两个Ⅰ型聚酮合酶功能结构域在异源宿主的表达
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摘要
链霉菌FR-008聚酮合酶(PKS)基因簇负责七烯大环内酯抗真菌抗生素杀假丝菌素(FR-008)的生物合成，将这个巨大的基因簇转入植物以探索产生抗真菌植物品种的可能性是我们深入研究杀假丝菌素生物合成基因簇的长远目标之一。
为探索在植物中表达极高G+C含量的PKS基因的可能性，构建了携带有编码FR-008 Ⅰ型PKS模块氨基端部分的基因的表达质粒，包括一个酮基合酶(KS)和部分酰基转移酶(AT)活性结构域。该载体携带有花椰菜花叶病毒35S RNA的启动子以指导PKS的表达。由于载体中2.7 kb的PKS基因编码了两种酶活性的结构域而不是完整的Ⅰ型PKS模块，因此我们目前并不期望这个截短的PKS基因在植物能产生抗真菌活性。
为在大肠杆菌超量表达该2.7 kb PKS基因所编码的两个功能结构域，构建了具有不同启动子组合的PKS表达质粒。其中一些可超量表达具有预期分子量的PKS蛋白。进一步截短的基因可以表达预期大小的50 kDa蛋白，表明这些超量表达的蛋白是由克隆在质粒上的PKS基因所编码。
接着将大肠杆菌表达的PKS作为抗原制备与天然FR-008 PKS对应的多克隆抗体。蛋白质印迹实验显示，部分提纯的抗体样品与大肠杆菌中表达的PKS蛋白有特异性反应。同时，这些抗体也可与天然存在于链霉菌FR-008的、巨大的PKS蛋白特异性地反应。这说明构建的大肠杆菌表达质粒中FR-008 PKS基因是以正确的读码框架克隆和表达的；同时也表明抗血清对天然的FR-008 Ⅰ型PKS具有特异性。利用抗体检测PKS的检出极限比考马斯亮蓝染色高1000倍，应可用于检测植物中低水平的PKS表达。
构建了两个链霉菌-大肠杆菌双功能PKS表达质粒，在重组PKS基因上游携带有λ噬菌体启动子。利用这些质粒在变铅青链霉菌和大肠杆菌中均表达出PKS蛋白，两种宿主中的表达都是热依赖的。暗示λ噬菌体启动子和温敏型λ阻遏物在变铅青链霉菌和大肠杆菌中都具有功能。表达PKS的变铅青链霉菌菌株在孢子形成和抗生素产生方面与没有2.7 kb PKS基因的菌株相比较是有区别的，因而推测在链霉菌中表达的双功能结构域PKS蛋白具有活性。
构建了带有λ噬菌体启动子和特异性抗原决定簇(表位)及2.7 kb PKS基因的整合型质粒，用于标记天然的FR-008 PKS。将这些质粒转入链霉菌FR-008的限制性缺陷菌株中得到抗性转化子。Southern杂交证实2.7 kb PKS基因和天然PKS基因之间通过同源重组发生了整合。衍生菌株合成抗真菌抗生素的产量与亲本菌株不同，表明FR-008基因的原始启动子已被改造后的启动子和抗原决定簇所代替。
根据受cIts857调控的P_R能引导PKS基因的成功表达，构建了大肠杆菌表达载体pHZ330以及在大肠杆菌和链霉菌两种宿主中都能表达外源基因的双功能表达载体pHZ1060。两种载体在宿主细胞中是稳定的，应可用于异源基因的表达。
A long term goal of our group is to introduce the very large and high G+C content polyketide synthase(PKS) genes for the biosynthesis of the heptaene macrolide antifungal antibiotic Candicidin from Streptomyces species FR-008 into plant to generate fungal resistance lines.
An expression vector carrying a fragment encoding the amino-terminal part of an FR-008 Type I PKS module, containing a keto-synthase(KS) and part of an acetyl-transferase(AT) domain was constructed for trial expression of the extremely high G+C content(76 %) PKS gene in plant. This vector containing the promoter of the Cauliflower mosaic virus 35S RNA for the expression of the 2.7 kb PKS gene. Expression of this truncated gene in plant was expected to give information about expression in plant of high G+C content genes but no antifungal activity was expected in this stage.
PKS expression plasmids containing strong, temperature-inducible, bacteriophage lambda promoters with or without the Escherichia coli phage T7 promoter were constructed and some of them lead to high expression of the expected c. 100 kDa PKS protein but some of them did not give reproducible high expression in E. coli. Truncating of the 2.7 kb PKS gene from these expression plasmids resulted in production of an expected 50 kDa protein, suggesting that these over expressed proteins were encoded by the cloned PKS gene. The over expressed PKS proteins in E. coli formed inclusion bodies.
Then the FR-008 PKS produced in E. coli was used as antigen to raise polyclonal antibodies against the natural FR-008 PKS. Non-specific anti-E. coli antibodies were removed by precipitation with E. coli extract. Western blot experiments indicated that the partially purified antibody preparations reacted specifically with the PKS proteins expressed in E. coli and, as expected, also with the very large PKS proteins naturally present in S. sp. FR-008. This confirmed that the FR-008 PKS gene in the E. coli expression vectors was cloned in the correct reading frame. The above detection of a very large protein in S. sp. FR-008 indicated that the antiserum had the desired specificity for the FR-008 PKS. The detection limitation of PKS using antibodies was 1000 fold higher than Commassie blue staining, ready for detection of the probably very low level of PKS expression in plant.
Two bifunctional Streptomyces-E. coli vectors were constructed that contained the phage lambda promoter(PR) upstream of the His6-tagged recombinant PKS gene. Using these vectors, expression of the PKS gene was achieved both in Streptomyces lividans and in E. coli in a heat-dependent manner, suggesting that the lambda promoter and temperature-sensitive lambda represser functioned in S. lividans as well as in E. coli. Also the CI represser was expressed, presumably from its own phage promoter and prevented transcription from PR at low temperature. Moreover, S. lividans strains expressing the c. 100 kDa PKS were different in sporulation and antibiotic production compared to strains without the 2.7 kb PKS gene, suggesting that the PKS protein was active in an unknown manner in Streptomyces.
Integrated plasmids containing phage lambda promoter PR -directed and epitope-tagged 2.7 kb PKS gene were constructed for tagging the natural FR-008 PKS with specific immunodeterminant(epitope). These constructs were transferred into Streptomyces sp. DX600, a
restriction deficient strain of the antibiotic producer S. sp. FR-008. Integration through homologous recombination between the 2.7 kb PKS gene and the natural PKS gene was confirmed by Southern hybridization. The resulting derivative strains produced antifungal activity in a manner different from the parental strain, indicating the original promoter was replaced with the engineered promoters and the epitopes.
Base on the successful expression of PKS gene by CIts857 controlled lambda promoter, an E. coli expression vector pHZ330, an E. coli and Streptomyces bi-functional vector pHZ1060 were constructed containing the dts857-PR for inducible expression in both hosts. Both vector
为探索在植物中表达极高G+C含量的PKS基因的可能性，构建了携带有编码FR-008 Ⅰ型PKS模块氨基端部分的基因的表达质粒，包括一个酮基合酶(KS)和部分酰基转移酶(AT)活性结构域。该载体携带有花椰菜花叶病毒35S RNA的启动子以指导PKS的表达。由于载体中2.7 kb的PKS基因编码了两种酶活性的结构域而不是完整的Ⅰ型PKS模块，因此我们目前并不期望这个截短的PKS基因在植物能产生抗真菌活性。
为在大肠杆菌超量表达该2.7 kb PKS基因所编码的两个功能结构域，构建了具有不同启动子组合的PKS表达质粒。其中一些可超量表达具有预期分子量的PKS蛋白。进一步截短的基因可以表达预期大小的50 kDa蛋白，表明这些超量表达的蛋白是由克隆在质粒上的PKS基因所编码。
接着将大肠杆菌表达的PKS作为抗原制备与天然FR-008 PKS对应的多克隆抗体。蛋白质印迹实验显示，部分提纯的抗体样品与大肠杆菌中表达的PKS蛋白有特异性反应。同时，这些抗体也可与天然存在于链霉菌FR-008的、巨大的PKS蛋白特异性地反应。这说明构建的大肠杆菌表达质粒中FR-008 PKS基因是以正确的读码框架克隆和表达的；同时也表明抗血清对天然的FR-008 Ⅰ型PKS具有特异性。利用抗体检测PKS的检出极限比考马斯亮蓝染色高1000倍，应可用于检测植物中低水平的PKS表达。
构建了两个链霉菌-大肠杆菌双功能PKS表达质粒，在重组PKS基因上游携带有λ噬菌体启动子。利用这些质粒在变铅青链霉菌和大肠杆菌中均表达出PKS蛋白，两种宿主中的表达都是热依赖的。暗示λ噬菌体启动子和温敏型λ阻遏物在变铅青链霉菌和大肠杆菌中都具有功能。表达PKS的变铅青链霉菌菌株在孢子形成和抗生素产生方面与没有2.7 kb PKS基因的菌株相比较是有区别的，因而推测在链霉菌中表达的双功能结构域PKS蛋白具有活性。
构建了带有λ噬菌体启动子和特异性抗原决定簇(表位)及2.7 kb PKS基因的整合型质粒，用于标记天然的FR-008 PKS。将这些质粒转入链霉菌FR-008的限制性缺陷菌株中得到抗性转化子。Southern杂交证实2.7 kb PKS基因和天然PKS基因之间通过同源重组发生了整合。衍生菌株合成抗真菌抗生素的产量与亲本菌株不同，表明FR-008基因的原始启动子已被改造后的启动子和抗原决定簇所代替。
根据受cIts857调控的P_R能引导PKS基因的成功表达，构建了大肠杆菌表达载体pHZ330以及在大肠杆菌和链霉菌两种宿主中都能表达外源基因的双功能表达载体pHZ1060。两种载体在宿主细胞中是稳定的，应可用于异源基因的表达。
A long term goal of our group is to introduce the very large and high G+C content polyketide synthase(PKS) genes for the biosynthesis of the heptaene macrolide antifungal antibiotic Candicidin from Streptomyces species FR-008 into plant to generate fungal resistance lines.
An expression vector carrying a fragment encoding the amino-terminal part of an FR-008 Type I PKS module, containing a keto-synthase(KS) and part of an acetyl-transferase(AT) domain was constructed for trial expression of the extremely high G+C content(76 %) PKS gene in plant. This vector containing the promoter of the Cauliflower mosaic virus 35S RNA for the expression of the 2.7 kb PKS gene. Expression of this truncated gene in plant was expected to give information about expression in plant of high G+C content genes but no antifungal activity was expected in this stage.
PKS expression plasmids containing strong, temperature-inducible, bacteriophage lambda promoters with or without the Escherichia coli phage T7 promoter were constructed and some of them lead to high expression of the expected c. 100 kDa PKS protein but some of them did not give reproducible high expression in E. coli. Truncating of the 2.7 kb PKS gene from these expression plasmids resulted in production of an expected 50 kDa protein, suggesting that these over expressed proteins were encoded by the cloned PKS gene. The over expressed PKS proteins in E. coli formed inclusion bodies.
Then the FR-008 PKS produced in E. coli was used as antigen to raise polyclonal antibodies against the natural FR-008 PKS. Non-specific anti-E. coli antibodies were removed by precipitation with E. coli extract. Western blot experiments indicated that the partially purified antibody preparations reacted specifically with the PKS proteins expressed in E. coli and, as expected, also with the very large PKS proteins naturally present in S. sp. FR-008. This confirmed that the FR-008 PKS gene in the E. coli expression vectors was cloned in the correct reading frame. The above detection of a very large protein in S. sp. FR-008 indicated that the antiserum had the desired specificity for the FR-008 PKS. The detection limitation of PKS using antibodies was 1000 fold higher than Commassie blue staining, ready for detection of the probably very low level of PKS expression in plant.
Two bifunctional Streptomyces-E. coli vectors were constructed that contained the phage lambda promoter(PR) upstream of the His6-tagged recombinant PKS gene. Using these vectors, expression of the PKS gene was achieved both in Streptomyces lividans and in E. coli in a heat-dependent manner, suggesting that the lambda promoter and temperature-sensitive lambda represser functioned in S. lividans as well as in E. coli. Also the CI represser was expressed, presumably from its own phage promoter and prevented transcription from PR at low temperature. Moreover, S. lividans strains expressing the c. 100 kDa PKS were different in sporulation and antibiotic production compared to strains without the 2.7 kb PKS gene, suggesting that the PKS protein was active in an unknown manner in Streptomyces.
Integrated plasmids containing phage lambda promoter PR -directed and epitope-tagged 2.7 kb PKS gene were constructed for tagging the natural FR-008 PKS with specific immunodeterminant(epitope). These constructs were transferred into Streptomyces sp. DX600, a
restriction deficient strain of the antibiotic producer S. sp. FR-008. Integration through homologous recombination between the 2.7 kb PKS gene and the natural PKS gene was confirmed by Southern hybridization. The resulting derivative strains produced antifungal activity in a manner different from the parental strain, indicating the original promoter was replaced with the engineered promoters and the epitopes.
Base on the successful expression of PKS gene by CIts857 controlled lambda promoter, an E. coli expression vector pHZ330, an E. coli and Streptomyces bi-functional vector pHZ1060 were constructed containing the dts857-PR for inducible expression in both hosts. Both vector
引文
上海植物生理研究所微生物室农抗组。庆丰霉素Ⅱ，分离、提纯及理化性质。微生物学报，1975，15：101-109
中科院微生物研究所菌种保藏管理委员会。菌种目录。科学出版社，1982
邓子新，周秀芬。一个链霉菌的质粒pHZ65及其载体的发展。见：中国的遗传学研究。北京：中国科技出版社，1991，318-319
邓子新，用秀芬，Kieser T，Hopwood D A．与多烯抗生素FR-008生物学合成有关的抗生素生物合成基因簇的克隆和鉴定。中国博士后首届学术大会文集。国防工业出版社，1993，1757-1762
孙乃恩，孙东旭，朱德煦。分子遗传学。南京：南京大学出版社，1990
张智清，姚立红，侯云德。含P_RP_L启动子的原核高效表达载体的组建及其应用。病毒学报，1990，6：111-115
杨闰英，胡志浩，邓子新，李季伦。大肠杆菌—链霉菌穿梭表达载体的构建及应用。生物工程学报，1998，14：7-13
陈葆堂。水稻原生质体培养、转基因及相关技术研究。[博士学位论文]。武汉，华中农业大学图书馆，1996
欧阳谅，涂国全，高勇生。南昌链霉菌新种及其产生的两种杀虫抗生素。江西农业大学学报，《杀虫抗生素研究》专辑，1993，15：148-153
胡志浩。多烯抗生索FR-008生物合成的分子生物学。[博士学位论文]武汉，华中农业大学图书馆，1995
袁丽蓉。麦迪霉素产生菌—生米卡链霉菌原生质体融合的研究。抗生素，1983，8：380-387
袁德军，周启。吸水链霉菌应城变种种内融合子FR-008产生新抗生素的杀虫活性。华中农业大学学报，1990，9：209
袁德军，周启。农抗5102产生菌原生质体融合育种的研究Ⅳ，融合子FR-008的验证及其产生新活性物质的分离和鉴定。生物工程学报，1991，7：142-147
梁蓉芳，周启。农抗5102产生菌株原生质体融合育种的研究。生物工程学报，1987，3：130-136
黄曦。链霉菌FR-008与灰色链霉菌IMRU3570及其代谢产物的比较研究。[博士学位论文]武汉，华中农业大学图书馆，1997
鲍锴，胡志浩，周秀芬，周启，邓子新。一个可在大肠杆菌和链霉菌之间进行间接合转移的柯斯质粒。科学通报，1995，40：1440。
鲍锴。链霉菌新载体系统的发展及其在抗生素生物合成和调节基因的克隆和分析中的应用。[博士学位论文]。武汉，华中农业大学图书馆，1997
Barz W, Bless W, Borger-Papendorf G, Gunia W, Mackenbrock U, Meier D, Otto C and Super E. Phytoalexins as part of induced defence reactions in plants: their elicitation, function and metabolism. Ci ba Found Symp, 1990,154:140-153
Bedford D, Jacobsen J R, Luo G, Cane D E and Khosla C. A functional chimeric modular polyketide synthase generated via domain replacement. Chem Biol, 1996, 3:827-831
Bevitt D J, Cortes J, Haydock S F and Leadley P E 6-deoxyerythronolide-B synthase 2 from Saccharopolyspora erythraea. Cloning of the structural gene, sequence analysis and inferred domain structure of the multifunctional enzyme. Eur J Biochem, 1992, 204:39-49
Bibb M J, Freeman R F and Hopwood D A. Physical and genetical eharacterisation of a second sex
factor, SCP2, for Streptomyces coelicolor A3(2). Mol Gen Genet, 1977, 154:155-166
Bibb M J, Findlay P R and Johnson M W. The relationship between base composition and eodon usage in bacterial genes and its use for the simple and reliable identification of protein-coding sequences. Gene, 1984, 30:157-166
Bibb M J, Janssen G R and Ward J M. Cloning and analysis of the promoter region of the erythromyein resistance gene ermE of Streptomyces erythraeus. Gene, 1985, 38:215-226
Bibb M J, White J, Ward J M and Janssen G R. The mRNA for the 23S rRNA methylase encoded by the ermE gene of Saccharopolyspora erythraea is translated in the absence of a conventional ribosome-binding site. MolMicrobiol, 1994, 14:533-545
Bio-Rad a. Mini trans-blot electrophoretic transfer cell instruction manual
Bio-Rad b. Mini-prortean Ⅱ electrophoresis cell instruction manual
Blattner F R, Pluktt I G, Bloch C A, Perna N T, Burland V, Riley M, Collado-Vides J, Glasner J D, Rode C K, Mayhew G F, Gregor J, Davis N W, Kirkpatrick H A, Goeden M A, Rose D J, Mau B and Shau Y. The complete genome sequence of Escherichia coli K12. Science, 1997, 277: 1453- 1462
Bohm I, Holzbaur I, Hanefeld U, Cortes J, Staunton J and Leadlay P. Engineering of a minimal modular polyketide synthase and targeted alteration of the stereospecificity of polyketide chain extension. Chem Biol, 1998, 5:407-412
Busby S and Ebright R H. Promoter structure, promoter recognition and transcription activation in prokaryotes. Cell, 1994, 79:743-746
Buttner M J. RNA polymerase heterogeneity in Streptomyces coelicolor A3(2). MolMicrobiol, 1989, 3: 1653-1659
Cases I and De Lorenzo V. Expression systems and physiological control of promoter activity in bacteria. Curr Opin Microbiol, 1998, 1:303-310
Chang H, Chen M, Shieh Y, Bibb M and Chen C. The cutRS signal transduction system of Streptomycer lividans represses the biosynthesis of the polykefide antibiotic actinorhodin. Mol Microbiol, 1996, 21:1075-1085
Chen C W, Yu T-W, Lin Y-S, Kieser H M and Hopwood D A. The conjugative plasmid SLP2 of Stretpomyces lividans is a 50 kb linear molecule. MolMicrobiol, 1993, 7:925-932
Christou P, Macabe D E, Swan W F and Russell D R. Legume transformation. In Verma DPS ed, Control of plant gene expression. BocoRaton: CRC Press, 1993, 547-561
Cortes J, Haydock S F, Roberts G A, Bevitt D J and Leadlay P F. An unusually large multifunctional polypeptide in the erythromycin-producing polyketide synthase of Saccharopolyspora erythraea. Nature, 1990, 348:176-178
Cortes J, Wiesmann K E H, Roberts G A, Brown M J B, Staunton J and Leadlay P F. Repositioning of a domain in a modular polyketide synthase to promote specific chain cleavage. Science, 1995, 268:1487-1489
Crowl R, Seamans C, Lomedico P and McAndrew S. Versatile expression vectors for high-level synthesis of cloned gene products in Escherichia coli. Gene, 1985, 38:31-38
Dary A, Kaiser P, Bourget N, Thompson C J, Simonet J-M and Deearis B. Large genomic rearrangements of the unstable region in Streptomyces ambofaciens are associated with major changes in global gene expression. Mol Microbiol, 1993, 10:759-769
De Block M, Botterman J, Wandewiele M, Dock X J, Thoen C, Gossele V, Mowa N, Thompson C, Van Montage M and Leemans J. Engineering herbicide resistance in plant by expression of a
detoxifying enzyme. EMBOJ, 1987, 6:2513
De Boer H A, Comstock L J and Vasser M. The tac promoter: a functional hybrid derived from the trp and lac promoters. Proc Natl Acad Sci USA, 1983, 80:21-25
Decker H and Haag S. Cloning and characterization of a polyketide synthase gene from Streptomyces fradiae Tu2717, which carries the genes for biosynthesis of the angucycline antibiotic urdamycin A and a gene probably involved in its oxygenation. J Bacteriol, 1995, 177:6126-6136
Deng Z, Kieser T and Hopwood D A. "Strong incompatability" between derivatives of the Streptomyces multi-copy plasmid pIJ101, Mol Gen Genet, 1988, 214:286-294
Dohren H, Keller U, vatre J and Zocher R. Multifunctional peptide synthetases. Chemical Reviews, 1997, 97:2675
Dombraski A J, Walter W A, Recod M T, Siegele D A and Gross C A. Polypeptides containing highly conserved regions of binding to promoter DNA. Cell, 1992, 70:501-512
Donadio S, Stayer M J, McAlpine J B, Swanson S J and Katz L. Modular organization of genes required for complex polyketide biosynthesis. Science, 1991,252:675-679
Donadio S and Katz L. Organization of the enzymatic domains in the multifunctional polyketide synthase involved in erythromycin formation in Saccharopolyspora erythraea. Gene, 1992, 111: 51-60
Dubendoff J W and Studier W E Controlling basal expression in an inducible T7 expression system by blocking the target T7 promoter with lac represser. J Mol Biol, 1987,219:45-59
Dutton C J, Gibson S P, Goudie A C, Holdom K S, Pacey M S, Ruddock J C, Bu'Lock J D and Richards M K. Novel avermectins produced by mutational biosynthesis. J Antibiot, 1991, 44: 357-365
Estrem S T, Gaal T, Ross W and Gourse R L. Identification of an UP element consensus sequence for bacterial promoters. Proc Natl Acad Sci USA, 1998, 95:9761-9766
Farewell A. Negative regulation by RpoS: a case of sigma factor competition. Mol Microbiol, 1998, 29: 1039-1051
Fliegmann J, Schroder G, Schanz S, Britsch L and Schroder J. Molecular analysis of chalcone and dihydropinosylvin synthase from Scots pine(Pinus sylvestris) and differential regulation of these and related enzyme activities in stressed plants. Plant Mol Biol, 1992, 18:489-503
Gil J A and Hopwood D A. Cloning and expression of a p-aminobenzoic acid synthetase gene of the candicidin-producing Streptomyces griseus. Gene , 1983, 25:119-132
Giordano T J, Deuschle U, Bujard H and MeAlister W T. Regulation of coliphage T3 and T7 RNA polymerase by the lac represser-operator system. Gene, 1989, 84:209-219
Gottesman S. Minimizing proteolysis in Escherichia coli: genetic solutions. Methods Enzymol, 1990, 185:119-129
Gramajo H C, White J, Hutchinson C R and Bibb M J. Overproduction and localization of components of the polyketide synthase of Streptomyces glaucescens involved in the production of the antibiotic tetracenomycin C. J Bacteriol, 1991, 173:6475-6483
Grossman A D, Erickson J W and Gross C A. The htpR gene product is a sigma factor for heat-shock promoters. Cell, 1984, 38:383-390
Gumpert J and Hoischen C. Use of cell wall-less bacteria(L-forms) for efficient expression and secretion of heterologous gene products. Curr Opin Biotechnol. 1998, 9:506-509
Harborne J B. Role of secondary metabolites in chemical defense mechanisms in plants. Ciba Found Symp, 1990, 154:126-134
Hopwood D A, Bibb M J, Crater K F, Kieser T, Bruton C J, Kieser H M, Lydiate D J, Smith C P, Ward J M and Schrempf H. Genetic Manipulation of Streptomyces A laboratory manual. Norwich: John Innes Foundation, 1985a
Hopwood D A, Malpartida F, Kieser H M, Ikeda H, Duncan J, Fujii I, Rudd B A M, Floss H G and Omura S. Production of'hybrid' antibiotics by genetic engineering. Nature, 1985b, 314:642-644
Hopwood D A. The Leeuwenhoek Lecture, 1987. Towards an understanding of gene switching in Streptomyces, the basis of sporulation and antibiotic production. Proc R Soc Lond B Biol Sci ,1988, 235:121-138
Hopwood D A and Sherman D H. Molecular genetics of polyketides and its comparison to fatty acid biosynthesis. Annu Rev Genet, 1990, 24:37-66
Hopwood D A. Genetic contributions to understanding polyketide synthases. Chemical Reviews, 1997, 97:2465-2497
Hu Z, Bao K, Zhou X, Zhou Q, Hopwood D A, Kieser T and Deng Z. Repeated polyketide synthase modules involved in the biosynthesis of a heptaene macrolide by Streptomyces sp. FR-008. Mol Microbiol, 1994, 14:163-172
Hutchinson C R. Biosynthetic studies of daunorubicin and tetracenomycin C. Chemical Reviews, 1997, 97:2525-2536
Hutchinson C R. Combinatorial biosynthesis for new drug discovery. Curr Opin Microbiol, 1998, 1 : 319-329
Ishizuka H, Horinouchi S, Kieser H M, Hopwood D A and Beppu T. A putative two-component regulatory system involved in secondary metabolism in Streptomyces spp. J Bacteriol, 1992, 174:7585-7594
Jack R, Bierbaum G, Heidrich C and Sahl H-G. The genetics of lantibiotic biosyuthesis. Bioessays,1995, 17:793-802
Jacob F and Monad J. Genetic regulatory mechanism in the synthesis of proteins. J Mol Biol, 1961, 3: 318-356
Jacobsen J R, Hutchinson C R, Cane D E and Khosla C. Precursor-directed biosynthesis of erythromycin analogs by an engineered polyketide synthase. Science, 1997, 277:367-369
Janssen G R, Ward J M and Bibb M J. Unusual transcriptional and translational features of the aminoglycoside phosphotransferase gene(aph) from Streptomyces fradiae. Genes Dev, 1989, 3: 415-429
Janssen G R and Bibb M J. Derivatives of pUC18 that have BglⅡ sites flanking a modified multiple cloning site and that retain the ability to identify recombinant clones by visual screening of Escherichia coli colonies. Gene, 1993, 124:133-134
Jaurin B and Cohen S N. Streptomyces lividans RNA polymerase recognizes and uses Escherichia coli transcription signals. Gene, 1984, 28:83-91
Kao C M, McPherson M, McDaniel R N, Fu H, Cane D E and Khosla C. Gain of function mutagenesis of the erythromycin polyketide synthase 2, Engineered biosynthesis of an eight-membered ring tetraketide lactone. J Am Chem Soc, 1997, 119:11339-11340
Katz E, Thompson C J and Hopwood D A. Cloning and expression of the tyrosinase gene from Streptomyces antibioticus in Streptomyces lividans 66. J Gen Microbiol, 1983, 129:2703-2714
Katz L and Donadio S. Polyketide synthesis: prospects for hybrid antibiotics. Annu Rev Microbiol, 1993, 47:875-912
Kelemen G H, Brown G L, Kormanec J, Potuckova L, Chater K F and Buttner M J. The positions of
the sigma factor genes, whig and sigF, in the hierarchy controlling the development of spore chains in the aerial hyphae of Streptomyces coelicolor A3(2). Mol Microbiol, 1996, 21:593-603
Kendall K J and Cohen S N. Complete nueleotide sequence of the Streptomyces lividans plasmid pIJ101 and correlation of the sequence with genetic properties.J Bacteriol, 1988, 170:4634-4651
Khosla C, McDaniel R, Ebort-Khosla S, Torres R, Sherman D H, Bibb M J and Hopwood D A. Genetic construction and functional analysis of hybrid polyketide synthases containing heterologous acyl carrier proteins. J Bacteriol, 1993, 175:2197-2204
Kieser H M, Henderson D J, Chen C W and Hopwood D A. A mutation of Streptomyces lividans which prevents intraplasmid recombination has no effect on chromosomal recombination. Mol Gen Genet, 1989, 220:60-64
Kieser H M, Kieser T and Hopwood D A. A combined genetic and physical map of the Streptomyces coelicolor A3(2) chromosome. J Bacteriol, 1992, 174:5496-5507
Kieser T, Hopwood D A, Wright H M and Thompson C J. pIJ101, a multi-copy broad host-range Streptomyces plasmid: functional anaysis and development of DNA cloning vectors. Mol Gen Genet, 1982, 185:223-238
Kieser T. Factors affecting the isolation of CCC DNA from Streptomyces lividans and Escherichia coli. Plasmid, 1984, 12:19-36
Kieser T and Hopwood D A. Genetic manipulation of Streptomyces: integrating vectors and gene replacement. Methods Enzymol, 1991, 204:430-458
Kirby P, and Hopwood D A. Genetic determination of methylenomycin synthesis by the SCP1 plasmid of Streptomyces coelicolor A3(2). J Gen Microbiol, 1977, 98:239-252
Konig A, Schwecke T, Molnar I, Bohm G A, Lowden P A, Staunton J and Leadlay P F. The pipecolate-incorporating enzyme for the biosynthesis of the immunosuppressant rapamycinnucleotide sequence analysis, disruption and heterologous expression of rapP from Streptomyces hygroscopicus. Eur J Biochem, 1997, 247:526-534
Kormanec J and Farkasovsky M. Differential expression of principal sigma factor homologues of Streptomyces aureofaciens correlates with the developmental stage. Nucleic Acids Res, 1993, 21: 3647-3652
Kuhstoss S and Rao R N. A thiostrepton-inducible expression vector for use in Streptomyces spp. Gene, 1991, 103:97-99
Kumar A and Patel S. Inhibition of T7 RNA polymerase: transcription initiation and transition from initiation to elongation are inhibited by T7 lysozyme via a ternary complex with RNA polymerase and promoter DNA. Biochemistry, 1997, 36:13954-13962
Kunkel B. Compartmentalized gene expression during sporulation in Bacillus subtilis. Trends Genet, 1991, 7:167-172
Lanz T, Tropf S, Marner F J, Schroder J and Schroder G. The role of cysteines in polyketide synthases. J Biol Chem, 1991, 266:9971-9976
Lau J, Fu H, Cane D E and Khosla C. Dissecting the role of acyltransferase domains of modular polyketide synthases in the choice and stereochemical fate of extender units. Biochemistry, 1999, 38:1643-1651
Leadlay P F, Staunton J, Aparicio J F, Bevitt D J, Caffrey P, Cortes J, Marsden A and Roberts GA. The erythromycin-producing polyketide synthase. Biochem Soc Trans, 1993, 21:218-222
Leskiw B K, Lawlor E J, Fernandez-Abalos J M and Chater K F. TTA codons in some genes prevent their expression in a class of developmental, ant:biotic-negative Streptomyces mntants. Proc Natl
Acad Sci USA,1991,88:2461-2465
Lilie H, Schwarz E and Rudolph R. Advances in refolding of proteins produced in E coli. Curr Opin Biotech, 1998, 9:497-501
Lin Y-S, Kieser H M, Hopwood D A and Chen C W. The chromosomal DNA of Streptomyces lividans 66 is linear. Mol Microbiol, 1993, 10:923-933
Lomovskaya N D, Mkrtumian N M, Gostimskaya N L and Danilenko V N. Characterisation of temperate actinophage φC31 isolated from Streptomyces coelicolor A3(2). J Virol, 1972, 9: 258- 262
Lowman H B and Bina M. Temperature-mediated regulation and downstream inducible selection for controlling gene expression from the bacteriophage lambda pL promoter. Gene,1990, 96:133-136
MacNeil D J, Gewain K M, Rnby C L, Dezeny G, Gibbons P H and MacNeil T. Analysis of Streptomyces avermitilis genes required for avermectin biosynthesis utilizing a novel integration vector. Gene, 1992, 111:61-68
MacNeil D J. Avermectins. Biotechnology, 1995, 28:421-442
Makrides S C. Strategies for achieving high-level expression of gene in Escherichia coli Microbiol Rev, 1996, 60:512-538
Malpartida F and Hopwood D A. Molecular cloning of the whole biosynthetic pathway of a Streptomyces antibiotic and its expression in a heterologous host. Nature, 1984, 309:462-464
Malpartida F, Niemi J, Navarrete R and Hopwood D A. Cloning and expression in a heterologous host of the complete set of genes for biosynthesis of the Streptomyces coelicolor antibiotic undecylprodigiosin. Gene, 1990, 93:91-99
Maplestone R A, Stone M J and Williams D H. The evolutionary role of secondary metabolites--a review. Gene, 1992, 115:151-157
Marahiel M A, Stachelhaus T and Mootz H D. Modular peptide synthetases involved in nonribosomal pepetide synthesis. Chemical Reviews, 1997, 97:2651-2674
Marcos A T, Gutierrez S, Diez, B Fernandez F J, Oguiza J A and Martin J F. Three genes hrdB, hrdD and hrdT of Streptomyces griseus IMRU 3570, encoding sigma factor-like proteins, are differentially expressed under specific nutritional conditions. Gene, 1995, 153:41-48
Marsden A F, Wilkinson B, Cortes J, Dunster N J, Staunton J and Leadlay P F. Engineering broader, specificity into an antibiotic-producing polyketide syntheses. Science, 1998, 279:199-202.
McAllister WT. Structure and function of the bacteriophage T7 RNA polymerase(or, the virtues of simplicity). Cell Mol Biol Res, 1993,39:385-391.
McClure W R. Mechanism and control of transcription initiation in procaryotes. Annu Rev Biochem, 1985, 54:171-204
McDaniel R, Ebert-Khosla S, Hopwood D A and Khosla C. Engineered biosynthesis of novel polyketides. Science, 1993, 262:1546-1550
McDaniel R, Kao C M, Hwang S J and Khosla C. Engineered intermodular and intramodular polyketide synthase fusions. Chem Biol, 1997,4:667-674
Membrillo-Hernandez J, Cook G M and Peele P K. Roles of RpoS(σ~s), IHF and ppGpp in the expression of the hmp gene encoding the flavohemoglobin(Hmp) of Escherichia coli K-12. Mol Gen Genet, 1997, 254:559-603
Moche M, Schneider G, Edwards P, Dehesh K and Lindqvist Y. Structure of the complex between the antibiotic cerulenin and its target, beta-ketoacyl-acyl carrier protein synthase. Biol Chem, 1999, 274:6031-6034
Moffatt B A and Studier F W. T7 lysozyme inhibits transcription by T7 RNA polymerase. Cell, 1987, 49:221-227
Mukamolova G V, Kaprelyants A S, Young D I, Young M and Keli D B. A Bacterial cytokine. Proc Natl Acad Sci USA,1998,95:8916-8921
Murrakami T, Holt T G and Thompson C J. Thiostrepton-induced gene expression in Streptomyces lividans, J Bacteriol, 1989, 171:1459-1466
Muth G, Nussbaumer B, Wohlleben W and Puhler A. A vector system with temperature-sensitive replication for gene disruption and mutational cloning in streptomycetes. Mol Gen Genet, 1989, 219:341-348
Muth G, Farr M, Hartmann V and Wohlleben W. Streptomyces ghanaensis plasmid pSG5: nucleotide sequence analysis of the self-transmissible minimal replicon and characterization of the replication mode. Plasmid, 1995, 33:113-26
Novogen. pET His-Tag~(TM) system protocols and application guide, 800-526-7319
Oh S-H and Chater K E Denaturation of circular or linear DNA facilitates targeted integrative transformation of Streptomyces coelicolor A3(2): possible relevance to other organisms. J Bacteriol, 1997, 179:122-127
O'Hagan D. The polyketide metabolites. Chichester: Ellis Horwood,1991
Oliynyk M, Brown M J, Cortes J, Staunton J and Leadlay P E A hybrid modular polyketide synthase obtained by domain swapping. Chem Biol, 1996, 3:833-839
Omura S and Tanaka H. Production, structure and antifungal activity ofpolyene macrolides. In Omura S ed., Macrolide antibiotics, chemistry, biology and practice. London: Academic Press, 1984: 351-404
Perez-Martin J and de Lorenzo V. Clues and consequences of DNA bending in transcription. Ann Rev Microbiol, 1997, 51:593-628
Peters N K, Frost J W and Long S R. A plant flavone, luteolin, induces expression of Rhizobium meliloti nodulation genes. Science, 1986, 233:977-980
Potuckova L, Kelemen G H, Findlay K C, Lonetto M A, Buttner M J and Kormanec J. A new RNA polymerase sigma factor, σ~F, is required for the late stages of morphological differentiation in Streptomyces spp. Mol Microbiol, 1995, 17:37-48
Rebollo A, Gil J A, Liras P, Asterias T A and Martin J F. Cloning and characterization of a phosphate- regulated promoter involved in phosphate control of eandicidin biosynthesis. Gene, 1989, 79: 47- 58
Reeves A R, Post D A and Vanden Boom T J. Physical-genetic map of the erythromycin-producing organism Saccharopolyspora erythraea. Microbiol, 1998, 144:2151-2159
Richardson M A, Kuhstoss S, Solenberg P, Schaus N A and Rao R N. A new shuttle cosmid vector, pKC505, for Streptomyces: its use in the cloning of three different spiramcin-resistance genes from a Streptomyces ambofaciens library. Gene, 1981, 61:231-241
Ross W, Gosink K K, Salomon J, Igarashi K, Zou C, lshihama A, Severinov K and Gourse R. A third recognition element in bacterial promoters: DNA binding by the alpha subunit of RNA polymerase. Science, 1993, 262:1407-1413
Rowe C J, Cortes J, Gaisser S, Staunton J and Leadlay P F. Construction of new vectors for high-level expression in actinomycetes. Gene, 1998, 216:215-223
Ruan X, Pereda A, Stassi D L, Zeidner D, Summers R G, Jackson M, Shivakumar A, Kakavas S, Stayer M J, Donadio S and Katz L. Acyltransferase domain substitutions in erythromycin
polyketide synthase yield novel erythromycin derivatives. J Bacteriol, 1997, 179:6416-6425
Sambrook J, Fritsch E F and Maniatis T. Molecular Cloning: a Laboratory Manual, 2nd ed. NY: Cold Spring Harbor, 1989
Sanger F, Coulson A R, Hong G F, Hill D F and Petersen G B. Nucleotide sequence of bacteriophage X DNA. J Mol Biol, 1982, 162:729-773
Schwecke T, Aparicio J F, Molnar I, Konig A, Khaw L E, Haydock S F, Oliynyk M, Caffrey P, Cortes J, Lester J B, Bohm G A, Staunton J and Leadlay P F. The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin. Proc Natl Acad Sci USA, 1995, 92:7839-7843
Servin-Gonzalez L, Jensen M R, White J and Bibb M. Transcriptional regulation of the four promoters of the agarase gene(dagA) of Streptomyces coelicolor A3(2). Microbiol, 1994, 140:2555-2565
Sherman D H, Kim E-S, Bibb M J and Hopwood D A. Functional replacement of genes for individual polyketide synthase components in Streptomyces coelicolor A3(2) by heterologous genes from a different polyketide pathway. J Bacteriol, 1992, 174:6184-6190
Shine J and Dalgarno L. The 3'-terminal sequence of E coli 16S ribosomal RNA: complementarity to nonsence triplets and ribosome binding sites. Proc Natl Acad Sci USA, 1974, 71:1342-1346
Smokvina T, Mazodier P, Boecard F, Thompson C J and Guerineau M. Construction of a series of pSAM2-based integrative vectors for use in aetinomycetes. Gene, 1990, 94:53-59
Sousa R, Chung Y J, Rose J P and Wang B. Crystal structure of bacteriophage T7 RNA polymerase at 3.3 A resolution. Nature, 1993, 364:593-599
Stephen D, Jones C and Schofield P J. A rapid method for isolating high quality plasmid DNA suitable for DNA sequencing. Nucleic Acid Research, 1990,18:7463-7464
Stock J B, Stock A M and Mottonen J M. Signal transduction in bacteria. Nature, 1990, 344:395-400
Strohl W R. Compilation and analysis of DNA sequences associated with apparent streptomycete promoters. Nucleic Acids Res , 1992, 20:961-974
Studier F W and Moffatt B A. Use of bacteriophage T7 RNA polymerase to direct selective high-level expression of cloned gene. J Mol Biol, 1986, 189:113
Studier F W, Rosenberg A H, Dunn J J and Dubendorff J W. Use of T7 RNA polymerase to direct expression of cloned genes. Methods Enzymol, 1990, 185:60-89
Tanaka K, Shiina T and Takahashi H. Nucleotide sequence of genes hrdA, hrdC and hrdD from Streptomyces coelicolor A3 (2)having similarity to rpoD genes. Mol Gen Genet, 1991, 229: 234- 240
Takano E, White J, Thompson C J and Bibb M J. Construction of thiostrepton-inducible, high-copy- number expression vectors for use in Streptomyces spp. Gene, 1995, 166:133-137
Tate W P and Mannering S A. Three, four or more: the translational stop signal at length. Mol Microbiol, 1996, 21:213-219
Thompson C J, Mowa N R, Tizard R, Crameri R, Davies J E, Lauwereys M and Botterman J. Characterization of the herbicide-resistance gene bar from Streptomyces hygroscopicus. EMBO J, 1987, 6:2519-2523
Travers A and Muskhelishvili G. DNA microloops and mierodomains: a general mechanism for transcription activation by torsional transmission. J Mol Biol, 1998, 279:1027-1043
Tsai J F-Y and Chen C W. Isolation and characterization of Streptomyces lividans mutants deficient in intraplasmid recombinatioin. Mol Gen Genet, 1987, 208:211-218
Ueda K, Kim K M, Beppu T and Horinouchi S. Overexpression of a gene cluster encoding a ehalcone synthase-like proteih confers redbrown pigment production in Streptomyces griseus. J
Antibiot(Tokyo), 1995, 48:638-646
Volff J N and Altenbuchner J. Genetic instability of the Streptomyces chromosome. Mol Microbiol, 1998, 27:239-246
Westpheling J, Ranes M and Losick R. RNA polymerase heterogeneity in Streptomyces coelicolor. Nature, 1985, 313:22-27
Williams R M and Rimsky S. Molecular aspects of the E coli nucleoid protein, H-NS: a central controller of gene regulatory networks. FEMS Microbiol Lett, 1997, 156:175-185
Wilm M, Shevchenko A, Houthaeve T, Breit S, Schweigerer L, Fotsis T and Mann M. Femtomole sequencing of proteins from polyaerylamide gels by nano-electrospray mass spectrometry. Nature, 1996,379:466-469
Woodcock D M, Crowther P J, Doherty J, Jefferson S, DeCruz E, Noyer-Weidner M, Smith S S, Michael M Z and Graham M W. Quantitative evaluation of Escherichia coli host strains for tolerance to cytosine methylation in plasmid and phage recombinants. Nucleic Acids Res, 1989, 17:3469-3478
Wosten M M. Eubacterial sigma-factors. FEMS Microbiol Rev, 1998, 22:127-150
Yanofsky C and Crawford I P. The tryptophan operon. In Neidhardt F C ed, Escherichia coli and Salmonella typhimurium. Washington DC: American Society for Microbiology, 1987, 1453-1472
Yu T-W and Hopwood D A. Ectopic expression of the Streptomyces coelicolor whiE genes for polyketide spore pigment synthesis and their interaction with the act genes for actinorhodin biosynthesis. Microbiol, 1995, 141: 2779-2791
Zhou X, Deng Z, Firmin J L, Hopwood D A and Kieser T. Site-specific degradation of Streptomyces lividans DNA during electrophoresis in buffers contaminated with ferrous iron. Nucleic Acids Res, 1988, 16:4341-4352
Zhou X, Deng Z, Hopwood D A and Kieser T. Streptomyces lividans 66 contains a gene for phage resistance which is similar to the phage lambda ea59 endonuclease gene. Mol Microbiol, 1994, 12: 789-797
Ziermann R and Betlach M C. Recombinant polyketide synthesis in Streptomyces: engineering of improved host strains. Biotechniques, 1999, 26:106-110
中科院微生物研究所菌种保藏管理委员会。菌种目录。科学出版社，1982
邓子新，周秀芬。一个链霉菌的质粒pHZ65及其载体的发展。见：中国的遗传学研究。北京：中国科技出版社，1991，318-319
邓子新，用秀芬，Kieser T，Hopwood D A．与多烯抗生素FR-008生物学合成有关的抗生素生物合成基因簇的克隆和鉴定。中国博士后首届学术大会文集。国防工业出版社，1993，1757-1762
孙乃恩，孙东旭，朱德煦。分子遗传学。南京：南京大学出版社，1990
张智清，姚立红，侯云德。含P_RP_L启动子的原核高效表达载体的组建及其应用。病毒学报，1990，6：111-115
杨闰英，胡志浩，邓子新，李季伦。大肠杆菌—链霉菌穿梭表达载体的构建及应用。生物工程学报，1998，14：7-13
陈葆堂。水稻原生质体培养、转基因及相关技术研究。[博士学位论文]。武汉，华中农业大学图书馆，1996
欧阳谅，涂国全，高勇生。南昌链霉菌新种及其产生的两种杀虫抗生素。江西农业大学学报，《杀虫抗生素研究》专辑，1993，15：148-153
胡志浩。多烯抗生索FR-008生物合成的分子生物学。[博士学位论文]武汉，华中农业大学图书馆，1995
袁丽蓉。麦迪霉素产生菌—生米卡链霉菌原生质体融合的研究。抗生素，1983，8：380-387
袁德军，周启。吸水链霉菌应城变种种内融合子FR-008产生新抗生素的杀虫活性。华中农业大学学报，1990，9：209
袁德军，周启。农抗5102产生菌原生质体融合育种的研究Ⅳ，融合子FR-008的验证及其产生新活性物质的分离和鉴定。生物工程学报，1991，7：142-147
梁蓉芳，周启。农抗5102产生菌株原生质体融合育种的研究。生物工程学报，1987，3：130-136
黄曦。链霉菌FR-008与灰色链霉菌IMRU3570及其代谢产物的比较研究。[博士学位论文]武汉，华中农业大学图书馆，1997
鲍锴，胡志浩，周秀芬，周启，邓子新。一个可在大肠杆菌和链霉菌之间进行间接合转移的柯斯质粒。科学通报，1995，40：1440。
鲍锴。链霉菌新载体系统的发展及其在抗生素生物合成和调节基因的克隆和分析中的应用。[博士学位论文]。武汉，华中农业大学图书馆，1997
Barz W, Bless W, Borger-Papendorf G, Gunia W, Mackenbrock U, Meier D, Otto C and Super E. Phytoalexins as part of induced defence reactions in plants: their elicitation, function and metabolism. Ci ba Found Symp, 1990,154:140-153
Bedford D, Jacobsen J R, Luo G, Cane D E and Khosla C. A functional chimeric modular polyketide synthase generated via domain replacement. Chem Biol, 1996, 3:827-831
Bevitt D J, Cortes J, Haydock S F and Leadley P E 6-deoxyerythronolide-B synthase 2 from Saccharopolyspora erythraea. Cloning of the structural gene, sequence analysis and inferred domain structure of the multifunctional enzyme. Eur J Biochem, 1992, 204:39-49
Bibb M J, Freeman R F and Hopwood D A. Physical and genetical eharacterisation of a second sex
factor, SCP2, for Streptomyces coelicolor A3(2). Mol Gen Genet, 1977, 154:155-166
Bibb M J, Findlay P R and Johnson M W. The relationship between base composition and eodon usage in bacterial genes and its use for the simple and reliable identification of protein-coding sequences. Gene, 1984, 30:157-166
Bibb M J, Janssen G R and Ward J M. Cloning and analysis of the promoter region of the erythromyein resistance gene ermE of Streptomyces erythraeus. Gene, 1985, 38:215-226
Bibb M J, White J, Ward J M and Janssen G R. The mRNA for the 23S rRNA methylase encoded by the ermE gene of Saccharopolyspora erythraea is translated in the absence of a conventional ribosome-binding site. MolMicrobiol, 1994, 14:533-545
Bio-Rad a. Mini trans-blot electrophoretic transfer cell instruction manual
Bio-Rad b. Mini-prortean Ⅱ electrophoresis cell instruction manual
Blattner F R, Pluktt I G, Bloch C A, Perna N T, Burland V, Riley M, Collado-Vides J, Glasner J D, Rode C K, Mayhew G F, Gregor J, Davis N W, Kirkpatrick H A, Goeden M A, Rose D J, Mau B and Shau Y. The complete genome sequence of Escherichia coli K12. Science, 1997, 277: 1453- 1462
Bohm I, Holzbaur I, Hanefeld U, Cortes J, Staunton J and Leadlay P. Engineering of a minimal modular polyketide synthase and targeted alteration of the stereospecificity of polyketide chain extension. Chem Biol, 1998, 5:407-412
Busby S and Ebright R H. Promoter structure, promoter recognition and transcription activation in prokaryotes. Cell, 1994, 79:743-746
Buttner M J. RNA polymerase heterogeneity in Streptomyces coelicolor A3(2). MolMicrobiol, 1989, 3: 1653-1659
Cases I and De Lorenzo V. Expression systems and physiological control of promoter activity in bacteria. Curr Opin Microbiol, 1998, 1:303-310
Chang H, Chen M, Shieh Y, Bibb M and Chen C. The cutRS signal transduction system of Streptomycer lividans represses the biosynthesis of the polykefide antibiotic actinorhodin. Mol Microbiol, 1996, 21:1075-1085
Chen C W, Yu T-W, Lin Y-S, Kieser H M and Hopwood D A. The conjugative plasmid SLP2 of Stretpomyces lividans is a 50 kb linear molecule. MolMicrobiol, 1993, 7:925-932
Christou P, Macabe D E, Swan W F and Russell D R. Legume transformation. In Verma DPS ed, Control of plant gene expression. BocoRaton: CRC Press, 1993, 547-561
Cortes J, Haydock S F, Roberts G A, Bevitt D J and Leadlay P F. An unusually large multifunctional polypeptide in the erythromycin-producing polyketide synthase of Saccharopolyspora erythraea. Nature, 1990, 348:176-178
Cortes J, Wiesmann K E H, Roberts G A, Brown M J B, Staunton J and Leadlay P F. Repositioning of a domain in a modular polyketide synthase to promote specific chain cleavage. Science, 1995, 268:1487-1489
Crowl R, Seamans C, Lomedico P and McAndrew S. Versatile expression vectors for high-level synthesis of cloned gene products in Escherichia coli. Gene, 1985, 38:31-38
Dary A, Kaiser P, Bourget N, Thompson C J, Simonet J-M and Deearis B. Large genomic rearrangements of the unstable region in Streptomyces ambofaciens are associated with major changes in global gene expression. Mol Microbiol, 1993, 10:759-769
De Block M, Botterman J, Wandewiele M, Dock X J, Thoen C, Gossele V, Mowa N, Thompson C, Van Montage M and Leemans J. Engineering herbicide resistance in plant by expression of a
detoxifying enzyme. EMBOJ, 1987, 6:2513
De Boer H A, Comstock L J and Vasser M. The tac promoter: a functional hybrid derived from the trp and lac promoters. Proc Natl Acad Sci USA, 1983, 80:21-25
Decker H and Haag S. Cloning and characterization of a polyketide synthase gene from Streptomyces fradiae Tu2717, which carries the genes for biosynthesis of the angucycline antibiotic urdamycin A and a gene probably involved in its oxygenation. J Bacteriol, 1995, 177:6126-6136
Deng Z, Kieser T and Hopwood D A. "Strong incompatability" between derivatives of the Streptomyces multi-copy plasmid pIJ101, Mol Gen Genet, 1988, 214:286-294
Dohren H, Keller U, vatre J and Zocher R. Multifunctional peptide synthetases. Chemical Reviews, 1997, 97:2675
Dombraski A J, Walter W A, Recod M T, Siegele D A and Gross C A. Polypeptides containing highly conserved regions of binding to promoter DNA. Cell, 1992, 70:501-512
Donadio S, Stayer M J, McAlpine J B, Swanson S J and Katz L. Modular organization of genes required for complex polyketide biosynthesis. Science, 1991,252:675-679
Donadio S and Katz L. Organization of the enzymatic domains in the multifunctional polyketide synthase involved in erythromycin formation in Saccharopolyspora erythraea. Gene, 1992, 111: 51-60
Dubendoff J W and Studier W E Controlling basal expression in an inducible T7 expression system by blocking the target T7 promoter with lac represser. J Mol Biol, 1987,219:45-59
Dutton C J, Gibson S P, Goudie A C, Holdom K S, Pacey M S, Ruddock J C, Bu'Lock J D and Richards M K. Novel avermectins produced by mutational biosynthesis. J Antibiot, 1991, 44: 357-365
Estrem S T, Gaal T, Ross W and Gourse R L. Identification of an UP element consensus sequence for bacterial promoters. Proc Natl Acad Sci USA, 1998, 95:9761-9766
Farewell A. Negative regulation by RpoS: a case of sigma factor competition. Mol Microbiol, 1998, 29: 1039-1051
Fliegmann J, Schroder G, Schanz S, Britsch L and Schroder J. Molecular analysis of chalcone and dihydropinosylvin synthase from Scots pine(Pinus sylvestris) and differential regulation of these and related enzyme activities in stressed plants. Plant Mol Biol, 1992, 18:489-503
Gil J A and Hopwood D A. Cloning and expression of a p-aminobenzoic acid synthetase gene of the candicidin-producing Streptomyces griseus. Gene , 1983, 25:119-132
Giordano T J, Deuschle U, Bujard H and MeAlister W T. Regulation of coliphage T3 and T7 RNA polymerase by the lac represser-operator system. Gene, 1989, 84:209-219
Gottesman S. Minimizing proteolysis in Escherichia coli: genetic solutions. Methods Enzymol, 1990, 185:119-129
Gramajo H C, White J, Hutchinson C R and Bibb M J. Overproduction and localization of components of the polyketide synthase of Streptomyces glaucescens involved in the production of the antibiotic tetracenomycin C. J Bacteriol, 1991, 173:6475-6483
Grossman A D, Erickson J W and Gross C A. The htpR gene product is a sigma factor for heat-shock promoters. Cell, 1984, 38:383-390
Gumpert J and Hoischen C. Use of cell wall-less bacteria(L-forms) for efficient expression and secretion of heterologous gene products. Curr Opin Biotechnol. 1998, 9:506-509
Harborne J B. Role of secondary metabolites in chemical defense mechanisms in plants. Ciba Found Symp, 1990, 154:126-134
Hopwood D A, Bibb M J, Crater K F, Kieser T, Bruton C J, Kieser H M, Lydiate D J, Smith C P, Ward J M and Schrempf H. Genetic Manipulation of Streptomyces A laboratory manual. Norwich: John Innes Foundation, 1985a
Hopwood D A, Malpartida F, Kieser H M, Ikeda H, Duncan J, Fujii I, Rudd B A M, Floss H G and Omura S. Production of'hybrid' antibiotics by genetic engineering. Nature, 1985b, 314:642-644
Hopwood D A. The Leeuwenhoek Lecture, 1987. Towards an understanding of gene switching in Streptomyces, the basis of sporulation and antibiotic production. Proc R Soc Lond B Biol Sci ,1988, 235:121-138
Hopwood D A and Sherman D H. Molecular genetics of polyketides and its comparison to fatty acid biosynthesis. Annu Rev Genet, 1990, 24:37-66
Hopwood D A. Genetic contributions to understanding polyketide synthases. Chemical Reviews, 1997, 97:2465-2497
Hu Z, Bao K, Zhou X, Zhou Q, Hopwood D A, Kieser T and Deng Z. Repeated polyketide synthase modules involved in the biosynthesis of a heptaene macrolide by Streptomyces sp. FR-008. Mol Microbiol, 1994, 14:163-172
Hutchinson C R. Biosynthetic studies of daunorubicin and tetracenomycin C. Chemical Reviews, 1997, 97:2525-2536
Hutchinson C R. Combinatorial biosynthesis for new drug discovery. Curr Opin Microbiol, 1998, 1 : 319-329
Ishizuka H, Horinouchi S, Kieser H M, Hopwood D A and Beppu T. A putative two-component regulatory system involved in secondary metabolism in Streptomyces spp. J Bacteriol, 1992, 174:7585-7594
Jack R, Bierbaum G, Heidrich C and Sahl H-G. The genetics of lantibiotic biosyuthesis. Bioessays,1995, 17:793-802
Jacob F and Monad J. Genetic regulatory mechanism in the synthesis of proteins. J Mol Biol, 1961, 3: 318-356
Jacobsen J R, Hutchinson C R, Cane D E and Khosla C. Precursor-directed biosynthesis of erythromycin analogs by an engineered polyketide synthase. Science, 1997, 277:367-369
Janssen G R, Ward J M and Bibb M J. Unusual transcriptional and translational features of the aminoglycoside phosphotransferase gene(aph) from Streptomyces fradiae. Genes Dev, 1989, 3: 415-429
Janssen G R and Bibb M J. Derivatives of pUC18 that have BglⅡ sites flanking a modified multiple cloning site and that retain the ability to identify recombinant clones by visual screening of Escherichia coli colonies. Gene, 1993, 124:133-134
Jaurin B and Cohen S N. Streptomyces lividans RNA polymerase recognizes and uses Escherichia coli transcription signals. Gene, 1984, 28:83-91
Kao C M, McPherson M, McDaniel R N, Fu H, Cane D E and Khosla C. Gain of function mutagenesis of the erythromycin polyketide synthase 2, Engineered biosynthesis of an eight-membered ring tetraketide lactone. J Am Chem Soc, 1997, 119:11339-11340
Katz E, Thompson C J and Hopwood D A. Cloning and expression of the tyrosinase gene from Streptomyces antibioticus in Streptomyces lividans 66. J Gen Microbiol, 1983, 129:2703-2714
Katz L and Donadio S. Polyketide synthesis: prospects for hybrid antibiotics. Annu Rev Microbiol, 1993, 47:875-912
Kelemen G H, Brown G L, Kormanec J, Potuckova L, Chater K F and Buttner M J. The positions of
the sigma factor genes, whig and sigF, in the hierarchy controlling the development of spore chains in the aerial hyphae of Streptomyces coelicolor A3(2). Mol Microbiol, 1996, 21:593-603
Kendall K J and Cohen S N. Complete nueleotide sequence of the Streptomyces lividans plasmid pIJ101 and correlation of the sequence with genetic properties.J Bacteriol, 1988, 170:4634-4651
Khosla C, McDaniel R, Ebort-Khosla S, Torres R, Sherman D H, Bibb M J and Hopwood D A. Genetic construction and functional analysis of hybrid polyketide synthases containing heterologous acyl carrier proteins. J Bacteriol, 1993, 175:2197-2204
Kieser H M, Henderson D J, Chen C W and Hopwood D A. A mutation of Streptomyces lividans which prevents intraplasmid recombination has no effect on chromosomal recombination. Mol Gen Genet, 1989, 220:60-64
Kieser H M, Kieser T and Hopwood D A. A combined genetic and physical map of the Streptomyces coelicolor A3(2) chromosome. J Bacteriol, 1992, 174:5496-5507
Kieser T, Hopwood D A, Wright H M and Thompson C J. pIJ101, a multi-copy broad host-range Streptomyces plasmid: functional anaysis and development of DNA cloning vectors. Mol Gen Genet, 1982, 185:223-238
Kieser T. Factors affecting the isolation of CCC DNA from Streptomyces lividans and Escherichia coli. Plasmid, 1984, 12:19-36
Kieser T and Hopwood D A. Genetic manipulation of Streptomyces: integrating vectors and gene replacement. Methods Enzymol, 1991, 204:430-458
Kirby P, and Hopwood D A. Genetic determination of methylenomycin synthesis by the SCP1 plasmid of Streptomyces coelicolor A3(2). J Gen Microbiol, 1977, 98:239-252
Konig A, Schwecke T, Molnar I, Bohm G A, Lowden P A, Staunton J and Leadlay P F. The pipecolate-incorporating enzyme for the biosynthesis of the immunosuppressant rapamycinnucleotide sequence analysis, disruption and heterologous expression of rapP from Streptomyces hygroscopicus. Eur J Biochem, 1997, 247:526-534
Kormanec J and Farkasovsky M. Differential expression of principal sigma factor homologues of Streptomyces aureofaciens correlates with the developmental stage. Nucleic Acids Res, 1993, 21: 3647-3652
Kuhstoss S and Rao R N. A thiostrepton-inducible expression vector for use in Streptomyces spp. Gene, 1991, 103:97-99
Kumar A and Patel S. Inhibition of T7 RNA polymerase: transcription initiation and transition from initiation to elongation are inhibited by T7 lysozyme via a ternary complex with RNA polymerase and promoter DNA. Biochemistry, 1997, 36:13954-13962
Kunkel B. Compartmentalized gene expression during sporulation in Bacillus subtilis. Trends Genet, 1991, 7:167-172
Lanz T, Tropf S, Marner F J, Schroder J and Schroder G. The role of cysteines in polyketide synthases. J Biol Chem, 1991, 266:9971-9976
Lau J, Fu H, Cane D E and Khosla C. Dissecting the role of acyltransferase domains of modular polyketide synthases in the choice and stereochemical fate of extender units. Biochemistry, 1999, 38:1643-1651
Leadlay P F, Staunton J, Aparicio J F, Bevitt D J, Caffrey P, Cortes J, Marsden A and Roberts GA. The erythromycin-producing polyketide synthase. Biochem Soc Trans, 1993, 21:218-222
Leskiw B K, Lawlor E J, Fernandez-Abalos J M and Chater K F. TTA codons in some genes prevent their expression in a class of developmental, ant:biotic-negative Streptomyces mntants. Proc Natl
Acad Sci USA,1991,88:2461-2465
Lilie H, Schwarz E and Rudolph R. Advances in refolding of proteins produced in E coli. Curr Opin Biotech, 1998, 9:497-501
Lin Y-S, Kieser H M, Hopwood D A and Chen C W. The chromosomal DNA of Streptomyces lividans 66 is linear. Mol Microbiol, 1993, 10:923-933
Lomovskaya N D, Mkrtumian N M, Gostimskaya N L and Danilenko V N. Characterisation of temperate actinophage φC31 isolated from Streptomyces coelicolor A3(2). J Virol, 1972, 9: 258- 262
Lowman H B and Bina M. Temperature-mediated regulation and downstream inducible selection for controlling gene expression from the bacteriophage lambda pL promoter. Gene,1990, 96:133-136
MacNeil D J, Gewain K M, Rnby C L, Dezeny G, Gibbons P H and MacNeil T. Analysis of Streptomyces avermitilis genes required for avermectin biosynthesis utilizing a novel integration vector. Gene, 1992, 111:61-68
MacNeil D J. Avermectins. Biotechnology, 1995, 28:421-442
Makrides S C. Strategies for achieving high-level expression of gene in Escherichia coli Microbiol Rev, 1996, 60:512-538
Malpartida F and Hopwood D A. Molecular cloning of the whole biosynthetic pathway of a Streptomyces antibiotic and its expression in a heterologous host. Nature, 1984, 309:462-464
Malpartida F, Niemi J, Navarrete R and Hopwood D A. Cloning and expression in a heterologous host of the complete set of genes for biosynthesis of the Streptomyces coelicolor antibiotic undecylprodigiosin. Gene, 1990, 93:91-99
Maplestone R A, Stone M J and Williams D H. The evolutionary role of secondary metabolites--a review. Gene, 1992, 115:151-157
Marahiel M A, Stachelhaus T and Mootz H D. Modular peptide synthetases involved in nonribosomal pepetide synthesis. Chemical Reviews, 1997, 97:2651-2674
Marcos A T, Gutierrez S, Diez, B Fernandez F J, Oguiza J A and Martin J F. Three genes hrdB, hrdD and hrdT of Streptomyces griseus IMRU 3570, encoding sigma factor-like proteins, are differentially expressed under specific nutritional conditions. Gene, 1995, 153:41-48
Marsden A F, Wilkinson B, Cortes J, Dunster N J, Staunton J and Leadlay P F. Engineering broader, specificity into an antibiotic-producing polyketide syntheses. Science, 1998, 279:199-202.
McAllister WT. Structure and function of the bacteriophage T7 RNA polymerase(or, the virtues of simplicity). Cell Mol Biol Res, 1993,39:385-391.
McClure W R. Mechanism and control of transcription initiation in procaryotes. Annu Rev Biochem, 1985, 54:171-204
McDaniel R, Ebert-Khosla S, Hopwood D A and Khosla C. Engineered biosynthesis of novel polyketides. Science, 1993, 262:1546-1550
McDaniel R, Kao C M, Hwang S J and Khosla C. Engineered intermodular and intramodular polyketide synthase fusions. Chem Biol, 1997,4:667-674
Membrillo-Hernandez J, Cook G M and Peele P K. Roles of RpoS(σ~s), IHF and ppGpp in the expression of the hmp gene encoding the flavohemoglobin(Hmp) of Escherichia coli K-12. Mol Gen Genet, 1997, 254:559-603
Moche M, Schneider G, Edwards P, Dehesh K and Lindqvist Y. Structure of the complex between the antibiotic cerulenin and its target, beta-ketoacyl-acyl carrier protein synthase. Biol Chem, 1999, 274:6031-6034
Moffatt B A and Studier F W. T7 lysozyme inhibits transcription by T7 RNA polymerase. Cell, 1987, 49:221-227
Mukamolova G V, Kaprelyants A S, Young D I, Young M and Keli D B. A Bacterial cytokine. Proc Natl Acad Sci USA,1998,95:8916-8921
Murrakami T, Holt T G and Thompson C J. Thiostrepton-induced gene expression in Streptomyces lividans, J Bacteriol, 1989, 171:1459-1466
Muth G, Nussbaumer B, Wohlleben W and Puhler A. A vector system with temperature-sensitive replication for gene disruption and mutational cloning in streptomycetes. Mol Gen Genet, 1989, 219:341-348
Muth G, Farr M, Hartmann V and Wohlleben W. Streptomyces ghanaensis plasmid pSG5: nucleotide sequence analysis of the self-transmissible minimal replicon and characterization of the replication mode. Plasmid, 1995, 33:113-26
Novogen. pET His-Tag~(TM) system protocols and application guide, 800-526-7319
Oh S-H and Chater K E Denaturation of circular or linear DNA facilitates targeted integrative transformation of Streptomyces coelicolor A3(2): possible relevance to other organisms. J Bacteriol, 1997, 179:122-127
O'Hagan D. The polyketide metabolites. Chichester: Ellis Horwood,1991
Oliynyk M, Brown M J, Cortes J, Staunton J and Leadlay P E A hybrid modular polyketide synthase obtained by domain swapping. Chem Biol, 1996, 3:833-839
Omura S and Tanaka H. Production, structure and antifungal activity ofpolyene macrolides. In Omura S ed., Macrolide antibiotics, chemistry, biology and practice. London: Academic Press, 1984: 351-404
Perez-Martin J and de Lorenzo V. Clues and consequences of DNA bending in transcription. Ann Rev Microbiol, 1997, 51:593-628
Peters N K, Frost J W and Long S R. A plant flavone, luteolin, induces expression of Rhizobium meliloti nodulation genes. Science, 1986, 233:977-980
Potuckova L, Kelemen G H, Findlay K C, Lonetto M A, Buttner M J and Kormanec J. A new RNA polymerase sigma factor, σ~F, is required for the late stages of morphological differentiation in Streptomyces spp. Mol Microbiol, 1995, 17:37-48
Rebollo A, Gil J A, Liras P, Asterias T A and Martin J F. Cloning and characterization of a phosphate- regulated promoter involved in phosphate control of eandicidin biosynthesis. Gene, 1989, 79: 47- 58
Reeves A R, Post D A and Vanden Boom T J. Physical-genetic map of the erythromycin-producing organism Saccharopolyspora erythraea. Microbiol, 1998, 144:2151-2159
Richardson M A, Kuhstoss S, Solenberg P, Schaus N A and Rao R N. A new shuttle cosmid vector, pKC505, for Streptomyces: its use in the cloning of three different spiramcin-resistance genes from a Streptomyces ambofaciens library. Gene, 1981, 61:231-241
Ross W, Gosink K K, Salomon J, Igarashi K, Zou C, lshihama A, Severinov K and Gourse R. A third recognition element in bacterial promoters: DNA binding by the alpha subunit of RNA polymerase. Science, 1993, 262:1407-1413
Rowe C J, Cortes J, Gaisser S, Staunton J and Leadlay P F. Construction of new vectors for high-level expression in actinomycetes. Gene, 1998, 216:215-223
Ruan X, Pereda A, Stassi D L, Zeidner D, Summers R G, Jackson M, Shivakumar A, Kakavas S, Stayer M J, Donadio S and Katz L. Acyltransferase domain substitutions in erythromycin
polyketide synthase yield novel erythromycin derivatives. J Bacteriol, 1997, 179:6416-6425
Sambrook J, Fritsch E F and Maniatis T. Molecular Cloning: a Laboratory Manual, 2nd ed. NY: Cold Spring Harbor, 1989
Sanger F, Coulson A R, Hong G F, Hill D F and Petersen G B. Nucleotide sequence of bacteriophage X DNA. J Mol Biol, 1982, 162:729-773
Schwecke T, Aparicio J F, Molnar I, Konig A, Khaw L E, Haydock S F, Oliynyk M, Caffrey P, Cortes J, Lester J B, Bohm G A, Staunton J and Leadlay P F. The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin. Proc Natl Acad Sci USA, 1995, 92:7839-7843
Servin-Gonzalez L, Jensen M R, White J and Bibb M. Transcriptional regulation of the four promoters of the agarase gene(dagA) of Streptomyces coelicolor A3(2). Microbiol, 1994, 140:2555-2565
Sherman D H, Kim E-S, Bibb M J and Hopwood D A. Functional replacement of genes for individual polyketide synthase components in Streptomyces coelicolor A3(2) by heterologous genes from a different polyketide pathway. J Bacteriol, 1992, 174:6184-6190
Shine J and Dalgarno L. The 3'-terminal sequence of E coli 16S ribosomal RNA: complementarity to nonsence triplets and ribosome binding sites. Proc Natl Acad Sci USA, 1974, 71:1342-1346
Smokvina T, Mazodier P, Boecard F, Thompson C J and Guerineau M. Construction of a series of pSAM2-based integrative vectors for use in aetinomycetes. Gene, 1990, 94:53-59
Sousa R, Chung Y J, Rose J P and Wang B. Crystal structure of bacteriophage T7 RNA polymerase at 3.3 A resolution. Nature, 1993, 364:593-599
Stephen D, Jones C and Schofield P J. A rapid method for isolating high quality plasmid DNA suitable for DNA sequencing. Nucleic Acid Research, 1990,18:7463-7464
Stock J B, Stock A M and Mottonen J M. Signal transduction in bacteria. Nature, 1990, 344:395-400
Strohl W R. Compilation and analysis of DNA sequences associated with apparent streptomycete promoters. Nucleic Acids Res , 1992, 20:961-974
Studier F W and Moffatt B A. Use of bacteriophage T7 RNA polymerase to direct selective high-level expression of cloned gene. J Mol Biol, 1986, 189:113
Studier F W, Rosenberg A H, Dunn J J and Dubendorff J W. Use of T7 RNA polymerase to direct expression of cloned genes. Methods Enzymol, 1990, 185:60-89
Tanaka K, Shiina T and Takahashi H. Nucleotide sequence of genes hrdA, hrdC and hrdD from Streptomyces coelicolor A3 (2)having similarity to rpoD genes. Mol Gen Genet, 1991, 229: 234- 240
Takano E, White J, Thompson C J and Bibb M J. Construction of thiostrepton-inducible, high-copy- number expression vectors for use in Streptomyces spp. Gene, 1995, 166:133-137
Tate W P and Mannering S A. Three, four or more: the translational stop signal at length. Mol Microbiol, 1996, 21:213-219
Thompson C J, Mowa N R, Tizard R, Crameri R, Davies J E, Lauwereys M and Botterman J. Characterization of the herbicide-resistance gene bar from Streptomyces hygroscopicus. EMBO J, 1987, 6:2519-2523
Travers A and Muskhelishvili G. DNA microloops and mierodomains: a general mechanism for transcription activation by torsional transmission. J Mol Biol, 1998, 279:1027-1043
Tsai J F-Y and Chen C W. Isolation and characterization of Streptomyces lividans mutants deficient in intraplasmid recombinatioin. Mol Gen Genet, 1987, 208:211-218
Ueda K, Kim K M, Beppu T and Horinouchi S. Overexpression of a gene cluster encoding a ehalcone synthase-like proteih confers redbrown pigment production in Streptomyces griseus. J
Antibiot(Tokyo), 1995, 48:638-646
Volff J N and Altenbuchner J. Genetic instability of the Streptomyces chromosome. Mol Microbiol, 1998, 27:239-246
Westpheling J, Ranes M and Losick R. RNA polymerase heterogeneity in Streptomyces coelicolor. Nature, 1985, 313:22-27
Williams R M and Rimsky S. Molecular aspects of the E coli nucleoid protein, H-NS: a central controller of gene regulatory networks. FEMS Microbiol Lett, 1997, 156:175-185
Wilm M, Shevchenko A, Houthaeve T, Breit S, Schweigerer L, Fotsis T and Mann M. Femtomole sequencing of proteins from polyaerylamide gels by nano-electrospray mass spectrometry. Nature, 1996,379:466-469
Woodcock D M, Crowther P J, Doherty J, Jefferson S, DeCruz E, Noyer-Weidner M, Smith S S, Michael M Z and Graham M W. Quantitative evaluation of Escherichia coli host strains for tolerance to cytosine methylation in plasmid and phage recombinants. Nucleic Acids Res, 1989, 17:3469-3478
Wosten M M. Eubacterial sigma-factors. FEMS Microbiol Rev, 1998, 22:127-150
Yanofsky C and Crawford I P. The tryptophan operon. In Neidhardt F C ed, Escherichia coli and Salmonella typhimurium. Washington DC: American Society for Microbiology, 1987, 1453-1472
Yu T-W and Hopwood D A. Ectopic expression of the Streptomyces coelicolor whiE genes for polyketide spore pigment synthesis and their interaction with the act genes for actinorhodin biosynthesis. Microbiol, 1995, 141: 2779-2791
Zhou X, Deng Z, Firmin J L, Hopwood D A and Kieser T. Site-specific degradation of Streptomyces lividans DNA during electrophoresis in buffers contaminated with ferrous iron. Nucleic Acids Res, 1988, 16:4341-4352
Zhou X, Deng Z, Hopwood D A and Kieser T. Streptomyces lividans 66 contains a gene for phage resistance which is similar to the phage lambda ea59 endonuclease gene. Mol Microbiol, 1994, 12: 789-797
Ziermann R and Betlach M C. Recombinant polyketide synthesis in Streptomyces: engineering of improved host strains. Biotechniques, 1999, 26:106-110