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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2023, Vol. 43 Issue (10): 109-119    DOI: 10.13523/j.cb.2303051
综述     
真菌中苦马豆素生物合成途径及相关基因研究进展*
杨帆,卢萍**()
内蒙古师范大学生命科学与技术学院 呼和浩特 010022
Advances in Research on Swainsonine Biosynthesis Pathway and Related Genes in Fungi
YANG Fan,LU Ping**()
College of Life Science and Technology, Inner Mongolia Normal University, Hohhot 010022, China
 全文: PDF(1196 KB)   HTML
摘要：

苦马豆素(swainsonine,SW)是由真菌合成的一类吲哚里西啶类生物碱,可以引起哺乳动物疯草病,同时也是一种具有潜力的抗癌药物。SW在不同真菌中的合成途径各不相同,主要通过多基因调控的次生代谢途径产生。早期研究发现酵母氨酸还原酶基因sac可促进真菌合成SW,疯草内生真菌中的吡咯啉-5-羧酸还原酶(pyrroline-5-carboxylate reductase,P5CR)可催化合成哌啶酸,哌啶酸是合成SW的底物,真菌中的SWN基因簇各基因所编码的酶催化从哌啶酸到SW的各步反应。综述豆类丝核菌(Rhizoctonia leguminicola)、罗伯茨绿僵菌(Metarhizium robertsii)及疯草内生真菌中的SW合成途径及相关基因的研究进展,为深入揭示真菌SW的生物合成途径与调控机制提供重要参考,同时对未来疯草SW的控制和利用也具有一定重要意义。
关键词： 内生真菌;  苦马豆素;  次生代谢;  SWN基因簇    
Abstract:

The indolizidine alkaloid swinsonine (SW), which is produced by fungi, induces severe locoweed diseases in mammals. SW is a potential anti-cancer medication. Different fungi have various swainsonine synthesis pathways. A number of genes regulate the secondary metabolism of SW synthesis pathways. Early research revealed that the sac gene can promote the level of SW produced. Subsequently, P5CR (pyrroline-5-carboxylate reductase), a catalytic enzyme for the synthesis of pipecolic acid, has been found in endophytic fungi of locoweed. Later, the SWN gene cluster is proposed and the enzymes that each gene in the SWN gene cluster encodes for are mainly responsible for catalyzing the reactions that transform pipecolic acid to SW. In this paper, the research on the SW synthetic pathways of Rhizoctonia leguminicola, Metarhizium robertsii, and endophytic fungi of locoweed is reviewed.
Key words: Endophytic fungi    Swainsonine    Secondary metabolism    SWN gene cluster
收稿日期: 2023-03-20 出版日期: 2023-11-02
ZTFLH:  Q78  
基金资助: *国家自然科学基金(31960130);内蒙古自然科学基金(2022MS03014)
通讯作者: **电子信箱:luping@imnu.edu.cn   
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杨帆, 卢萍. 真菌中苦马豆素生物合成途径及相关基因研究进展*[J]. 中国生物工程杂志, 2023, 43(10): 109-119.

YANG Fan, LU Ping. Advances in Research on Swainsonine Biosynthesis Pathway and Related Genes in Fungi. China Biotechnology, 2023, 43(10): 109-119.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2303051    或    https://manu60.magtech.com.cn/biotech/CN/Y2023/V43/I10/109

图1  SW的结构式
图2  豆类丝核菌中SW部分合成途径
图3  罗伯茨绿僵菌中SW部分合成途径[11]
图4  罗伯茨绿僵菌中SW合成途径[21]
图5  Alternaria oxytropis OW7.8中SW生物合成途径预测
图6  酵母氨酸催化的双向反应[27]
图7  金龟子绿僵菌中Sac酶催化L-赖氨酸形成P6C[13]
基因 功能
swnA 氨基转移酶
swnN 脱氢酶、还原酶
swnR 脱氢酶、还原酶
swnH1 氧戊二酸酯、Fe依赖的加氧酶
swnH2 氧戊二酸酯、Fe依赖的加氧酶
swnT 氨基酸转运体
swnK 非核糖肽-聚酮合酶(多功能)
表1  SWN基因簇基因编码产物的预测功能
结构域 功能
A 腺苷酰(化)作用
T 硫醇化作用
KS β-酮酰基合成酶
AT 脂肪酰转移酶
KR 酮还原酶
ACP 酰基载体蛋白
R 还原酶
表2  swnK所编码的PKS-NRPS结构域及其功能[7,22]
图8  swnK基因编码的蛋白各个结构域催化的过程
图9  哌啶酸的合成途径
[1] Yu Y T, Zhao Q M, Wang J N, et al. Swainsonine-producing fungal endophytes from major locoweed species in China. Toxicon, 2010, 56(3): 330-338.
doi: 10.1016/j.toxicon.2010.03.020 pmid: 20380845
[2] Guo C C, Zhang L, Zhao Q Q, et al. Host-species variation and environment influence endophyte symbiosis and mycotoxin levels in Chinese Oxytropis species. Toxins, 2022, 14(3): 181.
doi: 10.3390/toxins14030181
[3] 高新磊, 韩冰, 赵萌莉, 等. 疯草及毒性成分研究进展. 草业学报, 2011, 20(3): 279-286.
Gao X L, Han B, Zhao M L, et al. Locoweed and advances in research on toxic components. Acta Prataculturae Sinica, 2011, 20(3): 279-286.
[4] Cook D, Gardner D R, Lee S T, et al. A swainsonine survey of North American Astragalus and Oxytropis taxa implicated as locoweeds. Toxicon, 2016, 118: 104-111.
doi: 10.1016/j.toxicon.2016.04.033
[5] 浮晶晶, 郭亚洲, 黄文颖, 等. 疯草类植物在美国天然草地的分布及其动物中毒病研究现状与展望. 草地学报, 2019, 27(3): 519-530.
doi: 10.11733/j.issn.1007-0435.2019.03.001
Fu J J, Guo Y Z, Huang W Y, et al. The distribution of locoweed in natural grassland in the United States and the current status and prospects of research on animal poisoning. Acta Agrestia Sinica, 2019, 27(3): 519-530.
doi: 10.11733/j.issn.1007-0435.2019.03.001
[6] Molyneux R J, McKenzie R A, O’Sullivan B M, et al. Identification of the glycosidase inhibitors swainsonine and calystegine B2 in weir vine (Ipomoea sp. Q6{aff. calobra}) and correlation with toxicity. Journal of Natural Products, 1995, 58(6): 878-886.
doi: 10.1021/np50120a009 pmid: 7673932
[7] Panter K, James L, Stegelmeier B, et al. Locoweeds: effects on reproduction in livestock. Journal of Natural Toxins, 1999, 8(1): 53-62.
pmid: 10091128
[8] 李欣, 卢萍. 真菌中苦马豆素生物合成途径的研究进展. 生命的化学, 2018, 38(6): 815-820.
Li X, Lu P. Advances in research on swainsonine biosynthesis pathway in fungi. China Industrial Economics, 2018, 38(6): 815-820.
[9] Cook D, Gardner D R, Pfister J A. Swainsonine-containing plants and their relationship to endophytic fungi. Journal of Agricultural and Food Chemistry, 2014, 62(30): 7326-7334.
doi: 10.1021/jf501674r pmid: 24758700
[10] Quach Q N, Clay K, Lee S T, et al. Phylogenetic patterns of bioactive secondary metabolites produced by fungal endosymbionts in morning glories (Ipomoeeae, Convolvulaceae). New Phytologist, 2023, 238(4): 1351-1361.
doi: 10.1111/nph.v238.4
[11] Cook D, Donzelli B G G, Creamer R, et al. Swainsonine biosynthesis genes in diverse symbiotic and pathogenic fungi. G3-Genes Genomes Genetics, 2017, 7(6): 1791-1797.
doi: 10.1534/g3.117.041384 pmid: 28381497
[12] Colegate S M, Dorling P R, Huxtable C R. A spectroscopic investigation of swainsonine: an α-mannosidase inhibitor isolated from Swainsona canescens. Australian Journal of Chemistry, 1979, 32(10): 2257.
doi: 10.1071/CH9792257
[13] Sim K L, Perry D. Analysis of swainsonine and its early metabolic precursors in cultures of Metarhizium anisopliae. Glycoconjugate Journal, 1997, 14(5): 661-668.
pmid: 9298701
[14] Cook D, Beaulieu W T, Mott I W, et al. Production of the alkaloid swainsonine by a fungal endosymbiont of the ascomycete order Chaetothyriales in the host Ipomoea carnea. Journal of Agricultural and Food Chemistry, 2013, 61(16): 3797-3803.
doi: 10.1021/jf4008423
[15] 中国科学院中国植物志编辑委员会. 中国植物志(第四十二卷)第二分册. 北京: 科学出版社, 1998: 26.
Delectis Florae Reipublicae Popularis Sinicae, Agendae Academiae Sinice Edits. Flora reipublicae popularis siniese: tomus 42(2). Beijing: Science and Technology Press, 1998: 26.
[16] 吴可欣, 唐诗雨, 朱奕儒, 等. 野生型斜茎黄芪内生真菌分离鉴定及苦马豆素分析. 草地学报, 2022, 30(7): 1692-1700.
doi: 10.11733/j.issn.1007-0435.2022.07.010
Wu K X, Tang S Y, Zhu Y R, et al. Isolation and identification of endophytic fungi from wild-type Astragalus adsurgens and analysis of swainsonine. Acta Agrestia Sinica, 2022, 30(7): 1692-1700.
doi: 10.11733/j.issn.1007-0435.2022.07.010
[17] 卢萍, 霍红雁, 钱亚光, 等. 小花棘豆内生真菌中苦马豆素的鉴定及含量测定. 安徽农业科学, 2012, 40(8): 4544-4546, 4574.
Lu P, Huo H Y, Qian Y G, et al. Identification and content determination of swainsonine of endophytic fungi from Oxytropis glabra. Journal of Anhui Agricultural Sciences, 2012, 40(8): 4544-4546, 4574.
[18] 萨如拉, 席领军, 卢萍, 等. 不同添加物对小花棘豆内生真菌酵母氨酸还原酶基因缺失突变株M1合成苦马豆素的影响. 生命科学研究, 2018, 22(4): 298-304.
Sa R L, Xi L J, Lu P, et al. The influence of different additives on the swainsonine biosynthesis in saccharopine reductase gene disruption mutant M1 of an endophytic fungus from Oxytropis glabra. China Industrial Economics, 2018, 22(4): 298-304.
[19] Wickwire B M, Harris C M, Harris T M, et al. Pipecolic acid biosynthesis in Rhizoctonia leguminicola: I. the lysine, saccharopine, delta 1-piperideine-6-carboxylic acid pathway. Journal of Biological Chemistry, 1990, 265(25): 14742-14747.
pmid: 2118517
[20] Harris C M, Schneider M J, Ungemach F S, et al. Biosynthesis of the toxic indolizidine alkaloids slaframine and swainsonine in Rhizoctonia leguminicola: metabolism of 1-hydroxyindolizidines. Journal of the American Chemical Society, 1988, 110(3): 940-949.
doi: 10.1021/ja00211a039
[21] Luo F F, Hong S, Chen B, et al. Unveiling of swainsonine biosynthesis via a multibranched pathway in fungi. ACS Chemical Biology, 2020, 15(9): 2476-2484.
doi: 10.1021/acschembio.0c00466 pmid: 32786262
[22] Pérez-García F, Peters-Wendisch P, Wendisch V F. Engineering Corynebacterium glutamicum for fast production of L-lysine and L-pipecolic acid. Applied Microbiology and Biotechnology, 2016, 100(18): 8075-8090.
doi: 10.1007/s00253-016-7682-6 pmid: 27345060
[23] Lu P, Li X, Wang S Y, et al. Saccharopine reductase influences production of swainsonine in Alternaria oxytropis. Sydowia, 2021, 73: 69-74.
[24] Li X, Lu P. Transcriptome profiles of Alternaria oxytropis provides insights into swainsonine biosynthesis. Scientific Reports, 2019, 9(1): 6021.
doi: 10.1038/s41598-019-42173-2
[25] 余永涛, 毛彦妮, 赵清梅, 等. 甲基磺酸乙酯诱变的棘豆链格孢菌菌株苦马豆素合成基因簇相关基因表达模式分析. 畜牧兽医学报, 2022, 53(4): 1241-1251.
Yu Y T, Mao Y N, Zhao Q M, et al. Expression pattern analysis of related genes in SWN gene cluster of Alternaria oxytropis mutated by ethyl methylate. Acta Veterinaria et Zootechnica Sinica, 2022, 53(4): 1241-1251.
[26] 孙璐, 宋润杰, 路浩, 等. swnR基因在金龟子绿僵菌合成苦马豆素中的作用. 畜牧兽医学报, 2021, 52(5): 1439-1446.
Sun L, Song R J, Lu H, et al. The role of swnR gene on the biosynthetic pathway of the swainsonine in Metarhizium anisopliae. Acta Veterinaria et Zootechnica Sinica, 2021, 52(5): 1439-1446.
[27] Storts D R, Bhattacharjee J K. Purification and properties of saccharopine dehydrogenase (glutamate forming) in the Saccharomyces cerevisiae lysine biosynthetic pathway. Journal of Bacteriology, 1987, 169(1): 416-418.
pmid: 3098733
[28] Wickwire B M, Wagner C, Broquist H P. Pipecolic acid biosynthesis in Rhizoctonia leguminicola. II. saccharopine oxidase: a unique flavin enzyme involved in pipecolic acid biosynthesis. Journal of Biological Chemistry, 1990, 265(25): 14748-14753.
pmid: 2394693
[29] Mukherjee S, Dawe A L, Creamer R. Potential role for saccharopine reductase in swainsonine metabolism in endophytic fungus, Undifilum oxytropis. Fungal Biology, 2012, 116(8): 902-909.
doi: 10.1016/j.funbio.2012.05.007 pmid: 22862918
[30] 呼吉雅. 小花棘豆Embellisia内生真菌酵母氨酸还原酶基因缺失突变株的构建及筛选鉴定. 呼和浩特: 内蒙古师范大学, 2015.
Hu J Y. Construction and screening of saccharopine reductase gene disruption mutant of Embellisia fungal endophyte from Oxytropis glabra. Hohhot: Inner Mongolia Normal University, 2015.
[31] Lu H, Quan H Y, Ren Z H, et al. The genome of Undifilum oxytropis provides insights into swainsonine biosynthesis and locoism. Scientific Reports, 2016, 6(1): 30760.
doi: 10.1038/srep30760
[32] Gao Q, Jin K, Ying S H, et al. Genome sequencing and comparative transcriptomics of the model entomopathogenic fungi Metarhizium anisopliae and M. acridum. PLoS Genetics, 2011, 7(1): e1001264.
doi: 10.1371/journal.pgen.1001264
[33] Neyaz M, Das S, Cook D, et al. Phylogenetic comparison of swainsonine biosynthetic gene clusters among fungi. Journal of Fungi, 2022, 8(4): 359.
doi: 10.3390/jof8040359
[34] 凯乐, 卢萍, 姜凯, 等. 真菌苦马豆素合成途径中SWN基因簇的研究进展. 农业灾害研究, 2022, 12(11): 152-154.
Kai L, Lu P, Jiang K, et al. Research progress of SWN gene cluster in the synthetic pathway of swainsonine. Journal of Agricultural Catastrophology, 2022, 12(11): 152-154.
[35] 李金荣. 甘肃波状芽管孢的鉴定及波状芽管孢真菌LAAO、KS基因的检测. 银川: 宁夏大学, 2018.
Li J R. Identification of Alternaria Section Undifilum gansuense and detection of LAAO, KS genes in Alternaria Section Undifilum spp. Yinchuan: Ningxia University, 2018.
[36] 王维夫. 内生真菌Alternaria oxytropis OW7.8 swnK基因克隆及功能研究. 呼和浩特: 内蒙古师范大学, 2022.
Wang W F. Cloing and functional research of swnK gene in the endophytic fungus Alternaria oxytropis OW7.8. Hohhot: Inner Mongolia Normal University, 2022.
[37] Noor A I, Neyaz M, Cook D, et al. Molecular characterization of a fungal ketide synthase gene among swainsonine-producing Alternaria species in the USA. Current Microbiology, 2020, 77(9): 2554-2563.
doi: 10.1007/s00284-020-02111-2
[38] Huang E X, Zhang Y, Sun L, et al. Swnk plays an important role in the biosynthesis of swainsonine in Metarhizium anisopliae. Biotechnology Letters, 2023, 45(4): 509-519.
doi: 10.1007/s10529-023-03356-0
[39] 马秀奇, 张晓娟, 孙晓敏, 等. 甘蓝型油菜P5CR同源基因的克隆表达及其多态性分析. 福建农业学报, 2022, 37(6): 727-733.
Ma X Q, Zhang X J, Sun X M, et al. Cloning, expression, and polymorphism of homologous Brassica napus P5CR. Fujian Journal of Agricultural Sciences, 2022, 37(6): 727-733.
[40] Selim S, Akhtar N, Hagagy N, et al. Selection of newly identified growth-promoting Archaea Haloferax species with a potential action on cobalt resistance in maize plants. Frontiers in Plant Science, 2022, 13: 872654.
doi: 10.3389/fpls.2022.872654
[41] Sheteiwy M S, Ali D F I, Xiong Y C, et al. Physiological and biochemical responses of soybean plants inoculated with Arbuscular mycorrhizal fungi and Bradyrhizobium under drought stress. BMC Plant Biology, 2021, 21(1): 195.
doi: 10.1186/s12870-021-02949-z pmid: 33888066
[42] Fujii T, Narita T, Agematu H, et al. Characterization of L-lysine 6-aminotransferase and its structural gene from Flavobacterium lutescens IFO3084. The Journal of Biochemistry, 2000, 128(3): 391-397.
doi: 10.1093/oxfordjournals.jbchem.a022766
[43] Fujii T, Mukaihara M, Agematu H, et al. Biotransformation of L-lysine to L-pipecolic acid catalyzed by L-lysine 6-aminotransferase and pyrroline-5-carboxylate reductase. Bioscience, Biotechnology, and Biochemistry, 2002, 66(3): 622-627.
pmid: 12005058
[44] Zhang L, Wu R L, Mur L A J, et al. Assembly of high-quality genomes of the locoweed Oxytropis ochrocephala and its endophyte Alternaria oxytropis provides new evidence for their symbiotic relationship and swainsonine biosynthesis. Molecular Ecology Resources, 2023, 23(1): 253-272.
doi: 10.1111/men.v23.1
[45] Li Z, Xu X, Huang Y, et al. Swainsonine activates mitochondria-mediated apoptotic pathway in human lung cancer A 549 cells and retards the growth of lung cancer xenografts. International Journal of Biological Sciences, 2012, 8(3): 394-405.
doi: 10.7150/ijbs.3882
[46] Lee Z Y, Loo J S E, Wibowo A, et al. Targeting cancer via golgi α-mannosidase II inhibition: how far have we come in developing effective inhibitors. Carbohydrate Research, 2021, 508: 108395.
doi: 10.1016/j.carres.2021.108395
[47] Shi S L, Gu S Q, Han T, et al. Inhibition of MAN2A1 enhances the immune response to anti-PD-L1 in human tumors. Clinical Cancer Research, 2020, 26(22): 5990-6002.
doi: 10.1158/1078-0432.CCR-20-0778
[48] Fu K Y, Chen X, Shou N, et al. Swainsonine induces liver inflammation in mice via disturbance of gut microbiota and bile acid metabolism. Journal of Agricultural and Food Chemistry, 2023, 71(3): 1758-1767.
doi: 10.1021/acs.jafc.2c08519 pmid: 36638362
[49] Wu C C, Han T S, Lu H, et al. The toxicology mechanism of endophytic fungus and swainsonine in locoweed. Environmental Toxicology and Pharmacology, 2016, 47: 38-46.
doi: S1382-6689(16)30229-0 pmid: 27606974
[50] Luo F, Tang G, Hong S, et al. Promotion of Arabidopsis immune responses by a rhizosphere fungus via supply of pipecolic acid to plants and selective augment of phytoalexins. Science China Life Sciences, 2023, 66(5): 1119-1133.
doi: 10.1007/s11427-022-2238-8
[51] Magot F, Van Soen G, Buedenbender L, et al. Bioactivity and metabolome mining of deep-sea sediment-derived microorganisms reveal new hybrid PKS-NRPS macrolactone from Aspergillus versicolor PS108-62. Marine Drugs, 2023, 21(2): 95.
doi: 10.3390/md21020095
[52] Huang Z F, Hu T T, Yang S Z, et al. Genetic responses to adding nitrates to improve hydrophilic yellow pigment in Monascus fermentation. Applied Microbiology and Biotechnology, 2023, 107(4): 1341-1359.
doi: 10.1007/s00253-023-12392-9
[53] Dhakal D, Kokkaliari S, Rubin G M, et al. Biosynthesis of lyngbyastatins 1 and 3, cytotoxic depsipeptides from an Okeania sp. marine Cyanobacterium. Journal of Natural Products, 2023, 86(1): 85-93.
doi: 10.1021/acs.jnatprod.2c00782
[54] Gow N A R, Latge J P, Munro C A. The fungal cell wall: structure, biosynthesis, and function. Microbiology Spectrum, 2017, 5(3). DOI: 10.1128/microbiolspec.FUNK-0035-2016.
doi: 10.1128/microbiolspec.FUNK-0035-2016
[55] 王越, 李雅凝, 曲晓磊, 等. 丝状真菌遗传转化体系及筛选技术的研究进展. 中国林副特产, 2020, 169(6): 69-75.
Wang Y, Li Y N, Qu X L, et al. The research progress on genetic transformation system and screening techniques of filamentous fungi. Forest By-product and Speciality in China, 2020, 169(6): 69-75.
[56] He Z M, Price M S, Obrian G R, et al. Improved protocols for functional analysis in the pathogenic fungus Aspergillus flavus. BMC Microbiology, 2007, 7: 104.
doi: 10.1186/1471-2180-7-104
[57] 于鲲, 薛佳琪, 王进宽, 等. CRISPR/Cas9基因编辑技术在丝状真菌中的应用. 生物技术进展, 2022, 12(5): 696-704.
Yu K, Xue J Q, Wang J K, et al. Research progress on application of CRISPR/Cas 9 gene editing technique in filamentous fungi. Current Biotechnology, 2022, 12(5): 696-704.
[58] 毛彦妮, 余永涛, 赵清梅, 等. 产苦马豆素疯草内生真菌实时荧光定量PCR检测方法的建立. 中国草地学报, 2021, 43(1): 8-17.
Mao Y N, Yu Y T, Zhao Q M, et al. Establishment of real-time fluorescence quantitative PCR detection method for swainsonine-producing endophytic fungi in locoweed. Chinese Journal of Grassland, 2021, 43(1): 8-17.
[59] Zhang J, Hansen L G, Gudich O, et al. A microbial supply chain for production of the anti-cancer drug vinblastine. Nature, 2022, 609(7926): 341-347.
doi: 10.1038/s41586-022-05157-3
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[4] 吕志伟, 吴文平, 毕丽伟, 江星星, 王雅英. 建立金线莲原球茎悬浮体系生产次生代谢产物[J]. 中国生物工程杂志, 2012, 32(05): 43-50.
[5] 李霞, 刘佳佳, 陈建华, 栾明宝, 殷珍珍, 杨栋梁. 产喜树碱喜树内生真菌的筛选及喜树内生真菌的SRAP分析[J]. 中国生物工程杂志, 2011, 31(7): 60-64.
[6] 张晓含,竺锡武,谭济才,陈集双. 一株产凝集素的三叶半夏内生真菌的研究[J]. 中国生物工程杂志, 2009, 29(06): 63-67.
[7] 邱敏,谢瑞生,史彧,陈海敏. 植物内生真菌抗肿瘤药物研究进展[J]. 中国生物工程杂志, 2009, 29(01): 93-104.
[8] 陈宵峰,申屠旭萍,俞晓平,许灵波. 银杏内生真菌No.1028发酵条件的初步研究[J]. 中国生物工程杂志, 2006, 26(0): 87-89.
[9] 潘冰峰, 李祖义. 应用生物法合成内酯化合物[J]. 中国生物工程杂志, 1999, 19(2): 52-55.
[10] 杨玉敏, 元英进, 胡宗定. 植物细胞胞内产物释放行为研究进展[J]. 中国生物工程杂志, 1998, 18(1): 17-21.
[11] 陈士云, 侯嵩生. 生产植物次生代谢物几项新技术研究进展[J]. 中国生物工程杂志, 1993, 13(2): 43-45.
[12] 欧阳平凯, 陆永明, 肖民耕, 袁丽红. 大规模植物细胞培养生物反应器[J]. 中国生物工程杂志, 1992, 12(5): 9-13.
[13] 张冬. 生物工程在农业上取得的两大进展[J]. 中国生物工程杂志, 1988, 8(1): 73-74.
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