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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志  2021, Vol. 41 Issue (6): 71-88    DOI: 10.13523/j.cb.2103036
综述     
生物合成稀有人参皂苷的研究进展*
李冰,张传波,宋凯(),卢文玉()
天津大学化工学院 天津 300072
Research Progress in Biosynthesis of Rare Ginsenosides
LI Bing,ZHANG Chuan-bo,SONG Kai(),LU Wen-yu()
School of Chemical Engineering, Tianjin University, Tianjin 300072,China
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摘要:

人参皂苷是我国传统中药人参的主要活性物质,稀有人参皂苷相较人参皂苷具有更好的生物活性,也更利于身体吸收,具有镇静催眠、促进细胞分化增殖、抗肿瘤、降血糖、提升免疫力等作用。然而,稀有人参皂苷结构复杂且在人参中含量极低,限制了其开发利用。随着生物技术的发展,利用生物法合成稀有人参皂苷成为本领域的研究热点。因此,对近年来生物合成稀有人参皂苷研究进行汇总梳理,总结稀有人参皂苷的主要种类结构及近年来生物转化法和异源合成法合成稀有人参皂苷的研究进展,生物转化法汇总了以人参皂苷为底物的转化生物,异源合成法总结人参皂苷的生物合成途径及形成结构多样化人参皂苷的酶。对生物合成稀有人参皂苷存在的问题进行了讨论,同时展望了其前景以及未来研究方向,以期为从事人参研究者提供更多生物线索和制备策略。

关键词: 稀有人参皂苷糖苷酶表达系统糖基转移酶生物合成    
Abstract:

Ginseng, as a traditional Chinese medicine, has high medicinal value. Its main active component is ginsenoside. Ginsenoside is a series of glycosylated triterpenoids, which is also an active compound with health care function. It is stored in the roots, stems, leaves and flowers of Acanthopanax plants. The content and composition of ginsenoside vary in different kinds of ginseng and different parts of a plant same as. Ginsenoside has a good therapeutic effect on metabolic syndrome and cardiovascular disease.Compared with ginsenoside, rare ginsenoside has better biological activity and is more conducive to body absorption.However, the structure of rare ginsenosides is complex and its content in ginseng is very low, which limits its development and utilization. With the development of biotechnology, the use of biological synthesis of rare ginsenosides has become a research hot spot in this field.Therefore, the research on the synthesis of rare ginsenosides by biological methods in recent years is summarized, and the main types and structures of rare ginsenosides and the research progress of the synthesis of rare ginsenosides by biotransformation and heterologous synthesis are summarized in recent years. The biotransformation method summarizes the transformed organisms using ginsenosides Rb1 and Rg1 as substrates, and the heterologous synthesis method summarizes the biosynthetic pathway of ginsenosides and the enzymes that form ginsenosides with diverse structures. The problems in the biosynthesis of rare ginsenosides were discussed, and its prospects and future research directions were prospected, in order to provide more biological clues and preparation strategies for ginseng researchers.

Key words: Rare ginsenoside    Glycosidase    Expression system    Glycosyltransferase    Biosynthesis
收稿日期: 2021-03-17 出版日期: 2021-07-06
ZTFLH:  Q819  
基金资助: * 国家自然科学基金(21878220)
通讯作者: 宋凯,卢文玉     E-mail: ksong@tju.edu.cn;wenyulu@tju.edu.cn
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引用本文:

李冰,张传波,宋凯,卢文玉. 生物合成稀有人参皂苷的研究进展*[J]. 中国生物工程杂志, 2021, 41(6): 71-88.

LI Bing,ZHANG Chuan-bo,SONG Kai,LU Wen-yu. Research Progress in Biosynthesis of Rare Ginsenosides. China Biotechnology, 2021, 41(6): 71-88.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2103036        https://manu60.magtech.com.cn/biotech/CN/Y2021/V41/I6/71

图1  四种类型人参皂苷结构
图2  稀有人参皂苷结构
稀有人参皂苷 R1(3位) R2(6位) R3(20位)
PPD-type
Rg3 -Glc2-1Glc - -H
Rh2 -Glc - -H
PPD -H - -H
Gyp17 -Glc - -Glc6-1Glc
Gyp75 -H - -Glc6-1Glc
F2 -Glc - -Glc
C-K -H - -Glc
PPT-type
PPT - -H -H
F1 - -H -Glc
Rh1 - -Glc -H
多双键类 双键位置
Rh3 -Glc -
Rh4 -H -Glc
Rg5 -Glc2-1Glc -
Rk1 -Glc2-1Glc -
Rk2 -Glc -
Rk3 -H -Glc
表1  达玛烷型人参皂苷形成的稀有人参皂苷
底物 产物 年份 文献
Rb1 Gyp17、Gyp75 糖苷酶(BgpA) 细菌-地杆菌属(Terrabacter ginsenosidimutans) 2020 [15]
Rb1 C-K β-葡糖苷酶 细菌-芽孢杆菌属(Bacillus sp.strain AU3b4) 2020 [16]
Rb1 F2、C-K β-葡糖苷酶 真菌-曲霉属(Aspergillus terreus MF678562) 2020 [17]
Rb1 Rg3、C-K 未鉴定糖苷酶 真菌-虫草属(Cordyceps sinensis, Ascomycota sp.) 2020 [18]
Rb1 Rg3、C-K β-1,2-葡糖苷酶 细菌-纤维微菌属(Cellulosimicrobium cellulans sp.21) 2019 [19]
Rb1 C-K β-葡糖苷酶 真菌-拟青霉属(Paecilomyces bainier sp.229) 2018 [20]
Rb1 C-K 蜗牛酶 动物-蜗牛 2018 [21]
Rb1 Rg3、C-K β-葡糖苷酶 细菌-乳酸杆菌属[Lactococcus lactis(recombinant)] 2018 [22]
Rb1 Rg3 β-葡糖苷酶 细菌-伯克霍尔德氏菌属(Burkholderia sp. Endophytic
bacteria GE17-7)
2017 [23]
Rb1 C-K β-葡糖苷酶 真菌-褐孢霉属(Cladosporium GH26) 2016 [24]
Rb1 Rg3 未鉴定糖苷酶 真菌-灵芝属(灵芝5.0026) 2016 [25]
Rb1 F2、C-K 未鉴定糖苷酶 细菌-乳酸菌属(Lactobacillus fermentum;
Lactococcus plantarum)
2016 [26]
Rb1 Rg3、Rh2 β-葡糖苷酶 细菌-乳酸杆菌属(Lactobacillus paracasei subsp.
tolerans MJM60396)
2016 [27]
Rb1 Rd β-葡糖苷酶 细菌-乳酸杆菌属(Lactobacillus rhamnosus GG) 2016 [28]
Rb1 C-K 葡糖苷酶 真菌-蜜环菌属(Armillaria mellea) 2016 [29]
Rb1 C-K β-葡糖苷酶 真菌-节菱孢属(Arthrinium sp. GE 17-18) 2016 [30]
Rb1 F2 未鉴定糖苷酶 真菌-虫草属(Cordyceps sinensis) 2015 [31]
Rb1 Rd 未鉴定糖苷酶 真菌-蝙蝠蛾拟青霉(Paecilomyces hepiali) 2015 [32]
Rb1 C-K β-葡糖苷酶 真菌-虫草属(Cordyceps sinensis) 2015 [33]
Rb1 Rg3 GH3 β-葡糖苷酸酶 细菌-栖热菌属(Thermotoga thermarum DSM5069T) 2015 [34]
Rb1 Rd β-葡糖苷酶 真菌-曲霉属(Aspergillus sp. LFJ1403) 2015 [35]
Rb1 F2 β-葡糖苷酶(BglPm) 细菌-类芽孢杆菌属(Paenibacillus mucilaginosus) 2014 [36]
Rb1 Rd β-葡糖苷酶 细菌-芽孢杆菌属(Bacillus massiliensis No.24) 2014 [37]
Rb1 Rg3 葡糖苷酶 真菌-曲霉属(Aspergillus niger) 2014 [38]
Rb1 C-K 人参皂苷水解酶 真菌-附球霉属(Epicoccum) 2013 [39]
Rb1 C-K 糖苷酶 真菌-曲霉属(Aspergillus niger sp. J7) 2013 [40]
Rb1 Rd 胞内糖苷酶 真菌-虫草属(Paecilomyces hepiali) 2013 [41]
Rb1 Rd 葡萄糖耐β-葡糖苷酶 细菌-栖热菌属(Thermotoga thermarum DSM 5069T) 2013 [42]
Rb1 C-K β-葡糖苷酶 细菌-乳酸杆菌属(Lactobacillus paralimentarius LH4) 2013 [43]
Rb1 F2 β-葡糖苷酶 细菌-乳酸菌属(Lactobacillus ginsenosidimutans
sp. nov. EMML 3041)
2013 [44]
底物 产物 年份 文献
Rb1 Rg3 β-葡糖苷酶 细菌-醇香微杆菌(Microbacterium esteraromaticum BL21) 2012 [45]
Rb1 C-K β-葡糖水解酶 细菌-乳酸杆菌属(Lactobacillus pentosus Strain 6105) 2012 [46]
Rb1 C-K 未鉴定糖苷酶 真菌-镰刀属(Fusarium moniliforme) 2011 [47]
Rb1 C-K 人参皂苷糖苷酶 真菌-犁头霉属(Absidia sp.G8r) 2011 [48]
Rb1 C-K β-葡萄糖水解酶 细菌-鞘氨醇单胞菌属(Sphingomonas sp. ZY-3) 2011 [49]
Rb1 C-K β-葡糖苷酶 真菌-拟青霉属(Paecilomyces Bainier sp.229) 2010 [50]
Rb1 Rd 新β-葡糖苷酶 真菌-褐孢霉属(Cladosporium fulvum) 2009 [51]
Rb1 Rd β-葡糖苷酶 真菌-褐孢霉属[Cladosporium fulvum (syn. Fulvia fulva)] 2009 [52]
Rb1 C-K 新型β-葡糖苷酶 真菌-拟青霉属(Paecilomyces bainier sp.229) 2008 [53]
Rb1 Rd β-葡糖苷酶 细菌-栖热菌属(Thermus caldophilus GK24) 2008 [54]
Rg1 Rh1 人参皂苷糖苷酶 真菌-虫草属(Cordyceps sinensis) 2020 [55]
Rg1 F1 糖苷酶 细菌-嗜血杆菌属(Sanguibacter keddieii) 2012 [56]
Rg1 Rh1 人参皂苷糖苷酶 细菌-节杆菌属(Arthrobacter sp.No.3) 2011 [57]
Rg1 F1 未鉴定糖苷酶 真菌-镰刀属(Fusarium moniliforme CZ2) 2011 [58]
Rg1 F1 重组β-糖苷酶 真菌-曲霉属(Aspergillus niger) 2010 [59]
Rg1 F1 人参皂苷糖苷酶 细菌-节杆菌属(Arthrobacter chlorophenolicus GS0202) 2009 [60]
Rb1、Rc、Rb2,Rf Rg3、C-K,Rh1 蜗牛酶 动物-蜗牛 2021 [61]
PPD-ginsenosides C-K、C-Mx 糖苷酶type-I 真菌-曲霉属(Aspergillus sp.agl-84) 2021 [62]
人参总皂苷 Rh2 糖苷酶(BglPm,Bgp1) 真菌-丛赤壳属(nectria haematococca) 2020 [63]
人参茎叶皂苷 Rg3、Rh2、C-K β-葡糖苷酶 真菌-红曲霉属(Monascus purpureus Went) 2020 [64]
Rb1、Rb2、Rc,Re Rg3、C-K,Rh1 β-葡糖苷酶 真菌-曲霉属(Aspergillus)、毛壳菌属(Chaetomium) 2020 [65]
Rb1、Rb2、Rc Rg3 耐热糖苷酶
(Tpexyl3,Tpebgl3)
细菌-栖热菌属(Thermotoga petrophila DSM 13,995) 2019 [66]
Rb1,Rg1 C-K、PPD,F1、PPT β-葡糖苷酶 细菌-微杆菌属(Microbacterium testaceum ATCC 15829) 2019 [67]
Rb1,Rg1 Rg3、C-K、Rh2、
PPD,Rh1、PPT
β-葡糖苷酶 细菌-乳酸菌属(Lactobacillus) 2019 [68]
Rb1,Rg1 Rg3,Rh1 β-葡糖苷酶 真菌-文森虫草(Cordyceps fumosorosea;
玫烟色拟青霉(Isaria fumosorosea);粉棒束孢
(Isaria farinosa);蛹虫草拟青霉(Cordyceps militaris)
2019 [69]
Rg1、Re、Rf Rh4 β-D-葡糖苷酶 真菌-曲霉属(Aspergillus tubingensis) 2018 [70]
Rb1、Rb2、Rc C-K 新型耐热β-葡糖苷酶 细菌-热解纤维素果汁杆菌属(Caldicellulosiruptor bescii) 2018 [71]
Rg1、Re Rh1、Rg2 耐热β-葡糖苷酶 细菌-栖热菌属(Thermotoga thermarum) 2017 [72]
Rb1、Gyp17,
Rg1、Re
PPD,Rh1、Rg2 β-葡糖苷酶
(BglG167b)
细菌-微杆菌属(Microbacterium sp. Gsoil 167) 2017 [73]
Rb1、Rb2、Rc、
Rd,Rg1
F2、C-K,Rh1 β-葡糖苷酶 细菌-藤黄色杆菌属(Luteibacter JG09) 2016 [74]
Rb1、Rd,Re Rg3,Rg2 β-葡糖苷酶(Ccbgl1a) 细菌-乳酸菌属(Lactobacillus plantarum) 2015 [75]
Rb1、Rb2、Rc、Rd C-Mc、C-Y、F2、C-K β-葡糖苷酶 真菌-曲霉属(Aspergillus niger g.848) 2015 [76]
PPD-ginsenosides C-K β-葡糖苷酶 古细菌-硫化叶菌属(Sulfolobus solfataricus) 2015 [77]
Rb1、Rb2、Rc、Rd Gyp75、CO、Mb、F2 β-葡糖苷酶(Ccbgl1a) 细菌-纤维微菌属(Cellulosimicrobium cellulans sp. 21) 2015 [78]
Rb1,Rg1 Rg3,Rh1 β-葡糖苷酶 植物-大头茶属(Gordonia terrae) 2015 [79]
底物 产物 年份 文献
Rb1、Rb2、Rc、Rd Gyp75、C-O、C-Mc1、F2 β-葡糖苷酶 细菌-鞘脂单胞菌属(Sphingopyxis alaskensis) 2014 [80]
Rb1、Rc Rg3 糖苷酶(BglBX10,
Abf22-3)
细菌-明串珠菌属(Leuconostoc sp. 22-3) 2013 [81]
Rb1、Rg1 C-K、F1 β-葡糖苷酶 真菌-褐孢霉属(Cladosporium cladosporioides GH21) 2012 [82]
Rb1、Rc、Rd Rh2 β-葡糖苷酶 真菌-埃斯特属(Esteya vermicola CNU 120806) 2012 [83]
人参皂苷提取物 C-K 重组β-糖苷酶 细菌-火球菌属(Pyrococcus furiosus) 2011 [84]
Rb1、Rb2、Rc、Rd F2 新β-葡萄糖水解酶 细菌-鞘氨醇单胞菌属(Sphingomonas sp. 2F2) 2011 [85]
Rb1、Rb3 C-K、C-Mx、C-Mc 未鉴定糖苷酶 真菌-镰刀属(Fusarium sacchari) 2010 [86]
表2  人参皂苷Rb1、Rg1的转化
图3  人参皂苷Rb1、Rg1为底物的转化产物
图4  稀有人参皂苷的生物合成途径
基因 底盘系统 人参皂苷种类 产量 年份 文献
PgDDSPgPPDSVvCPRPn3-29 S.cerevisiae C-K 1 170 mg/L 2020 [109]
UGP1 S.cerevisiae C-K 1 700 mg/L 2020 [110]
PgDDSCYP716A47CYP716A53v2 Tobacco PPD、PPT 7.3、11.6 mg/g DCW 2019 [111]
UDPG(UGTPg45UGTPg29)、 S.cerevisiae PPD、Rh2 11 020、2 250 mg/L 2019 [112]
GTK1 E. coli Rh2 0.77 mg/L 2019 [113]
No Agrobacterium Rg3、Rh2 62.2、18.60 mg/L 2019 [114]
PPDSATR1 S.cerevisiae PPD 8 090 mg/L 2019 [115]
DDSUGT S.cerevisiae 3β-O-Glc-DM、
20S-O-Glc-DM
2 400、5 600 mg/L 2019 [116]
LRGT Escherichia coli BL21 glucosyl-Rh2 2019 [117]
UGT-Bs-YjiC Bacillus subtilis 168 Rh2 200 mg/L 2018 [118]
DDSPPDSATR2UGT51 S.cerevisiae Rh2 300 mg/L 2017 [119]
DDSPPDSUGT71A28 Tobacco C-K 1.55~2.64 μg/g DW 2017 [120]
PPDS-ATR2 S.cerevisiae PPD 4 250 mg/L 2017 [121]
UGT109APPDSATR1 Saccharomyces
cerevisiae INVSc1
3β,12β-Di-O-Glc-PPD 9.05 mg/L 2017 [103]
DDSPPDSOSCsCPRATR1 E. coli DM 8.63 mg/L 2016 [122]
PPDS-ATR1 S.cerevisiae PPD 1436.6 mg/L 2016 [123]
DDSPPDSATR2.1UGTPg45UGTPg29 S.cerevisiae Rh2、Rg3 1.5、3.5 μmol/g 2015 [124]
UDPG(UGTPg1UGTPg100) S.cerevisiae F1、Rh1 42.1、92.8 mg/L 2015 [125]
DDSPPDS Tobacco PPD 125.9 μg/g DW 2015 [126]
DDS Pischia pastoris DM 1.073 mg/g DCW 2015 [127]
DDSPPDSATR2UGT74AE2UGT94Q2 S.cerevisiae Rg3 1.3 mg/L 2014 [128]
ATR1DDSβ-ASOASPPDSPPTS S.cerevisiae PPD、PPT、OA 17.2、15.9、21.4 mg/L 2014 [129]
DDS Tobacco DM 5.2 mg/L 2014 [130]
DDSCYP716A47ATR2-1UGTPg1 S.cerevisiae C-K 1.4 mg/L 2014 [131]
DDSPPDSATR1 S.cerevisiae PPD 1 189 mg/L 2013 [132]
表3  异源表达系统合成人参皂苷
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