天然产物皂苷类化合物生物转化的研究进展
|
摘要
皂苷是苷元为三萜或螺甾烷类的一类较复杂的糖苷类化合物。天然来源皂苷为底物,采用生物转化技术获取了大量结构新颖的化合物,尤其是具有良好活性的皂苷转化产物,为新药的研究与开发提供了极为有价值的先导化合物。皂苷按母核结构可分为三萜皂苷和甾体皂苷,目前文献报道了89个天然来源皂苷单体的生物转化研究,其中三萜皂苷56个,甾体皂苷33个。皂苷类化合物的生物转化方法包括酶催化、微生物和肠道菌群转化,皂苷的生物酶和微生物转化工艺的研究与优化,是目前规模化制备活性次级皂苷的主要途径。皂苷类化合物的生物转化反应主要包括水解、氧化还原和重排等反应,最终生成苷元、次级糖苷或其衍生物。大多数皂苷的生物转化途径主要是经糖链水解反应,生成多个含糖基较少的次级皂苷,吸收入血并达到靶器官,发挥治疗作用。稀有次级皂苷制备、先导化合物发现和新药开发是皂苷类化合物生物转化研究的主要方向。利用微生物和肠道菌群转化技术研究皂苷的体内代谢与作用机制,也将成为该类成分生物转化研究中的热点。结合国内外近30年来的研究成果,对皂苷类成分的生物转化技术、转化反应类型和转化途径的研究进展进行总结,以期为皂苷类成分生物转化的深入研究和开发利用提供科学依据。
Saponin is a kind of complex compounds with triterpenoid or spiral aglycones. Natural saponins are used as substrates, and many novel compounds are obtained by biotransformation technology.Especially,converted products of saponins with strong activities provide valuable lead compounds for the research and development of new drugs. Saponins can be divided into triterpenoid saponin and steroidal saponin according to the structure of the mother nucleus. There are about 89 reported saponin components,including 56 triterpenoid saponins and 33 steroidal saponins. Biological enzyme catalysis,microbial transformation and intestinal microflora transformation are the main bioconversion technologies and key development directions of saponins. The research and optimization technology of biological enzyme and microbial transformation of saponins are the effective methods to prepare active secondary saponins. The biotransformation reaction of saponins mainly includes hydrolysis,redox and rearrangement, resulting in the formation of aglycones, secondary glycosides and their derivatives. The hydrolysis of saponin sugar chains was the main biological transformation pathway,and could generate a number of secondary saponins with less glycosyl groups. The secondary saponins could be absorbed into blood and become real active ingredients in body. Preparation of rare secondary saponins,discovery of lead compounds and development of new drugs are the main directions of biotransformation of saponins. The studies on the metabolism and mechanism of natural saponins by microbial and intestinal microbial biotransformation will also become hotspots.According to relevant papers at home and abroad, the researches on transformation technique, transformation approach and transformation reaction of saponins from natural products in the past thirty years were summarized,and the prospects of research and development were also analyzed to provide scientific basis for further study and comprehensive utilization of these conversion products.
Saponin is a kind of complex compounds with triterpenoid or spiral aglycones. Natural saponins are used as substrates, and many novel compounds are obtained by biotransformation technology.Especially,converted products of saponins with strong activities provide valuable lead compounds for the research and development of new drugs. Saponins can be divided into triterpenoid saponin and steroidal saponin according to the structure of the mother nucleus. There are about 89 reported saponin components,including 56 triterpenoid saponins and 33 steroidal saponins. Biological enzyme catalysis,microbial transformation and intestinal microflora transformation are the main bioconversion technologies and key development directions of saponins. The research and optimization technology of biological enzyme and microbial transformation of saponins are the effective methods to prepare active secondary saponins. The biotransformation reaction of saponins mainly includes hydrolysis,redox and rearrangement, resulting in the formation of aglycones, secondary glycosides and their derivatives. The hydrolysis of saponin sugar chains was the main biological transformation pathway,and could generate a number of secondary saponins with less glycosyl groups. The secondary saponins could be absorbed into blood and become real active ingredients in body. Preparation of rare secondary saponins,discovery of lead compounds and development of new drugs are the main directions of biotransformation of saponins. The studies on the metabolism and mechanism of natural saponins by microbial and intestinal microbial biotransformation will also become hotspots.According to relevant papers at home and abroad, the researches on transformation technique, transformation approach and transformation reaction of saponins from natural products in the past thirty years were summarized,and the prospects of research and development were also analyzed to provide scientific basis for further study and comprehensive utilization of these conversion products.
引文
[1]马骁驰,果德安.中药活性成分生物转化的研究思路与方法[J].中国天然药物,2007,5(3):162-168.
[2]戴承恩,李海龙,何小平,等.益生菌代谢中药有效成分的研究进展[J].中国中药杂志,2018,43(1):31-38.
[3]门薇,陈颖,李玉洁,等.肠道菌群对中药有效成分的生物转化研究进展[J].中国实验方剂学杂志,2015,21(2):229-234.
[4]王智磊,刘素娟,张鑫,等.黑曲霉生物转化黄酮类成分研究进展[J].中国实验方剂学杂志,2017,23(21):220-228.
[5]宋齐.人参化学成分和药理作用研究进展[J].人参研究,2017,29(2):47-54.
[6]彭婕,刘春莹,陈双,等.原人参二醇类皂苷(PPD)在酶反应中转化动态及其产物稀有皂苷的制备[J].中草药,2017,48(1):85-94.
[7] CUI L,WU S Q,ZHAO C A,et al. Microbial conversion of major ginsenosides in ginseng total saponins by Platycodon grandiflorum endophytes[J]. J Gins Res,2016,40(4):366-374.
[8] WANG W N,YAN B X,XU W D,et al. Highly selective bioconversion of ginsenoside Rb1to compound K by the Mycelium of Cordyceps sinensis under optimized conditions[J]. Molecules,2015,20(10):19291-19309.
[9] ZANG Y P,GUO N,JIAO J,et al. Application of magnetically immobilized edible fungus for the biotransformation of panax notoginseng saponin Rb1to Rd and Rg3[J]. J Chromatogr B,2017,1061-1062:306-313.
[10] SHEN H,Leung W I,RUAN J Q,et al. Biotransformation of ginsenoside Rb1via the gypenoside pathway by human gut bacteria[J]. Chin Med-UK,2013,8(1):22-32.
[11] WAN J Y,WANG C Z,LIU Z,et al. Determination of American ginseng saponins and their metabolites in human plasma,urine and feces samples by liquid chromatographycoupled with quadrupole time-of-flight mass spectrometry[J]. J Chromatogr B,2016,1015-1016:62-73.
[12] AN D S,CUI C H,Lee H G,et al. Identification and characterization of a novel Terrabacter ginsenosidimutans sp. nov.β-glucosidase that transforms ginsenoside Rb1into the rare gypenosidesⅩⅤⅡand LⅩⅩⅤ[J]. Appl Environ Microbiol,2010,76(17):5827-5836.
[13] QUAN L H,MIN J W,YANG D U,et al. Enzymatic biotransformation of ginsenoside Rb1to 20(S)-Rg3by recombinantβ-glucosidase from Microbacterium esteraromaticum[J]. Appl Microbiol Biotechnol,2012,94(2):377-384.
[14] JIN Y,SUN Y J,Kim Y J,et al. Microbial deglycosylation and ketonization of ginsenoside by Cladosporium cladosporioide and their anticancer activity[J]. Antonie Van Leenw,2016,109(2):179-185.
[15] LI Z P,JI G E. Ginseng fermented by mycotoxin nonproducing Aspergillus niger:ginsenoside analysis and anti-proliferative effects[J]. Food Sci Biotechnol,2017,26(4):987-991.
[16] CHEN G T,YANG M,NONG S J,et al. Microbial transformation of 20(S)-protopanaxadiol by Absidia corymbifera cytotoxic activity of the metabolites against human prostate cancer cells[J]. Fitoterapia,2013,84(1):6-10.
[17] MU L H,GU Y J,MA B P,et al. Two new triterpenoid saponins obtained by microbial hydrolysis with alternaria alternata AS 3. 6872[J]. Nat Prod Res,2015,29(7):638-643.
[18] MU L H,GU Y J,WANG L H,et al. Biotransformation on the triterpenoid saponin of Ardisia gigantifolia by Aspergillus avenaceus AS 3. 4454[J]. J Asian Nat Prod Res,2015,17(1):40-46.
[19] CAO W Y,WANG Y N,WANG P Y,et al.Ardipusilloside-I metabolites from human intestinal bacteria and their antitumor activity[J]. Molecules,2015,20(11):20569-20581.
[20]曹伟宇,王鹏远,冯斌,等.离体培养人肠道菌群对九节龙皂苷Ⅰ生物转化的研究[J].天然产物研究与开发,2015,27(8):1357-1361.
[21]关树光,於文博,徐东铭,等.白头翁药理作用的研究近况[J].吉林中医药,2006,26(3):60-61.
[22]代蕊,刘春莹,徐龙权,等.白头翁皂苷糖基水解Ⅱ型酶的分离纯化及酶性质[J].大连工业大学学报,2017,36(4):245-249.
[23] WAN J Y,ZHANG Y Z,YUAN J B,et al.Biotransformation and metabolic profile of anemoside B4with rat small and large intestine microflora by ultraperformance liquid chromatography-quadrupole time-offlight tandem mass spectrometry[J]. Biomed Chromatogr,2017,31(5):1-10.
[24]洪挺,钱媛,杨毅生.细梗香草中化学成分及其抗肿瘤活性研究进展[J].天然产物研究与开发,2018,30(6):1092-1097.
[25] CHENG Z Z,HUANG M L,CHEN G Y,et al. Cell-based assays in combination with ultra-high performance liquid chromatography-quadrupole time of flight tandem mass spectrometry for screening bioactive capilliposide C metabolites generated by rat intestinal microflora[J]. J Pharm Biomed Anal,2016,119:130-138.
[26] Huq M A,Kim Y J,MIN J W,et al. Enzymatic transformation of the major ginsenoside Rb1to compound K by Weissella hellenica DC06[J]. Indian J Biotechnol,2015,14(2):270-275.
[27] QUAN L H,PIAO J Y,MIN J W,et al. Biotransformation of ginsenoside Rb1to prosapogenins,gypenosideⅩⅤⅡ,ginsenoside Rd,ginsenoside F2,and compound K by Leuconostoc mesenteroides DC102[J]. J Ginseng Res,2011,35(3):344-351.
[28] CHENG L Q,NA J R,Kim M K,et al. Microbial conversion of ginsenoside Rb1to minor ginsenoside F2and gypenosideⅩⅤⅡby Intrasporangium sp. GS603isolated from soil[J]. J Microbiol Biotechnol,2008,17(12):1937-1943.
[29] YI E J,Lee J M,YI T H,et al. Biotransformation of ginsenoside by Lactobacillus brevis THK-D57 isolated from kimchi[J]. Korean J Food Sci An,2012,25(3):629-636.
[30] LIU C Y,JIN Y H,YU H S,et al. Biotransformation pathway and kinetics of the hydrolysis of the 3-O-and20-O-multi-glucosides of PPD-type ginsenosides byginsenosidase type I[J]. Process Biochem,2014,49(5):813-820.
[31]李冠亨,刘春莹,徐龙权,等.人参皂苷酶Ⅲ型转化人参皂苷Rc制备稀有皂苷C-Mc[J].大连工业大学学报,2017,36(4):250-254.
[32] Kim J K,CUI C H,LIU Q M,et al. Mass production of the ginsenoside Rg3(S)through the combinative use of two glycoside hydrolases[J]. Food Chem,2013,141(2):1369-1377.
[33] LIU L,ZHU X M,WANG Q J,et al. Enzymatic preparation of 20(S, R)-protopanaxadiol by transformation of 20(S,R)-Rg3from black ginseng[J].Phytochemistry,2010,71(13):1514-1520.
[34] WANG R F,ZHENG M M,CAO Y D,et al. Enzymatic transformation of vina-ginsenoside R7to rare notoginsenoside ST-4 using a new recombinant glycoside hydrolase from Herpetosiphon aurantiacus[J]. Appl Microbiol Biotech,2015,99(8):3433-3442.
[35]李东霄,邓小莉,王改霞,等.酵母菌对高含量人参皂苷的转化及其分子鉴定[J].江苏农业学报,2013,29(1):33-38.
[36] KU S,YOU H J,Park M S,et al. Effects of ascorbic acid onα-L-arabinofuranosidase andα-L-arabinopyranosidase activities from Bifidobacterium longum RD47 and its application to whole cell bioconversion of ginsenoside[J]. J Korean Soc Appl Biol Chem,2015,58(6):857-865.
[37]许春春,于渤浩,王红蕾,等.重组嗜热β-葡萄糖苷酶转化稀有人参皂苷Rd和CK[J].高等学校化学学报,2016,37(2):281-289.
[38] ZHONG F L,DONG W W,WU S Q,et al.Biotransformation of gypenosideⅩⅤⅡto compound K by a recombinantβ-glucosidase[J]. Biotechnol Lett,2016,38(7):1187-1193.
[39]于渤浩,李男,赵幻希,等.嗜热糖苷酶Fpendo5A转化绞股蓝皂苷XLIX的产物鉴定及分离纯化[J].中国生物制品学杂志,2017,30(3):307-311.
[40] PEI J J,WU T,YAO T,et al. Biotransformation of ginsenosides Re and Rg1into ginsenosides Rg2and Rh1by thermostableβ-glucosidase from Thermotoga thermarum[J]. Chem Nat Compd,2017,53(3):472-477.
[41] RUAN C C,ZHANG H,ZHANG L X,et al.Biotransformation of ginsenoside Rf to Rh1by recombinantβ-glucosidase[J]. Molecules,2009,14(6):2043-2048.
[42] CUI P,DOU T Y,SUN Y P,et al. Efficient enzymatic preparation of esculentoside B followingcondition optimization by response surface methodology[J]. J Mol Catal B-Enzym,2016,130:25-31.
[43] LI W,ZHAO L C,WANG Z,et al. Response surface methodology to optimize enzymatic preparation of deapioplatycodin D and platycodin D from Radix Platycodi[J].Int J Mol Sci,2012,13(12):4089-4100.
[44]吴少杰,杨志娟,朱丽华,等.甘草皂苷生物转化的研究[J].中草药,2003,34(6):516-518.
[45] Amin H A S,Mohamed S S. Immobilization of Aspergillus terreus on loofa sponge for soyasapogenol B production from soybean saponin[J]. J Mol Catal B-Enzym,2012,78:85-90.
[46]高霞,耿婷,马阳,等.离体大鼠肠道菌对6种皂苷类成分代谢研究[J].中国中药杂志,2016,41(12):2329-2338.
[47] XU R J,PENG Y,WANG M Y,et al. Effects of broadspectrum antibiotics on the metabolism and pharmacokinetics of ginsenoside Rb1:A study on rats'gut microflora influenced by lincomycin[J]. J Ethnopharmacol,2014,158:338-344.
[48]张喆,滕亚然,吕子燕,等.人参皂苷Rb2在大鼠体内的药代动力学行为及代谢产物研究[J].分析化学,2017,45(2):191-198.
[49] KONG H W,WANG M,Venema K,et al. Bioconversion of red ginseng saponins in the gastro-intestinal tract in vitro model studied by high-performance liquid chromatography-high resolution fourier transform ion cyclotron resonance mass spectrometry[J]. J Chromatogr A,2009,1216(11):2195-2203.
[50] HE C Y,LI J,XU N S,et al. Pharmacokinetics,bioavailability,and metabolism of notoginsenoside Fc in rats by liquid chromatography-electrospray ionization tandem mass spectrometry[J]. J Pharmaceut Biomed Anal,2015,109:150-157.
[51] CHEN D J,HU H G,XING S F,et al. Metabolite profiling of gypenoside LVI in rat after oral and intravenous administration[J]. Arch Pharm Res,2015,38(6):1157-1167.
[52] Kim U,Park M H,Kim D H,et al. Metabolite profiling of ginsenoside Re in rat urine and faeces after oral administration[J]. Food Chem,2013,136(3/4):1364-1369.
[53] WANG J,ZHENG P H,ZHENG S W,et al. Profiling and identification of the metabolites of ginsenoside Ro in rat faeces and urine after oral administration[J]. Eur Food Res Technol,2016,242(2):199-210.
[54] WANG Y Z,WANG Y S,CHU S F,et al.Protopanaxatriol metabolites identified by LC-MS/MS after oral administration in mice[J]. Int J Clin Pharmacol Ther,2010,48(4):282-290.
[55]于蓓蓓,王亮,尹利顺,等.基于HPLC-DAD-MSn的柴胡皂苷A的体外生物转化研究[J].中草药,2017,48(2):333-338.
[56]杨秀伟,赵静,崔景荣,等.七叶树皂苷-Ia的人肠内细菌生物转化产物及其抗肿瘤活性研究[J].北京大学学报:医学版,2004,36(1):31-35.
[57]曲方圆,喻凯,李甫,等.银莲花素A在大鼠肝匀浆中的代谢产物[J].华西药学杂志,2009,24(3):298-299.
[58]赵钟祥,李美芬,林朝展,等.大鼠肠内菌对毛冬青皂苷ilexsaponin A1的代谢转化[J].中国药科大学学报,2011,42(4):329-332.
[59] GAO J, XU W J, FANG Q, et al. Efficient biotransformation for preparation of pharmaceutically active ginsenoside compound K by Penicillium oxalicum sp. 68[J]. Ann Microbiol,2013,63(1):139-149.
[60] HAN Y, SUN B, JIANG B, et al. Microbial transformation of ginsenosides Rb1,Rb3and Rc by Fusarium sacchari[J]. J Appl Microbiol,2010,109(3):792-798.
[61]郭从亮,杨晓艳,陈子明,等.一株植物内生菌Coniochaeta sp.对三七总皂苷中人参皂苷Rb1的特异性转化含量测定[J].中药材,2016,39(5):1075-1078.
[62]李粟琳,张翔宇,王洋,等.可发酵三七等中药材的食用菌种筛选和皂苷生物转化产物的分析[J].食品与发酵工业,2017,43(12):164-168.
[63] Ten L N,Chae S M,Yoo S A. Biotransformation of ginsenoside Rb1into Rd by the Bacterium Lysobacter panaciterrae[J]. Chem Nat Compd,2013,49(4):773-774.
[64] CHEN G T,YANG M,SONG Y,et al. Microbial transformation of ginsenoside Rb1by Acremonium strictum[J]. Appl Microbiol Biotechno,2008,77(6):1345-1350.
[65] YE L,ZHANG C Y,LI J Y,et al. Effects of external calcium on the biotransformation of ginsenoside Rb1to ginsenoside Rd by Paecilomyces bainier 229-7[J]. World J Microbiol Biotechnol,2012,28(3):857-863.
[66] Kim E M,Kim J,Seo J H,et al. Identification and characterization of the Rhizobium sp. Strain GIN611glycoside oxidoreductase resulting in the deglycosylation of ginsenosides[J]. Appl Environ Microbiol,2012,78(1):242-249.
[67]刘慧敏,高雅军,曾鸣,等.保加利亚乳杆菌对绞股蓝皂苷gypenoside XLVI的微生物转化[J].食品科学,2014,35(17):133-136.
[68] YANG X D,LI X,XU Y,et al. Mechanism of incompatible herb pairs,panax ginseng and Veratrum nigrum L.:Material basis and metabolic profiles of ginsenosides in rat intestinal bacteria[J]. Chin J Chem,2015,33(9):1069-1076.
[69] GE F,HUANG Z J,YU H,et al. Transformation of Panax notoginseng saponins by steaming and Trichoderma longibrachiatum[J]. Biotechnol Biotec Eq,2016,30(1):165-172.
[70] Lee S,Lee Y H,Park J M,et al. Bioconversion of ginsenosides from red ginseng extract using candida allociferrii JNO301 isolated from meju[J]. Mycobiology,2014,42(4):368-375.
[71] CHEN G T,GE H J,LI J,et al. Microbial transformation of 20(R)-panaxadiol by Absidia corymbifera AS 3. 3387[J]. J Mol Catal B-Enzym,2016,123:154-159.
[72] LIN X H,CAO M N,HE W N,et al. Biotransformation of20(R)-panaxadiol by the fungus Rhizopus chinensis[J].Phytochemistry,2014,105(3):129-134.
[73] LI H F,YE M,GUO H Z,et al. Biotransformation of 20(S)-protopanaxadiol by Mucor spinosus[J].Phytochemistry,2009,70(11/12):1416-1420.
[74] LUO S L,DANG L Z,LI J F,et al. Biotransformation of saponins by endophytes isolated from Panax notoginseng[J]. Chem Biodivers,2013,10(11):2021-2031.
[75] CHEN G T,SONG Y,GE H J,et al. Biotransformation of20(S)-protopanaxatriol by Aspergillus niger and the cytotoxicity of the resulting metabolites[J]. Phytochem Lett,2014,11:111-115.
[76] SONG Y,LI J,YAN S S,et al. Biotransformation of 20(R)-panaxatriol by Aspergillus niger AS 3. 739[J].Phytochem Lett,2017,19:89-93.
[77] WANG L M,CHEN Y. Efficient biotransformation of astragalosideⅣto cycloastragenol by Bacillus sp. LG-502[J]. Appl Biochem Biotechnol,2017,18(4):1488-1502.
[78]隋玉辉,刘岱琳,邱峰,等.长柄链格孢对百两金皂苷的生物转化[J].中草药,2008,39(7):990-993.
[79]梅建凤,金航,李靓,等.生物转化法提高积雪草中积雪草酸的质量分数[J].浙江工业大学学报,2015,43(5):573-577.
[80] ZHU Y Y,QIAN L W,ZHANG J,et al. New approaches to the structural modification of olean-type pentacylic triterpenes via microbial oxidation and glycosylation[J].Tetrahedron,2011,67(23):4206-4211.
[81]张新新.盾叶薯蓣的化学成分及其药理作用研究[D].西安:西北大学,2015.
[82] ZHU H,XU J D,MAO Q,et al. Metabolic profiles of dioscin in rats revealed by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry[J]. Biomed Chromatogr,2015,29(9):1415-1421.
[83] CHEN H,WANG Z,SHU G W. A cleaner production of diosgenin from Dioscorea zingiberensis Wright biotransformed by Lactobacillus casei[J]. Emir J Food Agr,2017,29(10):760-769.
[84] DONG T,WU G W,WANG X N,et al. Microbiological transformation of diosgenin by resting cells of filamentous fungus,Cunninghamella echinulata CGMCC 3. 2716[J]. J Mol Catal B-Enzym,2010,67(3/4):251-256.
[85]刘忠荣,邹文俊,王若竹,等.地奥心血康十年临床应用概述及疗效分析[J].中国医药学报,2004,19(10):620-622.
[86] DONG X R,GAO Z H,HU H X,et al. Microbial transformation of pseudoprotodioscin by Chaetomium olivaceum[J]. J Mol Catal B-Enzym,2016,130:88-95.
[87]冯菲.知母的药理作用研究进展[J].中医临床研究,2017,9(12):133,137.
[88] LIU Z R,ZHU D L,LV L,et al. Metabolism profile of timosaponin B-Ⅱin urine after oral administration to rats by ultrahigh-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry[J]. Rapid Commun Mass Spectrom,2012,26(17):1955-1964.
[89] LI D D,XUE X R,LI Z X,et al. In vivo metabolism study of timosaponin BⅢin rat using HPLC-QTOF-MS/MS[J]. Chromatographia,2014,77(11/12):853-858.
[90] ZHOU W B,FENG B,HUANG H Z,et al. Hydrolysis of timosaponin BⅡby the crude enzyme from Aspergillus niger AS 3. 0739[J]. J Asian Nat Prod Res,2010,12(11):955-961.
[91] JIA Y,FU Z W,LI Z X,et al. In vivo and in vitro metabolism study of timosaponin B-ⅡUsing HPLC-ESIMSn[J]. Chromatographia,2015,78(17/18):1175-1184.
[92] ZHAO Y,JIANG T C,HAN B Q,et al. Preparation of some metabolites of timosaponin BⅡby biotransformation in vitro[J]. Process Biochem,2015,50(12):2182-2187.
[93] HU Y M,YU Z L,FONG W F. Stereoselective biotransformation of timosaponin A-Ⅲby Saccharomyces cerevisiae[J]. J Microbiol Biotechn,2011,21(6):582-589.
[94] JIANG W X,GUO J,XUE R,et al. Anti-depressive activities and biotransformation of timosaponin B-Ⅲand its derivatives[J]. Nat Prod Res,2014,28(18):1446-1453.
[95] ZHU Y L,HUANG W,NI J R,et al. Production of diosgenin from Dioscorea zingiberensis tubers through enzymatic saccharification and microbial transformation[J]. Appl Microbiol Biotechnol,2010,85(5):1409-1416.
[96] LIU T Q,YU H S,LIU C Y,et al. Protodioscinglycosidase-1 hydrolyzing 26-O-β-D-glucoside and 3-O-(1→4)-α-L-rhamnoside of steroidal saponins from Aspergillus oryzae[J]. Appl Microbiol Biotechnol,2013,97(23):10035-10043.
[97] DONG Y S,TENG H,QI S S,et al. Pathways and kinetics analysis of biotransformation of Dioscorea zingiberensis by Aspergillus oryzae[J]. Biochem Eng J,2010,52(2/3):123-130.
[98] HUANG H Z,ZHAO M,LU L,et al. Pathways of biotransformation of zingiberen newsaponin from Dioscorea zingiberensis C. H. Wright to diosgenin[J].J Mol Catal B-Enzym,2013,98:1-7.
[99] QI S S,DONG Y S,ZHAO Y K,et al. Qualitative and quantitative analysis of microbial transformation of steroidal saponins in Dioscorea zingiberensis[J].Chromatographia,2009,69(9/10):865-870.
[100]高冉冉,郜昭慧,董欣然,等.淡紫青霉ACCC31890对纤细薯蓣皂苷的生物转化[J].中国药师,2017,20(6):988-993.
[101] Jr M J,Gianfagna T J. Antifungal activity and fungal metabolism of steroidal glycosides of Easter lily(Lilium longiflorum Thunb.)by the plant pathogenic fungus,Botrytis cinerea[J]. J Agric Food Chem,2011,59(11):5945-5954.
[102] HE D X,LI G H,GU X T,et al. A new agent developed by biotransformation of polyphyllin VⅡinhibits chemoresistance in breast cancer[J]. Oncotarget,2015,7(22):31814-31824.
[103]牛红军,王芃,杨官娥.微生物转化技术在中药研究中的应用[J].中国实验方剂学杂志,2013,19(18):346-349.
[2]戴承恩,李海龙,何小平,等.益生菌代谢中药有效成分的研究进展[J].中国中药杂志,2018,43(1):31-38.
[3]门薇,陈颖,李玉洁,等.肠道菌群对中药有效成分的生物转化研究进展[J].中国实验方剂学杂志,2015,21(2):229-234.
[4]王智磊,刘素娟,张鑫,等.黑曲霉生物转化黄酮类成分研究进展[J].中国实验方剂学杂志,2017,23(21):220-228.
[5]宋齐.人参化学成分和药理作用研究进展[J].人参研究,2017,29(2):47-54.
[6]彭婕,刘春莹,陈双,等.原人参二醇类皂苷(PPD)在酶反应中转化动态及其产物稀有皂苷的制备[J].中草药,2017,48(1):85-94.
[7] CUI L,WU S Q,ZHAO C A,et al. Microbial conversion of major ginsenosides in ginseng total saponins by Platycodon grandiflorum endophytes[J]. J Gins Res,2016,40(4):366-374.
[8] WANG W N,YAN B X,XU W D,et al. Highly selective bioconversion of ginsenoside Rb1to compound K by the Mycelium of Cordyceps sinensis under optimized conditions[J]. Molecules,2015,20(10):19291-19309.
[9] ZANG Y P,GUO N,JIAO J,et al. Application of magnetically immobilized edible fungus for the biotransformation of panax notoginseng saponin Rb1to Rd and Rg3[J]. J Chromatogr B,2017,1061-1062:306-313.
[10] SHEN H,Leung W I,RUAN J Q,et al. Biotransformation of ginsenoside Rb1via the gypenoside pathway by human gut bacteria[J]. Chin Med-UK,2013,8(1):22-32.
[11] WAN J Y,WANG C Z,LIU Z,et al. Determination of American ginseng saponins and their metabolites in human plasma,urine and feces samples by liquid chromatographycoupled with quadrupole time-of-flight mass spectrometry[J]. J Chromatogr B,2016,1015-1016:62-73.
[12] AN D S,CUI C H,Lee H G,et al. Identification and characterization of a novel Terrabacter ginsenosidimutans sp. nov.β-glucosidase that transforms ginsenoside Rb1into the rare gypenosidesⅩⅤⅡand LⅩⅩⅤ[J]. Appl Environ Microbiol,2010,76(17):5827-5836.
[13] QUAN L H,MIN J W,YANG D U,et al. Enzymatic biotransformation of ginsenoside Rb1to 20(S)-Rg3by recombinantβ-glucosidase from Microbacterium esteraromaticum[J]. Appl Microbiol Biotechnol,2012,94(2):377-384.
[14] JIN Y,SUN Y J,Kim Y J,et al. Microbial deglycosylation and ketonization of ginsenoside by Cladosporium cladosporioide and their anticancer activity[J]. Antonie Van Leenw,2016,109(2):179-185.
[15] LI Z P,JI G E. Ginseng fermented by mycotoxin nonproducing Aspergillus niger:ginsenoside analysis and anti-proliferative effects[J]. Food Sci Biotechnol,2017,26(4):987-991.
[16] CHEN G T,YANG M,NONG S J,et al. Microbial transformation of 20(S)-protopanaxadiol by Absidia corymbifera cytotoxic activity of the metabolites against human prostate cancer cells[J]. Fitoterapia,2013,84(1):6-10.
[17] MU L H,GU Y J,MA B P,et al. Two new triterpenoid saponins obtained by microbial hydrolysis with alternaria alternata AS 3. 6872[J]. Nat Prod Res,2015,29(7):638-643.
[18] MU L H,GU Y J,WANG L H,et al. Biotransformation on the triterpenoid saponin of Ardisia gigantifolia by Aspergillus avenaceus AS 3. 4454[J]. J Asian Nat Prod Res,2015,17(1):40-46.
[19] CAO W Y,WANG Y N,WANG P Y,et al.Ardipusilloside-I metabolites from human intestinal bacteria and their antitumor activity[J]. Molecules,2015,20(11):20569-20581.
[20]曹伟宇,王鹏远,冯斌,等.离体培养人肠道菌群对九节龙皂苷Ⅰ生物转化的研究[J].天然产物研究与开发,2015,27(8):1357-1361.
[21]关树光,於文博,徐东铭,等.白头翁药理作用的研究近况[J].吉林中医药,2006,26(3):60-61.
[22]代蕊,刘春莹,徐龙权,等.白头翁皂苷糖基水解Ⅱ型酶的分离纯化及酶性质[J].大连工业大学学报,2017,36(4):245-249.
[23] WAN J Y,ZHANG Y Z,YUAN J B,et al.Biotransformation and metabolic profile of anemoside B4with rat small and large intestine microflora by ultraperformance liquid chromatography-quadrupole time-offlight tandem mass spectrometry[J]. Biomed Chromatogr,2017,31(5):1-10.
[24]洪挺,钱媛,杨毅生.细梗香草中化学成分及其抗肿瘤活性研究进展[J].天然产物研究与开发,2018,30(6):1092-1097.
[25] CHENG Z Z,HUANG M L,CHEN G Y,et al. Cell-based assays in combination with ultra-high performance liquid chromatography-quadrupole time of flight tandem mass spectrometry for screening bioactive capilliposide C metabolites generated by rat intestinal microflora[J]. J Pharm Biomed Anal,2016,119:130-138.
[26] Huq M A,Kim Y J,MIN J W,et al. Enzymatic transformation of the major ginsenoside Rb1to compound K by Weissella hellenica DC06[J]. Indian J Biotechnol,2015,14(2):270-275.
[27] QUAN L H,PIAO J Y,MIN J W,et al. Biotransformation of ginsenoside Rb1to prosapogenins,gypenosideⅩⅤⅡ,ginsenoside Rd,ginsenoside F2,and compound K by Leuconostoc mesenteroides DC102[J]. J Ginseng Res,2011,35(3):344-351.
[28] CHENG L Q,NA J R,Kim M K,et al. Microbial conversion of ginsenoside Rb1to minor ginsenoside F2and gypenosideⅩⅤⅡby Intrasporangium sp. GS603isolated from soil[J]. J Microbiol Biotechnol,2008,17(12):1937-1943.
[29] YI E J,Lee J M,YI T H,et al. Biotransformation of ginsenoside by Lactobacillus brevis THK-D57 isolated from kimchi[J]. Korean J Food Sci An,2012,25(3):629-636.
[30] LIU C Y,JIN Y H,YU H S,et al. Biotransformation pathway and kinetics of the hydrolysis of the 3-O-and20-O-multi-glucosides of PPD-type ginsenosides byginsenosidase type I[J]. Process Biochem,2014,49(5):813-820.
[31]李冠亨,刘春莹,徐龙权,等.人参皂苷酶Ⅲ型转化人参皂苷Rc制备稀有皂苷C-Mc[J].大连工业大学学报,2017,36(4):250-254.
[32] Kim J K,CUI C H,LIU Q M,et al. Mass production of the ginsenoside Rg3(S)through the combinative use of two glycoside hydrolases[J]. Food Chem,2013,141(2):1369-1377.
[33] LIU L,ZHU X M,WANG Q J,et al. Enzymatic preparation of 20(S, R)-protopanaxadiol by transformation of 20(S,R)-Rg3from black ginseng[J].Phytochemistry,2010,71(13):1514-1520.
[34] WANG R F,ZHENG M M,CAO Y D,et al. Enzymatic transformation of vina-ginsenoside R7to rare notoginsenoside ST-4 using a new recombinant glycoside hydrolase from Herpetosiphon aurantiacus[J]. Appl Microbiol Biotech,2015,99(8):3433-3442.
[35]李东霄,邓小莉,王改霞,等.酵母菌对高含量人参皂苷的转化及其分子鉴定[J].江苏农业学报,2013,29(1):33-38.
[36] KU S,YOU H J,Park M S,et al. Effects of ascorbic acid onα-L-arabinofuranosidase andα-L-arabinopyranosidase activities from Bifidobacterium longum RD47 and its application to whole cell bioconversion of ginsenoside[J]. J Korean Soc Appl Biol Chem,2015,58(6):857-865.
[37]许春春,于渤浩,王红蕾,等.重组嗜热β-葡萄糖苷酶转化稀有人参皂苷Rd和CK[J].高等学校化学学报,2016,37(2):281-289.
[38] ZHONG F L,DONG W W,WU S Q,et al.Biotransformation of gypenosideⅩⅤⅡto compound K by a recombinantβ-glucosidase[J]. Biotechnol Lett,2016,38(7):1187-1193.
[39]于渤浩,李男,赵幻希,等.嗜热糖苷酶Fpendo5A转化绞股蓝皂苷XLIX的产物鉴定及分离纯化[J].中国生物制品学杂志,2017,30(3):307-311.
[40] PEI J J,WU T,YAO T,et al. Biotransformation of ginsenosides Re and Rg1into ginsenosides Rg2and Rh1by thermostableβ-glucosidase from Thermotoga thermarum[J]. Chem Nat Compd,2017,53(3):472-477.
[41] RUAN C C,ZHANG H,ZHANG L X,et al.Biotransformation of ginsenoside Rf to Rh1by recombinantβ-glucosidase[J]. Molecules,2009,14(6):2043-2048.
[42] CUI P,DOU T Y,SUN Y P,et al. Efficient enzymatic preparation of esculentoside B followingcondition optimization by response surface methodology[J]. J Mol Catal B-Enzym,2016,130:25-31.
[43] LI W,ZHAO L C,WANG Z,et al. Response surface methodology to optimize enzymatic preparation of deapioplatycodin D and platycodin D from Radix Platycodi[J].Int J Mol Sci,2012,13(12):4089-4100.
[44]吴少杰,杨志娟,朱丽华,等.甘草皂苷生物转化的研究[J].中草药,2003,34(6):516-518.
[45] Amin H A S,Mohamed S S. Immobilization of Aspergillus terreus on loofa sponge for soyasapogenol B production from soybean saponin[J]. J Mol Catal B-Enzym,2012,78:85-90.
[46]高霞,耿婷,马阳,等.离体大鼠肠道菌对6种皂苷类成分代谢研究[J].中国中药杂志,2016,41(12):2329-2338.
[47] XU R J,PENG Y,WANG M Y,et al. Effects of broadspectrum antibiotics on the metabolism and pharmacokinetics of ginsenoside Rb1:A study on rats'gut microflora influenced by lincomycin[J]. J Ethnopharmacol,2014,158:338-344.
[48]张喆,滕亚然,吕子燕,等.人参皂苷Rb2在大鼠体内的药代动力学行为及代谢产物研究[J].分析化学,2017,45(2):191-198.
[49] KONG H W,WANG M,Venema K,et al. Bioconversion of red ginseng saponins in the gastro-intestinal tract in vitro model studied by high-performance liquid chromatography-high resolution fourier transform ion cyclotron resonance mass spectrometry[J]. J Chromatogr A,2009,1216(11):2195-2203.
[50] HE C Y,LI J,XU N S,et al. Pharmacokinetics,bioavailability,and metabolism of notoginsenoside Fc in rats by liquid chromatography-electrospray ionization tandem mass spectrometry[J]. J Pharmaceut Biomed Anal,2015,109:150-157.
[51] CHEN D J,HU H G,XING S F,et al. Metabolite profiling of gypenoside LVI in rat after oral and intravenous administration[J]. Arch Pharm Res,2015,38(6):1157-1167.
[52] Kim U,Park M H,Kim D H,et al. Metabolite profiling of ginsenoside Re in rat urine and faeces after oral administration[J]. Food Chem,2013,136(3/4):1364-1369.
[53] WANG J,ZHENG P H,ZHENG S W,et al. Profiling and identification of the metabolites of ginsenoside Ro in rat faeces and urine after oral administration[J]. Eur Food Res Technol,2016,242(2):199-210.
[54] WANG Y Z,WANG Y S,CHU S F,et al.Protopanaxatriol metabolites identified by LC-MS/MS after oral administration in mice[J]. Int J Clin Pharmacol Ther,2010,48(4):282-290.
[55]于蓓蓓,王亮,尹利顺,等.基于HPLC-DAD-MSn的柴胡皂苷A的体外生物转化研究[J].中草药,2017,48(2):333-338.
[56]杨秀伟,赵静,崔景荣,等.七叶树皂苷-Ia的人肠内细菌生物转化产物及其抗肿瘤活性研究[J].北京大学学报:医学版,2004,36(1):31-35.
[57]曲方圆,喻凯,李甫,等.银莲花素A在大鼠肝匀浆中的代谢产物[J].华西药学杂志,2009,24(3):298-299.
[58]赵钟祥,李美芬,林朝展,等.大鼠肠内菌对毛冬青皂苷ilexsaponin A1的代谢转化[J].中国药科大学学报,2011,42(4):329-332.
[59] GAO J, XU W J, FANG Q, et al. Efficient biotransformation for preparation of pharmaceutically active ginsenoside compound K by Penicillium oxalicum sp. 68[J]. Ann Microbiol,2013,63(1):139-149.
[60] HAN Y, SUN B, JIANG B, et al. Microbial transformation of ginsenosides Rb1,Rb3and Rc by Fusarium sacchari[J]. J Appl Microbiol,2010,109(3):792-798.
[61]郭从亮,杨晓艳,陈子明,等.一株植物内生菌Coniochaeta sp.对三七总皂苷中人参皂苷Rb1的特异性转化含量测定[J].中药材,2016,39(5):1075-1078.
[62]李粟琳,张翔宇,王洋,等.可发酵三七等中药材的食用菌种筛选和皂苷生物转化产物的分析[J].食品与发酵工业,2017,43(12):164-168.
[63] Ten L N,Chae S M,Yoo S A. Biotransformation of ginsenoside Rb1into Rd by the Bacterium Lysobacter panaciterrae[J]. Chem Nat Compd,2013,49(4):773-774.
[64] CHEN G T,YANG M,SONG Y,et al. Microbial transformation of ginsenoside Rb1by Acremonium strictum[J]. Appl Microbiol Biotechno,2008,77(6):1345-1350.
[65] YE L,ZHANG C Y,LI J Y,et al. Effects of external calcium on the biotransformation of ginsenoside Rb1to ginsenoside Rd by Paecilomyces bainier 229-7[J]. World J Microbiol Biotechnol,2012,28(3):857-863.
[66] Kim E M,Kim J,Seo J H,et al. Identification and characterization of the Rhizobium sp. Strain GIN611glycoside oxidoreductase resulting in the deglycosylation of ginsenosides[J]. Appl Environ Microbiol,2012,78(1):242-249.
[67]刘慧敏,高雅军,曾鸣,等.保加利亚乳杆菌对绞股蓝皂苷gypenoside XLVI的微生物转化[J].食品科学,2014,35(17):133-136.
[68] YANG X D,LI X,XU Y,et al. Mechanism of incompatible herb pairs,panax ginseng and Veratrum nigrum L.:Material basis and metabolic profiles of ginsenosides in rat intestinal bacteria[J]. Chin J Chem,2015,33(9):1069-1076.
[69] GE F,HUANG Z J,YU H,et al. Transformation of Panax notoginseng saponins by steaming and Trichoderma longibrachiatum[J]. Biotechnol Biotec Eq,2016,30(1):165-172.
[70] Lee S,Lee Y H,Park J M,et al. Bioconversion of ginsenosides from red ginseng extract using candida allociferrii JNO301 isolated from meju[J]. Mycobiology,2014,42(4):368-375.
[71] CHEN G T,GE H J,LI J,et al. Microbial transformation of 20(R)-panaxadiol by Absidia corymbifera AS 3. 3387[J]. J Mol Catal B-Enzym,2016,123:154-159.
[72] LIN X H,CAO M N,HE W N,et al. Biotransformation of20(R)-panaxadiol by the fungus Rhizopus chinensis[J].Phytochemistry,2014,105(3):129-134.
[73] LI H F,YE M,GUO H Z,et al. Biotransformation of 20(S)-protopanaxadiol by Mucor spinosus[J].Phytochemistry,2009,70(11/12):1416-1420.
[74] LUO S L,DANG L Z,LI J F,et al. Biotransformation of saponins by endophytes isolated from Panax notoginseng[J]. Chem Biodivers,2013,10(11):2021-2031.
[75] CHEN G T,SONG Y,GE H J,et al. Biotransformation of20(S)-protopanaxatriol by Aspergillus niger and the cytotoxicity of the resulting metabolites[J]. Phytochem Lett,2014,11:111-115.
[76] SONG Y,LI J,YAN S S,et al. Biotransformation of 20(R)-panaxatriol by Aspergillus niger AS 3. 739[J].Phytochem Lett,2017,19:89-93.
[77] WANG L M,CHEN Y. Efficient biotransformation of astragalosideⅣto cycloastragenol by Bacillus sp. LG-502[J]. Appl Biochem Biotechnol,2017,18(4):1488-1502.
[78]隋玉辉,刘岱琳,邱峰,等.长柄链格孢对百两金皂苷的生物转化[J].中草药,2008,39(7):990-993.
[79]梅建凤,金航,李靓,等.生物转化法提高积雪草中积雪草酸的质量分数[J].浙江工业大学学报,2015,43(5):573-577.
[80] ZHU Y Y,QIAN L W,ZHANG J,et al. New approaches to the structural modification of olean-type pentacylic triterpenes via microbial oxidation and glycosylation[J].Tetrahedron,2011,67(23):4206-4211.
[81]张新新.盾叶薯蓣的化学成分及其药理作用研究[D].西安:西北大学,2015.
[82] ZHU H,XU J D,MAO Q,et al. Metabolic profiles of dioscin in rats revealed by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry[J]. Biomed Chromatogr,2015,29(9):1415-1421.
[83] CHEN H,WANG Z,SHU G W. A cleaner production of diosgenin from Dioscorea zingiberensis Wright biotransformed by Lactobacillus casei[J]. Emir J Food Agr,2017,29(10):760-769.
[84] DONG T,WU G W,WANG X N,et al. Microbiological transformation of diosgenin by resting cells of filamentous fungus,Cunninghamella echinulata CGMCC 3. 2716[J]. J Mol Catal B-Enzym,2010,67(3/4):251-256.
[85]刘忠荣,邹文俊,王若竹,等.地奥心血康十年临床应用概述及疗效分析[J].中国医药学报,2004,19(10):620-622.
[86] DONG X R,GAO Z H,HU H X,et al. Microbial transformation of pseudoprotodioscin by Chaetomium olivaceum[J]. J Mol Catal B-Enzym,2016,130:88-95.
[87]冯菲.知母的药理作用研究进展[J].中医临床研究,2017,9(12):133,137.
[88] LIU Z R,ZHU D L,LV L,et al. Metabolism profile of timosaponin B-Ⅱin urine after oral administration to rats by ultrahigh-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry[J]. Rapid Commun Mass Spectrom,2012,26(17):1955-1964.
[89] LI D D,XUE X R,LI Z X,et al. In vivo metabolism study of timosaponin BⅢin rat using HPLC-QTOF-MS/MS[J]. Chromatographia,2014,77(11/12):853-858.
[90] ZHOU W B,FENG B,HUANG H Z,et al. Hydrolysis of timosaponin BⅡby the crude enzyme from Aspergillus niger AS 3. 0739[J]. J Asian Nat Prod Res,2010,12(11):955-961.
[91] JIA Y,FU Z W,LI Z X,et al. In vivo and in vitro metabolism study of timosaponin B-ⅡUsing HPLC-ESIMSn[J]. Chromatographia,2015,78(17/18):1175-1184.
[92] ZHAO Y,JIANG T C,HAN B Q,et al. Preparation of some metabolites of timosaponin BⅡby biotransformation in vitro[J]. Process Biochem,2015,50(12):2182-2187.
[93] HU Y M,YU Z L,FONG W F. Stereoselective biotransformation of timosaponin A-Ⅲby Saccharomyces cerevisiae[J]. J Microbiol Biotechn,2011,21(6):582-589.
[94] JIANG W X,GUO J,XUE R,et al. Anti-depressive activities and biotransformation of timosaponin B-Ⅲand its derivatives[J]. Nat Prod Res,2014,28(18):1446-1453.
[95] ZHU Y L,HUANG W,NI J R,et al. Production of diosgenin from Dioscorea zingiberensis tubers through enzymatic saccharification and microbial transformation[J]. Appl Microbiol Biotechnol,2010,85(5):1409-1416.
[96] LIU T Q,YU H S,LIU C Y,et al. Protodioscinglycosidase-1 hydrolyzing 26-O-β-D-glucoside and 3-O-(1→4)-α-L-rhamnoside of steroidal saponins from Aspergillus oryzae[J]. Appl Microbiol Biotechnol,2013,97(23):10035-10043.
[97] DONG Y S,TENG H,QI S S,et al. Pathways and kinetics analysis of biotransformation of Dioscorea zingiberensis by Aspergillus oryzae[J]. Biochem Eng J,2010,52(2/3):123-130.
[98] HUANG H Z,ZHAO M,LU L,et al. Pathways of biotransformation of zingiberen newsaponin from Dioscorea zingiberensis C. H. Wright to diosgenin[J].J Mol Catal B-Enzym,2013,98:1-7.
[99] QI S S,DONG Y S,ZHAO Y K,et al. Qualitative and quantitative analysis of microbial transformation of steroidal saponins in Dioscorea zingiberensis[J].Chromatographia,2009,69(9/10):865-870.
[100]高冉冉,郜昭慧,董欣然,等.淡紫青霉ACCC31890对纤细薯蓣皂苷的生物转化[J].中国药师,2017,20(6):988-993.
[101] Jr M J,Gianfagna T J. Antifungal activity and fungal metabolism of steroidal glycosides of Easter lily(Lilium longiflorum Thunb.)by the plant pathogenic fungus,Botrytis cinerea[J]. J Agric Food Chem,2011,59(11):5945-5954.
[102] HE D X,LI G H,GU X T,et al. A new agent developed by biotransformation of polyphyllin VⅡinhibits chemoresistance in breast cancer[J]. Oncotarget,2015,7(22):31814-31824.
[103]牛红军,王芃,杨官娥.微生物转化技术在中药研究中的应用[J].中国实验方剂学杂志,2013,19(18):346-349.