OSMAC策略及其在烟曲霉菌次级代谢产物研究中的应用
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摘要
微生物次级代谢产物是新药或新药前驱体的重要来源,但是传统单一的微生物培养模式使微生物中大量的代谢途径不被表达,大大限制了次级代谢产物的数量和质量,对微生物资源造成极大的浪费。单菌多化合物(one strain-many compounds,OSMAC)策略通过激活不同功能基因簇,进而改变其代谢途径,产生新的次级代谢产物,已经逐渐成为应对天然产物资源枯竭危机的重要手段。本文介绍了OSMAC策略中常用的研究手段,主要有改变培养基成分、培养条件和添加酶抑制剂等,以及最新的研究思路,如混合培养和与基因扫描技术相结合等。在此基础上,结合我们的研究成果以及文献资料,综述了OSMAC策略在烟曲霉菌的研究应用,共提取分离次级代谢产物得到的新化合物33个,远远超过传统研究模式。
Natural compounds derived from microbial secondary metabolites were an important source of drug or drug leads. But a large number of metabolic pathways of microorganisms were not expressed during the traditional single microbial culture mode and it greatly limited the quantity and quality of secondary metabolites. The method caused great waste of microbial resources. One Strain Many Compounds( OSMAC) approach was an important mean to deal with the crisis of resources depletion of natural products. Different functional gene clusters could be activated by OSMAC approach including common research methods and new research ideas. The research methods,such as the change in the medium composition,culture conditions and enzyme inhibitors adding,as well as new research ideas of the mixed culture and gene scanning technology were described in this article. The application of OSMAC approach in Aspergillus fumigatus was reviewed by our research and literatures. 33 new compounds were discovered from the secondary metabolites,which was far more than traditional approach.
Natural compounds derived from microbial secondary metabolites were an important source of drug or drug leads. But a large number of metabolic pathways of microorganisms were not expressed during the traditional single microbial culture mode and it greatly limited the quantity and quality of secondary metabolites. The method caused great waste of microbial resources. One Strain Many Compounds( OSMAC) approach was an important mean to deal with the crisis of resources depletion of natural products. Different functional gene clusters could be activated by OSMAC approach including common research methods and new research ideas. The research methods,such as the change in the medium composition,culture conditions and enzyme inhibitors adding,as well as new research ideas of the mixed culture and gene scanning technology were described in this article. The application of OSMAC approach in Aspergillus fumigatus was reviewed by our research and literatures. 33 new compounds were discovered from the secondary metabolites,which was far more than traditional approach.
引文
1 Wei HJ(韦洪娟),et al.OSMAC(One Strain Many Compounds)approach in the research of microbial metabolites-A review.Acta Microbiol Sin(微生物学报),2010,50:701-709.
2 Zhao Q(赵琪),et al.Studies on activating silent biosynthetic gene clusters to synthesize new natural products in microorganisms.World Clin Drugs(世界临床药物),2014,35:501-505.
3 Hewage RT,et al.One strain-many compounds(OSMAC)method for production of polyketides,azaphilones,and an isochromanone using the endophytic fungus Dothideomycete sp.Phytochem,2014,108:87-94.
4 Bode HB,et al.Big effects from small changes:Possible ways to explore nature's chemical diversity.ChemB ioC hem,2002,3:619-627.
5 Zhao WY(赵文英),et al.Studies on chemical constituents of secondary metabolites of marine-derived Aspergillus fumigatus(I):alkaloids.J Qingdao Univ Sci Technol,Sci Ed(青岛科技大学学报:自科版),2007,3:199-201.
6 Wei HJ(韦洪娟).OSMAC approach and application in the research of Marine-derived Fungi Spicaria elegans KLA03.Qingdao:Ocean University of China(中国海洋大学),PhD.2010.
7 Qi HW(祁宏伟),et al.Effects of different culture conditions on lactic acid bacteria fermentation metabolites of CLA.Anhui Agri Sci Bull(安徽农学通报),2011,21:38-40.
8 Miller JD,et al.Marine fungi of the Bay of Fundy VI:Growth and metabolites of Leptoshpaeria oraemaris,Sphaerulina oraemaris,Monodictys pelagica and Dendryphiella salina.Proc Nova Scot Inst Sci,1984,34.
9 Masuma R,et al.Effect of sea water concentration on hyphal growth and antimicrobial metabolite production in marine fungi.Mycoscience,2001,42:455-459.
10 Louro R,et al.Practical approaches to biological inorganic chemistry.Elsevier,2012.
11 Paranagama PA,et al.Uncovering biosynthetic potential of plant-associated fungi:Effect of culture conditions on metabolite production by Paraphaeosphaeria quadriseptata and Chaetomium chiversii.J Nat Prod,2007,70:1939-1945.
12 Wang WJ,et al.Caryophyllene sesquiterpenes from the Marine-Derived Fungus Ascotricha sp.ZJ-M-5 by the One Strain-Many Compounds Strategy.J Nat Prod,2014,77:1367-1371.
13 Shi TH(石天虹),et al.Influence factors and control of microbial fermentation.Poultry Sci(家禽科学),2005,2:45-48.
14 Ruan FC(阮复昌),et al.Control of temperature and pH value in the fermentation process.Mod Food Sci Technol(现代食品科技),1991,4:15-17.
15 Wang FZ,et al.Seven new prenylated indole diketopiperazine alkaloids from holothurian-derived fungus Aspergillus fumigatus.Tetrahedr Lett,2008,64:7986-7991.
16 Cui CB,et al.Novel mammalian cell cycle inhibitors,spirotryprostatins A and B,produced by Aspergillus fumigatus,which inhibit mammalian cell cycle at G2/M phase.Tetrahedr Lett,1996,52:12651-12666.
17 Kepler CR,et al.Intermediates and products of the biohydrogenation of linoleic acid by Butyrivibrio fibrisolvens.J Biol Chem,1966,241:1350-1354.
18 Burgess JG,et al.Microbial antagonism:a neglected avenue of natural products research.J Biotechnol,1999,70:27-32.
19 Cueto M,et al.Pestalone,a new antibiotic produced by amarine fungus in response to bacterial challenge.J Nat Prod,2001,64:1444-1446.
20 Zhang DH,et al.Two new indole alkaloids,2-(3,3-dimethylprop-1-ene)-costaclavine and 2-(3,3-dimethylprop-1-ene)-epicostaclavine,from the marine-derived fungus Aspergillus fumigatus.J Nat Med,2012,66:222-226.
21 Banskota AH,et al.Isolation and identification of three new5 -alkenyl-3,3(2H)-furanones from two Streptomyces species using a genomic screening approach.J Antibiot,2006,59:168-176.
22 Han XX(韩小贤),et al.Alkaloidal compounds produced by a marine-derived fungus,Aspergillus fumigatus H1-04,and their antitumor activities.Chin J Med Chem(中国药物化学杂志),2007,17:232-237.
23 Wang FZ(王发左).Studies on the antitumor constituents and biotransformation of secondary metabolites produced by marine-derived fungi.Qingdao:Ocean University of China(中国海洋大学),PhD.2008.
24 Cui CB,et al.Novel mammalian cell cycle inhibitors,tryprostatins A,B and other diketopiperazines produced by Aspergillus fumigatus.I.Taxonomy,fermentation,isolation and biological properties.J Antibiot,1996,49:527-533.
25 Numata A,et al.Fumiquinazolines,novel metabolites of a fungus isolated from a saltfish.Tetrahedr Lett,1992,33:1621-1624.
26 Takahashi C,et al.Fumiquinazolines A-G,novel metabolites of a fungus separated from a Pseudolabrus marine fish.J Chem Soc,1995,18:2345-2353.
27 Yamamoto Y,et al.Studies on the metabolic products of Aspergillus fumigatus(J-4)Chemical structure of metabolic products.Chem Pharm Bull,1968,16:304-310.
28 Li XJ,et al.Metabolites from Aspergillus fumigatus,an endophytic fungus associated with Melia azedarach,and their antifungal,antifeedant,and toxic activities.J Agric Food Chem,2012,60:3424-3431.
29 Ye BP(叶波平),et al.Study on rhizosphere soil of Rhizophora stylosa of Aspergillus fumigatus F3 and its active metabolites.Hainan haikou China(中国海南海口),2008.
30 Alcazar FL,et al.Ergosterol biosynthesis pathway in Aspergillus fumigatus.Steroids,2008,73:339-347.
31 Nieminen SM,et al.Genotoxicity of gliotoxin,a secondary metabolite of Aspergillus fumigatus,in a battery of short-term test systems.Mutat Res,2002,520:161-170.
2 Zhao Q(赵琪),et al.Studies on activating silent biosynthetic gene clusters to synthesize new natural products in microorganisms.World Clin Drugs(世界临床药物),2014,35:501-505.
3 Hewage RT,et al.One strain-many compounds(OSMAC)method for production of polyketides,azaphilones,and an isochromanone using the endophytic fungus Dothideomycete sp.Phytochem,2014,108:87-94.
4 Bode HB,et al.Big effects from small changes:Possible ways to explore nature's chemical diversity.ChemB ioC hem,2002,3:619-627.
5 Zhao WY(赵文英),et al.Studies on chemical constituents of secondary metabolites of marine-derived Aspergillus fumigatus(I):alkaloids.J Qingdao Univ Sci Technol,Sci Ed(青岛科技大学学报:自科版),2007,3:199-201.
6 Wei HJ(韦洪娟).OSMAC approach and application in the research of Marine-derived Fungi Spicaria elegans KLA03.Qingdao:Ocean University of China(中国海洋大学),PhD.2010.
7 Qi HW(祁宏伟),et al.Effects of different culture conditions on lactic acid bacteria fermentation metabolites of CLA.Anhui Agri Sci Bull(安徽农学通报),2011,21:38-40.
8 Miller JD,et al.Marine fungi of the Bay of Fundy VI:Growth and metabolites of Leptoshpaeria oraemaris,Sphaerulina oraemaris,Monodictys pelagica and Dendryphiella salina.Proc Nova Scot Inst Sci,1984,34.
9 Masuma R,et al.Effect of sea water concentration on hyphal growth and antimicrobial metabolite production in marine fungi.Mycoscience,2001,42:455-459.
10 Louro R,et al.Practical approaches to biological inorganic chemistry.Elsevier,2012.
11 Paranagama PA,et al.Uncovering biosynthetic potential of plant-associated fungi:Effect of culture conditions on metabolite production by Paraphaeosphaeria quadriseptata and Chaetomium chiversii.J Nat Prod,2007,70:1939-1945.
12 Wang WJ,et al.Caryophyllene sesquiterpenes from the Marine-Derived Fungus Ascotricha sp.ZJ-M-5 by the One Strain-Many Compounds Strategy.J Nat Prod,2014,77:1367-1371.
13 Shi TH(石天虹),et al.Influence factors and control of microbial fermentation.Poultry Sci(家禽科学),2005,2:45-48.
14 Ruan FC(阮复昌),et al.Control of temperature and pH value in the fermentation process.Mod Food Sci Technol(现代食品科技),1991,4:15-17.
15 Wang FZ,et al.Seven new prenylated indole diketopiperazine alkaloids from holothurian-derived fungus Aspergillus fumigatus.Tetrahedr Lett,2008,64:7986-7991.
16 Cui CB,et al.Novel mammalian cell cycle inhibitors,spirotryprostatins A and B,produced by Aspergillus fumigatus,which inhibit mammalian cell cycle at G2/M phase.Tetrahedr Lett,1996,52:12651-12666.
17 Kepler CR,et al.Intermediates and products of the biohydrogenation of linoleic acid by Butyrivibrio fibrisolvens.J Biol Chem,1966,241:1350-1354.
18 Burgess JG,et al.Microbial antagonism:a neglected avenue of natural products research.J Biotechnol,1999,70:27-32.
19 Cueto M,et al.Pestalone,a new antibiotic produced by amarine fungus in response to bacterial challenge.J Nat Prod,2001,64:1444-1446.
20 Zhang DH,et al.Two new indole alkaloids,2-(3,3-dimethylprop-1-ene)-costaclavine and 2-(3,3-dimethylprop-1-ene)-epicostaclavine,from the marine-derived fungus Aspergillus fumigatus.J Nat Med,2012,66:222-226.
21 Banskota AH,et al.Isolation and identification of three new5 -alkenyl-3,3(2H)-furanones from two Streptomyces species using a genomic screening approach.J Antibiot,2006,59:168-176.
22 Han XX(韩小贤),et al.Alkaloidal compounds produced by a marine-derived fungus,Aspergillus fumigatus H1-04,and their antitumor activities.Chin J Med Chem(中国药物化学杂志),2007,17:232-237.
23 Wang FZ(王发左).Studies on the antitumor constituents and biotransformation of secondary metabolites produced by marine-derived fungi.Qingdao:Ocean University of China(中国海洋大学),PhD.2008.
24 Cui CB,et al.Novel mammalian cell cycle inhibitors,tryprostatins A,B and other diketopiperazines produced by Aspergillus fumigatus.I.Taxonomy,fermentation,isolation and biological properties.J Antibiot,1996,49:527-533.
25 Numata A,et al.Fumiquinazolines,novel metabolites of a fungus isolated from a saltfish.Tetrahedr Lett,1992,33:1621-1624.
26 Takahashi C,et al.Fumiquinazolines A-G,novel metabolites of a fungus separated from a Pseudolabrus marine fish.J Chem Soc,1995,18:2345-2353.
27 Yamamoto Y,et al.Studies on the metabolic products of Aspergillus fumigatus(J-4)Chemical structure of metabolic products.Chem Pharm Bull,1968,16:304-310.
28 Li XJ,et al.Metabolites from Aspergillus fumigatus,an endophytic fungus associated with Melia azedarach,and their antifungal,antifeedant,and toxic activities.J Agric Food Chem,2012,60:3424-3431.
29 Ye BP(叶波平),et al.Study on rhizosphere soil of Rhizophora stylosa of Aspergillus fumigatus F3 and its active metabolites.Hainan haikou China(中国海南海口),2008.
30 Alcazar FL,et al.Ergosterol biosynthesis pathway in Aspergillus fumigatus.Steroids,2008,73:339-347.
31 Nieminen SM,et al.Genotoxicity of gliotoxin,a secondary metabolite of Aspergillus fumigatus,in a battery of short-term test systems.Mutat Res,2002,520:161-170.