿日期:2024-07-18 修回日期:2024-11-08 出版日期:2025-01-31 发布日期:2025-03-12
通讯作者: 冯尚国
作者简介:仲泉周（1999—），男，硕士研究生。研究方向为酶定向催化、天然产物生物合成。E-mail：2023112010028@stu.hznu.edu.cn
冯尚国（1980—），男，博士，副教授，硕士生导师。研究方向为药用种质资源评价、酶定向催化及天然产物生物合成。E-mail：fengsg@hznu.edu.cn
基金资助:
国家自然科学基金(31970346);浙江省自然科学基金(LY20H280012);广东省科技计划(2023B1212060046);杭州市科技基金(20191203B02);杭州师范大学生命与环境科学学院教学改革项目

Research progress in the production of α-arbutin through biosynthesis

Quanzhou ZHONG¹^,², Yiyi SHAN¹^,², Qingyun PEI¹^,², Yanyun JIN¹^,², Yihan WANG¹^,², Luyuan MENG¹, Xinyun WANG¹, Yuxin ZHANG¹, Kunyuan LIU¹, Huizhong WANG¹^,², Shangguo FENG¹^,²

^1.College of Life and Environmental Science，Hangzhou Normal University，Hangzhou 311121，Zhejiang，China
^2.Zhejiang Provincial Key Laboratory for Genetic Improvement and Quality Control of Medicinal Plants，Hangzhou 311121，Zhejiang，China

Received:2024-07-18 Revised:2024-11-08 Online:2025-01-31 Published:2025-03-12
Contact: Shangguo FENG

摘要/Abstract

摘要：

熊果苷（arbutin）是一种天然的糖苷类化合物，广泛存在于自然界中。α-熊果苷（α-arbutin）是其一种异构体，由于其高效安全的美白作用和许多优秀的药理作用，受到越来越多的市场关注。研究发现，生物合成法生产α-熊果苷相较于自然提取法和化学合成法有着更高的产量、更安全的环境、更有竞争力的价格等优势，已经成为主流生产方式。本文介绍了常用于α-熊果苷生产的七种酶类的相关研究，分别为α-淀粉酶、蔗糖磷酸化酶、环糊精糖基转移酶、α-葡萄糖基酶、葡聚糖蔗糖酶、淀粉蔗糖酶和蔗糖异构酶。另外对全细胞催化法、微生物发酵法生产α-熊果苷的研究进展进行综述，对α-熊果苷生产过程中存在的问题进行了剖析并提出在工业化发展上的建议，最后对α-熊果苷合成的未来方向进行了展望，以期能够为实现更高效、更低成本的α-熊果苷生产提供新思路。

关键词: 熊果苷, α-熊果苷, 生物合成, 葡萄糖苷, 氢醌

Abstract:

Arbutins are a kind of natural glycoside compounds found widely in nature. α-arbutin, one of its isomers, has received increasing market attention due to its efficient and safe whitening effect and other excellent pharmacological effects. Studies have revealed that the production methods of α-arbutin mainly fall into three categories: plant extraction, chemical synthesis, and biosynthesis. For the plant extraction, raw materials are widely available, and the process is simple, but the yield fails to meet the requirement for large scale production and applications. The chemical synthesis has a higher yield but with harsh reaction conditions, and thus is not environmentally friendly. Through research has found that the biosynthesis of α-arbutin has higher yield, safer environment, more competitive cost and other advantages compared with the natural extraction and chemical synthesis as well, making it the mainstream production method. This article discusses the advantages and disadvantages of different synthetic methods and studies on the seven enzymes commonly used in the biosynthesis of α-arbutin including α-amylase, sucrose phosphorylase, cyclodextrin glycosyltransferase, α-glucosylase, dextransucrase, amylosucrase, and sucrose isomerase. These enzymes use different sugar donors and catalyze the transglycosylation reaction with hydroquinone as the receptor substrate to synthesize α-arbutin. Additionally, we provide a comprehensive review on research progress in the whole-cell catalysis and microbial fermentation to produce α-arbutin, and potentials for its industrial production are assessed. Furthermore, we highlight challenges that exist in the biosynthesis of α-arbutin, such as the oxidation of hydroquinone during synthesis that increases cell toxicity and reduces the yield, the low utilization rate of glucose and the generation of other glycoside products, and the poor performance of experimental strains, and corresponding solutions are proposed. Finally, future directions for α-arbutin synthesis are prospected, with the aim of providing new ideas for achieving more efficient and lower-cost production of α-arbutin and enhancing its applications in the fields of cosmetics and medicines.

Key words: arbutins, α-arbutin, biosynthesis, glucoside, hydroquinone

中图分类号:

仲泉周, 单依怡, 裴清云, 金艳芸, 王艺涵, 孟璐远, 王歆韵, 张雨鑫, 刘坤媛, 王慧中, 冯尚国. 生物合成法生产α-熊果苷的研究进展[J]. 合成生物学, 2025, 6(1): 118-135.

Quanzhou ZHONG, Yiyi SHAN, Qingyun PEI, Yanyun JIN, Yihan WANG, Luyuan MENG, Xinyun WANG, Yuxin ZHANG, Kunyuan LIU, Huizhong WANG, Shangguo FENG. Research progress in the production of α-arbutin through biosynthesis[J]. Synthetic Biology Journal, 2025, 6(1): 118-135.

图/表 7

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活性	模型	培养时间	材料	参考文献
祛痰平喘	体内	3天	动物实验-小鼠	[17]
拮抗H₂O₂损伤	体外	36时	人脐静脉内皮细胞	[18]
低温保护	体外	2～3月	人胫骨细胞	[19]
放射防护	体内	7天	动物实验-小鼠	[20]
伤口愈合	体外	48时	人真皮成纤维细胞	[21]
治疗多发性硬化症	体内	14天	动物实验-大鼠	[22]
降低前列腺癌	体外	5天	LNCaP细胞系	[23]
治疗心肌梗死	体内	25天	动物实验-大鼠	[24]
降低肝癌	体内	3周	动物实验-大鼠	[25]
美白	体内	4天	3D黑色素皮肤模型	[26]
神经保护	体内	21天	动物实验-大鼠	[27]
改善肝纤维化	体内	6周	动物实验-小鼠	[28]

活性	模型	培养时间	材料	参考文献
祛痰平喘	体内	3天	动物实验-小鼠	[17]
拮抗H₂O₂损伤	体外	36时	人脐静脉内皮细胞	[18]
低温保护	体外	2～3月	人胫骨细胞	[19]
放射防护	体内	7天	动物实验-小鼠	[20]
伤口愈合	体外	48时	人真皮成纤维细胞	[21]
治疗多发性硬化症	体内	14天	动物实验-大鼠	[22]
降低前列腺癌	体外	5天	LNCaP细胞系	[23]
治疗心肌梗死	体内	25天	动物实验-大鼠	[24]
降低肝癌	体内	3周	动物实验-大鼠	[25]
美白	体内	4天	3D黑色素皮肤模型	[26]
神经保护	体内	21天	动物实验-大鼠	[27]
改善肝纤维化	体内	6周	动物实验-小鼠	[28]

来源	所用试剂	提取方法	定量方法	产率	参考文献
日本梨树（枝条）	10%甲醇	超声均质	液相色谱/质谱（LC/MS）	12.8 mg/g	[32]
玉露香(果皮)	色谱级甲醇	超声过滤	高效液相色谱（HPLC）	0.872 mg/g	[33]
鸭梨（果肉）	色谱级甲醇	超声过滤	高效液相色谱（HPLC）	0.012 mg/g	[33]
鸭梨（果心）	色谱级甲醇	超声过滤	高效液相色谱（HPLC）	0.268 mg/g	[33]
红景天	60%乙醇	超声过滤	高效液相色谱（HPLC）	3.2 mg/g	[34]
皇冠梨（果皮）	无水乙醇	超声辅助	高效液相色谱（HPLC）	0.229 mg/g	[35]

来源	所用试剂	提取方法	定量方法	产率	参考文献
日本梨树（枝条）	10%甲醇	超声均质	液相色谱/质谱（LC/MS）	12.8 mg/g	[32]
玉露香(果皮)	色谱级甲醇	超声过滤	高效液相色谱（HPLC）	0.872 mg/g	[33]
鸭梨（果肉）	色谱级甲醇	超声过滤	高效液相色谱（HPLC）	0.012 mg/g	[33]
鸭梨（果心）	色谱级甲醇	超声过滤	高效液相色谱（HPLC）	0.268 mg/g	[33]
红景天	60%乙醇	超声过滤	高效液相色谱（HPLC）	3.2 mg/g	[34]
皇冠梨（果皮）	无水乙醇	超声辅助	高效液相色谱（HPLC）	0.229 mg/g	[35]

酶类	来源	供体	供体/氢醌	转化率	参考文献
Sucrose phosphorylase	Streptococcus mutans UA159	Sucrose	2∶1	72.4%	[43]
Sucrose phosphorylase	Bacillus velezensis	Sucrose	4∶1	44.09%	[44]
Sucrose phosphorylase	Leuconostoc mesenteroides ATCC 12291	Sucrose	5∶1	99%	[45]
Sucrose phosphorylase	Paenibacillus elgii	Sucrose	5∶1	60.9%	[46]
Sucrose phosphorylase	Lactobacillus mesenteroides	Sucrose	20∶1	95.3%	[47]
Sucrose phosphorylase	Streptococcus mutans	Sucrose	6∶1	80.15%	[48]
α-Amylase	bacillus subtilis X-23	Maltose	2∶1	9%	[49]
α-Amylase	bacillus subtilis X-23	Maltotriose	2∶1	22.4%	[49]
α-Amylase	bacillus subtilis X-23	Maltopentaose	2∶1	24.8%	[49]
α-Amylase	bacillus subtilis X-23	Soluble starch	2∶1	32.4%	[49]
α-Amylase	Thermus thermophilus ATCC 33923	Cassava starch	—	83%^①	[50]
Amylosucrase	Deinococcus geothermalis	Sucrose	10∶1	90%	[51]
Amylosucrase	Xanthomonas campestris pv. campestris 8004	Sucrose	80∶1	95%	[52]
Amylosucrase	Thermal spring metagenome	Sucrose	5∶1	75%	[53]
Cyclodextrin glycosyltransferase	Thermoanaerobacter sp.	Maltodextrin	—	61%	[54]
Cyclodextrin glycosyltransferase	Anaerobranca gottschalkii	Maltodextrin	6∶1	25%	[55]
Cyclodextrin glycosyltransferase	Paenibacillus macerans	Maltodextrin	6∶1	20%	[55]
Cyclodextrin glycosyltransferase	Bacillus stearothermophilus NO2	Maltodextrin	6∶1	14%	[55]
Cyclodextrin glycosyltransferase	Bacillus circulans 251	Maltodextrin	6∶1	11%	[55]
Cyclodextrin glycosyltransferase	Anaerobranca gottschalkii	Maltodextrin	6∶1	63%	[56]
α-Glucosidase	Xanthomonas campestris	Maltose	—	72%	[57]
α-Glucosidase	Xanthomonas campestris	Sucrose	9∶1	94%	[58]
Dextransucrase	Leuconostoc mesenteroides B-1299	Sucrose	—	0.4%	[59]
Sucrose isomerase	Erwinia rhapontici	Sucrose	50∶1	33.2%	[60]

生物合成法生产α-熊果苷的研究进展

Research progress in the production of α-arbutin through biosynthesis

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