力达霉素生物合成调控基因sgcR3功能研究及其与sgcR1和sgcR2调控关系的研究
摘要
力达霉素(lidamycin)是一种新型的烯二炔类抗肿瘤抗生素,又名C-1027,由球孢链霉菌C-1027(S.globisporus C-1027)产生。经过十余年的新药研究和开发,目前力达霉素已经进入临床Ⅱ期研究。力达霉素生物合成基因簇已被克隆和测序,其基因簇中一些生物合成酶的功能和生物合成步骤已经阐明,但其生物合成的调控机制尚未见报道。
根据生物信息学分析的结果,力达霉素的生物合成基因簇中至少存在三个调控基因sgcR1、sgcR2和sgcR3。sgcR3基因的产物SgcR3蛋白与泰乐菌素生物合成途径特异性正调控蛋白TylR具有较高的同源性。sgcR1基因的产物SgcR1蛋白与S.griseus链霉素生物合成的途径特异性激活因子StrR高度同源。蛋白SgcR2属于AraC/XylS转录因子家族。sgcR2与sgcR1串联,两基因间相隔25个碱基,推测其与sgcR1位于同一个操纵子。sgcR3和sgcR2基因内部各含有一个TTA稀有密码子。在三个已知的九元环类烯二炔基因簇(C-1027,新制癌菌素和maduropeptin)中,sgcR1、sgcR2和sgcR3及它们的同源基因均围绕在烯二炔聚酮合酶基因(PKSE)及其相关基因附近,并且基因排列组成也非常相似,推测sgcR1、sgcR2和sgcR3对这类抗生素生物合成具有重要的调控作用。
本工作采用同源重组双交换的方法将sgcR3基因阻断,研究sgcR3的生物学功能。分别以阿普霉素和硫链丝菌素抗性基因片段作为插入片段构建了sgcR3阻断突变株S.globisporus R3KO1和S.globisporus R3KO,阻断突变株不产生力达霉素。用三种质粒pKCR3、pSETR3和pLR3分别导入在自身启动子控制下和强启动子控制下的sgcR3对阻断突变株S.globisporus R3KO进行互补,均能恢复力达霉素的产生。在野生菌株中过量表达sgcR3可提高力达霉素的产量。以上结果说明SgcR3是力达霉素生物合成的正调控因子。为了确定sgcR3所调控的下游基因,本工作在大肠杆菌BL21(DE3)中表达并纯化了SgcR3蛋白。凝胶阻滞实验结果表明SgcR3可结合于sgcR1R2基因上游片段。
将带有自身启动子和/或强启动子ermE~*p的sgcR1、sgcR2以及sgcR1R2分别克隆至载体pKC1139的多克隆位点,导入野生菌株中进行过表达研究,结果发现均能不同程度的提高力达霉素的产量,提示sgcR1和sgcR2对力达霉素的产生有促进作用。交叉互补实验结果表明,sgcR3的导入不能使sgcR1R2阻断突变株S.globisporus R1R2KO恢复力达霉素的产生,sgcR1、sgcR1R2的导入则可使S.globisporus R3KO恢复力达霉素的产生,表明sgcR3在力达霉素生物合成途径特异性调控网络中位于sgcR1和sgcR2上游。实时定量RT-PCR结果显示,sgcR1和sgcR2的转录水平在S.globisporus R3KO中明显下降,而sgcR3的转录水平在S.globisporusR1R2KO中无明显变化,证明了sgcR3可调控sgcR1和sgcR2表达,这与交叉互补和SgcR3凝胶阻滞的实验结果一致。几个结构基因sgcA1、sgcC4、sgcD6和sgcE8在S.globisporus R3KO和S.globisporus R1R2KO中的表达量也都显著下降。本工作还构建了sgcR1和sgcR2的大肠杆菌表达质粒,并转入大肠杆菌BL21(DE3)进行了表达和纯化。为进一步研究sgcR1和sgcR2的功能奠定了基础。
综上所述,本工作通过对球孢链霉菌C-1027力达霉素生物合成基因簇中sgcR3基因进行阻断、互补和过表达研究,确定了sgcR3的正调控功能。并对sgcR3的分子调控机制进行初步研究,确定了其靶基因为sgcR1R2,在途径特异性级联调控网络中位于sgcR1R2的上游,为阐明力达霉素生物合成调控网络并应用代谢工程手段构建力达霉素高产菌株奠定了基础。
Lidamycin(C-1027),produced by Streptomyces globisporus C-1027,is a novel enediyne antitumor antibiotic and has entered phaseⅡclinical trial in China recently.C-1027 biosynthetic gene cluster has been cloned,sequenced and characterized.Bioinformatic analysis and biochemical studies revealed a distinct iterative typeⅠenediyne polyketide synthase(PKSE) and provided a convergent biosynthetic strategy for C-1027 from four biosynthetic building blocks.However,almost nothing was known about the transcriptional regulation of enediyne antibiotic production prior to the present work.
The biosynthetic gene cluster for 9-membered enediyne C-1027 contains at least three putative regulatory genes,i.e.,sgcR1,sgcR2 and sgcR3.The predicted gene products of sgcR1,sgcR2 and sgcR3 share sequence similarities to StrR,regulators of AraC/XylS family and TylR,respectively,sgcR1 and sgcR2 are two adjacent genes transcribed in the same direction with a gap of only 25 bp,suggesting that they might be transcriptionally coupled within an operon,sgcR2 and sgcR3 contain a TTA leucine codon respectively. Furthermore,the biosynthetic gene clusters for three 9-membered enediynes(C-1027, neocarzinostatin and maduropeptin) show high similarity in the organization of genes around these regulatory genes.Despite varying degrees of chromophore structural uniqueness,all homologues of three genes are located adjacent to the genes of PKSEs (sgcE,ncsE and mdpE) and the tailoring enzymes(E1 to E11),which are responsible for the biosynthesis of enediyne core.This may represent a further indication for a regulatory role of the three genes in C-1027 biosynthesis.
Disruption of sgcR3 abolished C-1027 production,suggesting that it is a positive regulator of C-1027 production.Complementation of the sgcR3 disrupted strain R3KO with intact sgcR3 gene restored C-1027 production and overexpression of sgcR3 in wild type strain resulted in a substantial increase in C-1027 production,confirming their positive regulatory role in C-1027 biosynthesis.SgcR3 was expressed and purified in E. coli BL21(DE3).Purified N-terminal His_6-tagged SgcR3 showed specific DNA-binding activity for upstream sequence of sgcR1 and sgcR2 of C-1027 biosynthetic gene cluster.
sgcR1,sgcR2 and sgcR1R2 with its own upstream sequence or the strong constitutive promoter ermE~*p were cloned into the vector pKC1139 and the recombinant plasmids were introduced into S.globisporus C-1027.Overexpression of sgcR1,sgcR2 and sgcR1R2 in wild type strain increased C-1027 production respectively,suggesting their positive role in C-1027 biosynthesis.The cross-complementation studies showed sgcR1R2 could functionally complement sgcR3 in trans,suggesting that sgcR1R2 occupies a lower rung than sgcR3 in the hierarchy of these genes.Consistent with this, the results from gene expression analysis via real time reverse transcriptase polymerase chain reaction(RT-PCR) showed that transcripts of sgcR1 and sgcR2 were significantly lower in R3KO mutant than in wild type strain,while sgcR3 transcripts were statistically at similar level in R1R2KO mutant as in wild type strain.A positive effect of sgcR1R2 and sgcR3 gene products on the transcription of biosynthetic structural genes such as sgcA1,sgcC4,sgcD6 and sgcE8 was also observed.To further investigate the functions of the sgcR1 and sgcR2,SgcR1 and SgcR2 were expressed and purified in E.coli BL21(DE3).
In this work,the results from disruption,complementation and overexpression analyses suggested a positive regulatory role of sgcR3 in C-1027 biosynthesis.Furthermore, purified SgcR3 showed specific DNA-binding activity for the upstream region of sgcR1R2.Consisting with this,cross-complementation experiments suggested that sgcR3 occupies a higher rung than sgcR1 and sgcR2 in the hierarchy of C-1027 regulatory genes. Additional evidence was observed through the study of the gene expression in mutants by using quantitative real time RT-PCR.The data presented in this work set the stage for subsequent studies to delineate the complexity of the regulation of C-1027 biosynthesis, as well as for designing strategies for the construction of strains with enhanced C-1027 production.
根据生物信息学分析的结果,力达霉素的生物合成基因簇中至少存在三个调控基因sgcR1、sgcR2和sgcR3。sgcR3基因的产物SgcR3蛋白与泰乐菌素生物合成途径特异性正调控蛋白TylR具有较高的同源性。sgcR1基因的产物SgcR1蛋白与S.griseus链霉素生物合成的途径特异性激活因子StrR高度同源。蛋白SgcR2属于AraC/XylS转录因子家族。sgcR2与sgcR1串联,两基因间相隔25个碱基,推测其与sgcR1位于同一个操纵子。sgcR3和sgcR2基因内部各含有一个TTA稀有密码子。在三个已知的九元环类烯二炔基因簇(C-1027,新制癌菌素和maduropeptin)中,sgcR1、sgcR2和sgcR3及它们的同源基因均围绕在烯二炔聚酮合酶基因(PKSE)及其相关基因附近,并且基因排列组成也非常相似,推测sgcR1、sgcR2和sgcR3对这类抗生素生物合成具有重要的调控作用。
本工作采用同源重组双交换的方法将sgcR3基因阻断,研究sgcR3的生物学功能。分别以阿普霉素和硫链丝菌素抗性基因片段作为插入片段构建了sgcR3阻断突变株S.globisporus R3KO1和S.globisporus R3KO,阻断突变株不产生力达霉素。用三种质粒pKCR3、pSETR3和pLR3分别导入在自身启动子控制下和强启动子控制下的sgcR3对阻断突变株S.globisporus R3KO进行互补,均能恢复力达霉素的产生。在野生菌株中过量表达sgcR3可提高力达霉素的产量。以上结果说明SgcR3是力达霉素生物合成的正调控因子。为了确定sgcR3所调控的下游基因,本工作在大肠杆菌BL21(DE3)中表达并纯化了SgcR3蛋白。凝胶阻滞实验结果表明SgcR3可结合于sgcR1R2基因上游片段。
将带有自身启动子和/或强启动子ermE~*p的sgcR1、sgcR2以及sgcR1R2分别克隆至载体pKC1139的多克隆位点,导入野生菌株中进行过表达研究,结果发现均能不同程度的提高力达霉素的产量,提示sgcR1和sgcR2对力达霉素的产生有促进作用。交叉互补实验结果表明,sgcR3的导入不能使sgcR1R2阻断突变株S.globisporus R1R2KO恢复力达霉素的产生,sgcR1、sgcR1R2的导入则可使S.globisporus R3KO恢复力达霉素的产生,表明sgcR3在力达霉素生物合成途径特异性调控网络中位于sgcR1和sgcR2上游。实时定量RT-PCR结果显示,sgcR1和sgcR2的转录水平在S.globisporus R3KO中明显下降,而sgcR3的转录水平在S.globisporusR1R2KO中无明显变化,证明了sgcR3可调控sgcR1和sgcR2表达,这与交叉互补和SgcR3凝胶阻滞的实验结果一致。几个结构基因sgcA1、sgcC4、sgcD6和sgcE8在S.globisporus R3KO和S.globisporus R1R2KO中的表达量也都显著下降。本工作还构建了sgcR1和sgcR2的大肠杆菌表达质粒,并转入大肠杆菌BL21(DE3)进行了表达和纯化。为进一步研究sgcR1和sgcR2的功能奠定了基础。
综上所述,本工作通过对球孢链霉菌C-1027力达霉素生物合成基因簇中sgcR3基因进行阻断、互补和过表达研究,确定了sgcR3的正调控功能。并对sgcR3的分子调控机制进行初步研究,确定了其靶基因为sgcR1R2,在途径特异性级联调控网络中位于sgcR1R2的上游,为阐明力达霉素生物合成调控网络并应用代谢工程手段构建力达霉素高产菌株奠定了基础。
Lidamycin(C-1027),produced by Streptomyces globisporus C-1027,is a novel enediyne antitumor antibiotic and has entered phaseⅡclinical trial in China recently.C-1027 biosynthetic gene cluster has been cloned,sequenced and characterized.Bioinformatic analysis and biochemical studies revealed a distinct iterative typeⅠenediyne polyketide synthase(PKSE) and provided a convergent biosynthetic strategy for C-1027 from four biosynthetic building blocks.However,almost nothing was known about the transcriptional regulation of enediyne antibiotic production prior to the present work.
The biosynthetic gene cluster for 9-membered enediyne C-1027 contains at least three putative regulatory genes,i.e.,sgcR1,sgcR2 and sgcR3.The predicted gene products of sgcR1,sgcR2 and sgcR3 share sequence similarities to StrR,regulators of AraC/XylS family and TylR,respectively,sgcR1 and sgcR2 are two adjacent genes transcribed in the same direction with a gap of only 25 bp,suggesting that they might be transcriptionally coupled within an operon,sgcR2 and sgcR3 contain a TTA leucine codon respectively. Furthermore,the biosynthetic gene clusters for three 9-membered enediynes(C-1027, neocarzinostatin and maduropeptin) show high similarity in the organization of genes around these regulatory genes.Despite varying degrees of chromophore structural uniqueness,all homologues of three genes are located adjacent to the genes of PKSEs (sgcE,ncsE and mdpE) and the tailoring enzymes(E1 to E11),which are responsible for the biosynthesis of enediyne core.This may represent a further indication for a regulatory role of the three genes in C-1027 biosynthesis.
Disruption of sgcR3 abolished C-1027 production,suggesting that it is a positive regulator of C-1027 production.Complementation of the sgcR3 disrupted strain R3KO with intact sgcR3 gene restored C-1027 production and overexpression of sgcR3 in wild type strain resulted in a substantial increase in C-1027 production,confirming their positive regulatory role in C-1027 biosynthesis.SgcR3 was expressed and purified in E. coli BL21(DE3).Purified N-terminal His_6-tagged SgcR3 showed specific DNA-binding activity for upstream sequence of sgcR1 and sgcR2 of C-1027 biosynthetic gene cluster.
sgcR1,sgcR2 and sgcR1R2 with its own upstream sequence or the strong constitutive promoter ermE~*p were cloned into the vector pKC1139 and the recombinant plasmids were introduced into S.globisporus C-1027.Overexpression of sgcR1,sgcR2 and sgcR1R2 in wild type strain increased C-1027 production respectively,suggesting their positive role in C-1027 biosynthesis.The cross-complementation studies showed sgcR1R2 could functionally complement sgcR3 in trans,suggesting that sgcR1R2 occupies a lower rung than sgcR3 in the hierarchy of these genes.Consistent with this, the results from gene expression analysis via real time reverse transcriptase polymerase chain reaction(RT-PCR) showed that transcripts of sgcR1 and sgcR2 were significantly lower in R3KO mutant than in wild type strain,while sgcR3 transcripts were statistically at similar level in R1R2KO mutant as in wild type strain.A positive effect of sgcR1R2 and sgcR3 gene products on the transcription of biosynthetic structural genes such as sgcA1,sgcC4,sgcD6 and sgcE8 was also observed.To further investigate the functions of the sgcR1 and sgcR2,SgcR1 and SgcR2 were expressed and purified in E.coli BL21(DE3).
In this work,the results from disruption,complementation and overexpression analyses suggested a positive regulatory role of sgcR3 in C-1027 biosynthesis.Furthermore, purified SgcR3 showed specific DNA-binding activity for the upstream region of sgcR1R2.Consisting with this,cross-complementation experiments suggested that sgcR3 occupies a higher rung than sgcR1 and sgcR2 in the hierarchy of C-1027 regulatory genes. Additional evidence was observed through the study of the gene expression in mutants by using quantitative real time RT-PCR.The data presented in this work set the stage for subsequent studies to delineate the complexity of the regulation of C-1027 biosynthesis, as well as for designing strategies for the construction of strains with enhanced C-1027 production.
引文
[1]Hu JL,Xue YC,Xie MY,et al.A new macromolecular antitumor antibiotic,C-1027.I.Discovery,taxonomy of producing organism,fermentation and biological activity,J.Antibiot.(Tokyo).1988,41(11):1575-1579
[2]Zhen YS,Ming XY,Yu B,et al.A new macromolecular antitumor antibiotic,C-1027.Ⅲ.Antitumor activity.J.Antibiot.(Tokyo).1989,42(8):1294-1298
[3]Shao RG and Zhen YS.Enediyne anticancer antibiotic lidamycin:chemistry,biology and pharmacology.Anticancer Agents Med.Chem.2008,8(2):123-131
[4]Dedon PC and Goldberg IH.Free-radical mechanisms involved in the formation of sequence-dependent bistranded DNA lesions by the antitumor antibiotics bleomycin,neocarzinostatin,and calicheamicin.Chem Res.Toxicol.1992,5(3):311-332
[5]Smith AL and Nicolaou KC.The enediyne antibiotics.J.Med.Chem.1996,39(11):2103-2117
[6]Maeda H,Edo K,and Ishida NE(1997) Neocarzinostatin:The Past,Present,and Future of an Anticancer Drug.,Springer-Verlag,NY
[7]Bross PF,Beitz J,Chen G,et al.Approval summary:gemtuzumab ozogamicin in relapsed acutemyeloid leukemia.Clin.Cancer Res.2001,7 1490-1496
[8]Liu W,Christenson SD,Standage S,et al.Biosynthesis of the enediyne antitumor antibiotic C-1027.Science.2002,297(5584):1170-1173
[9]Lin S,Van Lanen SG,and Shen B.Regiospecific chlorination of (S)-beta-tyrosyl-S-carrier protein catalyzed by SgcC3 in the biosynthesis of the enediyne antitumor antibiotic C-1027.J.Am.Chem Soc.2007,129(41):12432-12438
[10]Van Lanen SG,Lin S,Dorrestein PC,et al.Substrate specificity of the adenylation enzyme SgcC1 involved in the biosynthesis of the enediyne antitumor antibiotic C-1027.J.Biol Chem.2006,281(40):29633-29640
[11]Van Lanen SG,Lin S,and Shen B.Biosynthesis of the enediyne antitumor antibiotic C-1027 involves a new branching point in chorismate metabolism.Proc.Natl.Acad.Sci.U.S.A.2008,105(2):494-499
[12]Van Lanen SG,Dorrestein PC,Christenson SD,et al.Biosynthesis of the beta-amino acid moiety of the enediyne antitumor antibiotic C-1027 featuring beta-amino acyl-S-carrier protein intermediates.J.Am.Chem Soc.2005,127(33):11594-11595
[13]Murrell JM,Liu W,and Shen B.Biochemical characterization of the SgcA1alpha-D-glucopyranosyl-1-phosphate thymidylyltransferase from the enediyne antitumor antibiotic C-1027 biosynthetic pathway and overexpression of sgcA1 in Streptomyces globisporus to improve C-1027 production.J.Nat.Prod.2004,67(2):206-213
[14]Christenson SD,Wu W,Spies MA,et al.Kinetic analysis of the 4-methylideneimidazole-5-one-containing tyrosine aminomutase in enediyne antitumor antibiotic C-1027 biosynthesis.Biochemistry.2003,42(43):12708-12718
[15]Christenson SD,Liu W,Toney MD,et al.A novel 4-methylideneimidazole-5-one-containing tyrosine aminomutase in enediyne antitumor antibiotic C-1027 biosynthesis.J.Am.Chem Soc.2003,125(20):6062-6063
[16]Christianson CV,Montavon TJ,Van Lanen SG,et al.The structure of L-tyrosine 2,3-aminomutase from the C-1027 enediyne antitumor antibiotic biosynthetic pathway.Biochemistry.2007,46(24):7205-7214
[17]Bibb MJ.Regulation of secondary metabolism in streptomycetes.Curr.Opin.Microbiol.2005,8(2):208-215
[18]Fernandez-Moreno MA,Caballero JL,Hopwood DA,et al.The act cluster contains regulatory and antibiotic export genes,direct targets for translational control by the bldA tRNA gene of Streptomyces.Cell.1991,66(4):769-780
[19]Arias P,Fernandez-Moreno MA,and Malpartida F.Characterization of the pathway-specific positive transcriptional regulator for actinorhodin biosynthesis in Streptomyces coelicolor A3(2) as a DNA-binding protein.J.Bacteriol.1999,181(22):6958-6968
[20]Retzlaff L and Distler J.The regulator of streptomycin gene expression,StrR,of Streptomyces griseus is a DNA binding activator protein with multiple recognition sites.Mol.Microbiol.1995,18(1):151-162
[21]Tomono A,Tsai Y,Yamazaki H,et al.Transcriptional control by A-factor of strR,the pathway-specific transcriptional activator for streptomycin biosynthesis in Streptomyces griseus.J.Bacteriol.2005,187(16):5595-5604
[22]Furuya K and Hutchinson CR.The DnrN protein of Streptomyces peucetius,a pseudo-response regulator,is a DNA-binding protein involved in the regulation of daunorubicin biosynthesis.J.Bacteriol.1996,178(21):6310-6318
[23]Furuya K and Hutchinson CR.The DrrC protein of Streptomyces peucetius,a UvrA-like protein,is a DNA-binding protein whose gene is induced by daunorubicin.FEMS Microbiol.Lett.1998,168(2):243-249
[24]Stutzman-Engwall KJ,Otten SL,and Hutchinson CR.Regulation of secondary metabolism in Streptomyces spp.and overproduction of daunorubicin in Streptomyces peucetius.J.Bacteriol.1992,174(1):144-154
[25]Gallo MA,Ward J,and Hutchinson CR.The dnrM gene in Streptomyces peucetius contains a naturally occurring frameshift mutation that is suppressed by another locus outside of the daunorubicin-production gene cluster.Microbiology.1996,142(Pt 2)269-275
[26]Otten SL,Olano C,and Hutchinson CR.The dnrO gene encodes a DNA-binding protein that regulates daunorubicin production in Streptomyces peucetius by controlling expression of the dnrN pseudo response regulator gene.Microbiology.2000,146(Pt 6)1457-1468
[27]Otten SL,Ferguson J,and Hutchinson CR.Regulation of daunorubicin production in Streptomyces peucetius by the dnrR2 locus.J.Bacteriol.1995,177(5):1216-1224
[28]Bate N,Stratigopoulos G,and Cundliffe E.Differential roles of two SARP-encoding regulatory genes during tylosin biosynthesis.Mol.Microbiol.2002,43(2):449-458
[29]Bate N,Bignell DR,and Cundliffe E.Regulation of tylosin biosynthesis involving 'SARP-helper' activity.Mol.Microbiol.2006,62(1):148-156
[30]Bate N,Butler AR,Gandecha AR,et al.Multiple regulatory genes in the tylosin biosynthetic cluster of Streptomyces fradiae.Chem Biol.1999,6(9):617-624
[31]Bignell DR,Bate N,and Cundliffe E.Regulation of tylosin production:role of a TylP-interactive ligand.Mol.Microbiol.2007,63(3):838-847
[32]Stratigopoulos G,Gandecha AR,and Cundliffe E.Regulation of tylosin production and morphological differentiation in Streptomyces fradiae by TylP,a deduced gamma-butyrolactone receptor.Mol.Microbiol.2002,45(3):735-744
[33]Stratigopoulos G,Bate N,and Cundliffe E.Positive control of tylosin biosynthesis:pivotal role of TylR.Mol.Microbiol.2004,54(5):1326-1334
[34]Kuscer E,Coates N,Challis I,et al.Roles of rapH and rapG in positive regulation of rapamycin biosynthesis in Streptomyces hygroscopicus.J.Bacteriol.2007,189(13):4756-4763
[35]Sambrook J and Russell DW(2001) Molecular Cloning:a Laboratory Manual,3rd edn.,Cold Spring Harbor Laboratory.,Cold Spring Harbor,NY
[36]Zhao CY,Wang YF,L R,et al.Microbiological assay of lidamycin.Chinese Journal of Antibiotics.2005,30 535-537
[37]Hu JL,Xue YC,Xie MY,et al.A new macromolecular antitumor antibiotic,C-1027.I.Discovery,taxonomy of producing organism,fermentation and biological activity.J.Antibiot.(Tokyo).1988,41(11):1575-1579
[38]Bierman M,Logan R,O'Brien K,et al.Plasmid cloning vectors for the conjugal transfer of DNA from Escherichia coli to Streptomyces spp.Gene.1992,116(1):43-49
[39]Hong B,Phornphisutthimas S,Tilley E,et al.Streptomycin production by Streptomyces griseus can be modulated by a mechanism not associated with change in the adpA component of the A-factor cascade.Biotechnol.Lett.2007,29(1):57-64
[40]Liu W,Nonaka K,Nie L,et al.The neocarzinostatin biosynthetic gene cluster from Streptomyces carzinostaticus ATCC 15944 involving two iterative type Ⅰ polyketide synthases.Chem.Biol.2005,12(3):293-302
[41]Van Lanen SG,Oh T J,Liu W,et al.Characterization of the maduropeptin biosynthetic gene cluster from Actinomadura madurae ATCC 39144 supporting a unifying paradigm for enediyne biosynthesis.J.Am.Chem Soc.2007,129(43):13082-13094
[42]Liu W and Shen B.Genes for production of the enediyne antitumor antibiotic C-1027 in Streptomyces globisporus are clustered with the cagA gene that encodes the C-1027 apoprotein.Antimicrob.Agents Chemother.2000,44(2):382-392
[43]Eustaquio AS,Li SM,and Heide L.NovG,a DNA-binding protein acting as a positive regulator of novobiocin biosynthesis.Microbiology.2005,151(Pt 6):1949-1961
[44]Thamm S and Distler J.Properties of C-terminal truncated derivatives of the activator,StrR,of the streptomycin biosynthesis in Streptomyces griseus.FEMS Microbiol.Lett.1997,149(2):265-272
[45]Gallegos MT,Schleif R,Bairoch A,et al.Arac/XylS family of transcriptional regulators.Microbiol.Mol.Biol.Rev.1997,61(4):393-410
[46]Geistlich M,Losick R,Turner JR,et al.Characterization of a novel regulatory gene governing the expression of a polyketide synthase gene in Streptomyces ambofaciens.Mol.Microbiol.1992,6(14):2019-2029
[47]Perez-Llarena FJ,Liras P,Rodriguez-Garcia A,et al.A regulatory gene(ccaR)required for cephamycin and clavulanic acid production in Streptomyces clavuligerus:amplification results in overproduction of both beta-lactam compounds.J.Bacteriol.1997,179(6):2053-2059
[48]Chater KF and Bruton CJ.Resistance,regulatory and production genes for the antibiotic methylenomycin are clustered.EMBO J.1985,4(7):1893-1897
[49]Champness WC(2000) Actinomycete development,antibiotic production,and phylogeny:questions and challenges.In Prokaryotic Development,American Society for Microbiology,Washington DC
[50]Femandez-Moreno MA,Martinez E,Caballero JL,et al.DNA sequence and functions of the actVI region of the actinorhodin biosynthetic gene cluster of Streptomyces coelicolor A3(2).J.Biol Chem.1994,269(40):24854-24863
[51]Sevcikova B and Kormanec J.Differential production of two antibiotics of Streptomyces coelicolor A3(2),actinorhodin and undecylprodigiosin,upon salt stress conditions.Arch.Microbiol.2004,181(5):384-389
[52]Tang L,Grimm A,Zhang YX,et al.Purification and characterization of the DNA-binding protein DnrI,a transcriptional factor of daunorubicin biosynthesis in Streptomyces peucetius.Mol.Microbiol.1996,22(5):801-813
[53]Huang J,Shi J,Molle V,et al.Cross-regulation among disparate antibiotic biosynthetic pathways of Streptomyces coelicolor.Mol.Mierobiol.2005,58(5):1276-1287
[54]Horinouchi S.A microbial hormone,A-factor,as a master switch for morphological differentiation and secondary metabolism in Streptomyees griseus.Front Biosci.2002,7d2045-d2057
[55]Nihira T.(2008) Virginiamycin:biosynthetic pathway and its regulation,with special emphasis on the genetic aspects and autoregulator-dependent regulation.In Microbial Secondary Metabolites:Biosynthesis,Genetics and Regulation.,Research Signpost,Kerala,India
[56]Yamada Y(1999) Autoregulatory faetors and regulation of antibiotic production in Streptomyces:in microbial signaling and communication.,Society for General Microbiology,Cambridge University Press,Cambridge,UK
[57]Natsume R,Ohnishi Y,Senda T,et al.Crystal structure of a gamma-butyrolactone autoregulator receptor protein in Streptomyees coelicolor A3(2).J.Mol.Biol.2004, 336(2):409-419
[58]Yamazaki H,Tomono A,Ohnishi Y,et al.DNA-binding specificity of AdpA,a transcriptional activator in the A-factor regulatory cascade in Streptomyces griseus.Mol.Microbiol.2004,53(2):555-572
[59]Kato JY,Miyahisa I,Mashiko M,et al.A single target is sufficient to account for the biological effects of the A-factor receptor protein of Streptomyces griseus.J.BacterioL 2004,186(7):2206-2211
[60]Yamazaki H,Ohnishi Y,and Horinouchi S.An A-factor-dependent extracytoplasmic function sigma factor(sigma(AdsA)) that is essential for morphological development in Streptomyces griseus.J.Bacteriol.2000,182(16):4596-4605
[61]Yamazaki H,Ohnishi Y,and Horinouchi S.Transcriptional switch on of ssgA by A-factor,which is essential for spore septum formation in Streptomyces griseus.J.Bacteriol.2003,185(4):1273-1283
[62]Yamazaki H,Takano Y,Ohnishi Y,et al.amfR,an essential gene for aerial mycelium formation,is a member of the AdpA regulon in the A-factor regulatory cascade in Streptomyces griseus.Mol.Microbiol.2003,50(4):1173-1187
[63]Kato JY,Chi WJ,Ohnishi Y,et al.Transcriptional control by A-factor of two trypsin genes in Streptomyces griseus.J.Bacteriol.2005,187(1):286-295
[64]Higashi T,Iwasaki Y,Ohnishi Y,et al.A-factor and phosphate depletion signals are transmitted to the grixazone biosynthesis genes via the pathway-specific transcriptional activator GriR.J.Bacteriol.2007,189(9):3515-3524
[65]Natsume R,Takeshita R,Sugiyama M,et al.Crystallization of CprB,an autoregulator-receptor protein from Streptomyces coelicolor A3(2).Acta Crystallogr.D.Biol.Crystallogr.2003,59(Pt 12):2313-2315
[66]Kawachi R,Akashi T,Kamitani Y,et al.Identification of an AfsA homologue(BarX)from Streptomyces virginiae as a pleiotropic regulator controlling autoregulator biosynthesis,virginiamycin biosynthesis and virginiamycin M1 resistance.Mol.Microbiol.2000,36(2):302-313
[67]Nakano H,Takehara E,Nihira T,et al.Gene replacement analysis of the Streptomyces virginiae barA gene encoding the butyrolactone autoregulator receptor reveals that BarA acts as a repressor in virginiamycin biosynthesis.J.Bacteriol.1998,180(13):3317-3322
[68]Akashi T,Blinova IN,Efremenkova OV,et al(1984) Development regulators in Streptomyces coelicolor A3(2).In Izvestiya Akademii Nauk SSSR Seriya Biologicheskaya MM Shemyakin,Institute of Bioorganic Chemistry,Moscow
[69]Takano E,Nihira T,Hara Y,et al.Purification and structural determination of SCB1,a gamma-butyrolactone that elicits antibiotic production in Streptomyces coelicolor A3(2).J.Biol.Chem.2000,275(15):11010-11016
[70]Takano E,Chakraburtty R,Nihira T,et al.A complex role for the gamma-butyrolactone SCB1 in regulating antibiotic production in Streptomyces coelicolor A3(2).Mol.Microbiol.2001,41(5):1015-1028
[71]Takano E,Kinoshita H,Mersinias V,et al.A bacterial hormone(the SCB 1) directly controls the expression of a pathway-specific regulatory gene in the cryptic type Ⅰpolyketide biosynthetic gene cluster of Streptomyces coelicolor.Mol.Microbiol.2005,56(2):465-479
[72]Kitani S,Yamada Y,and Nihira T.Gene replacement analysis of the butyrolactone autoregulator receptor(FarA) reveals that FarA acts as a Novel regulator in secondary metabolism of Streptomyces lavendulae FRI-5.J.Bacteriol.2001,183(14):4357-4363
[73]Bentley SD,Chater KF,Cerdeno-Tarraga AM,et al.Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2).Nature.2002,417(6885):141-147
[74]Ikeda H,Ishikawa J,Hanamoto A,et al.Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis.Nat.Biotechnol.2003,21(5):526-531
[75]Folcher M,Gaillard H,Nguyen LT,et al.Pleiotropic functions of a Streptomyces pristinaespiralis autoregulator receptor in development,antibiotic biosynthesis,and expression of a superoxide dismutase.J.Biol.Chem.2001,276(47):44297-44306
[76]Li W,Liu G,and Tan H.Disruption of sabR affects nikkomycin biosynthesis and morphogenesis in Streptomyces ansochromogenes.Biotechnol.Lett.2003,25(18):1491-1497
[77]Engel P,Scharfenstein LL,Dyer JM,et al.Disruption of a gene encoding a putative gamma-butyrolactone-binding protein in Streptomyces tendae affects nikkomycin production.Appl.Microbiol.Biotechnol.2001,56(3-4):414-419
[78]Onaka H,Nakagawa T,and Horinouchi S.Involvement of two A-factor receptor homologues in Streptomyces coelicolor A3(2) in the regulation of secondary metabolism and morphogenesis.Mol.Microbiol.1998,28(4):743-753
[79]Gust B,Challis GL,Fowler K,et al.PCR-targeted Streptomyces gene replacement identifies a protein domain needed for biosynthesis of the sesquiterpene soil odor geosmin.Proc.Natl.Acad.Sci.U.S.A.2003,100(4):1541-1546
[80]Recio E,Colinas A,Rumbero A,et al.PI factor,a novel type quorum-sensing inducer elicits pimaricin production in Streptomyces natalensis.J.Biol.Chem.2004,279(40):41586-41593
[81]Anton N,Mendes MV,Martin JF,et al.Identification of PimR as a positive regulator of pimaricin biosynthesis in Streptomyces natalensis.J.Bacteriol.2004,186(9):2567-2575
[82]Magnusson LU,Farewell A,and Nystrom T.ppGpp:a global regulator in Escherichia coli.Trends Microbiol.2005,13(5):236-242
[83]Chakraburtty R and Bibb M.The ppGpp synthetase gene(relA) of Streptomyces coelicolor A3(2) plays a conditional role in antibiotic production and morphological differentiation.J.Bacteriol.1997,179(18):5854-5861
[84]Sun J,Hesketh A,and Bibb M.Functional analysis of relA and rshA,two relA/spoT homologues of Streptomyces coelicolor A3(2).J.Bacteriol.2001,183(11):3488-3498
[85]Hesketh A,Sun J,and Bibb M.Induction of ppGpp synthesis in Streptomyces coelicolor A3(2) grown under conditions of nutritional sufficiency elicits actⅡ-ORF4transcription and actinorhodin biosynthesis.Mol.Microbiol.2001,39(1):136-144
[86]Kelly KS,Ochi K,and Jones GH.Pleiotropic effects of a relC mutation in Streptomyces antibioticus.J.Bacteriol.1991,173(7):2297-2300
[87]Ochi K.A rel mutation abolishes the enzyme induction needed for actinomycin synthesis by Streptomyces antibioticus.Agric Biol Chem.1987,829-835
[88]Ochi K.Metabolic initiation of differentiation and secondary metabolism by Streptomyces griseus:significance of the stringent response(ppGpp) and GTP content in relation to A factor.J.Bacteriol.1987,169(8):3608-3616
[89]Ochi K.A relaxed(rel) mutant of Streptomyces coelicolor A3(2) with a missing ribosomal protein lacks the ability to accumulate ppGpp,A-factor and prodigiosin,J.Gen.Microbiol.1990,136(12):2405-2412
[90]Ochi K.Streptomyces relC mutants with an altered ribosomal protein ST-L11 and genetic analysis of a Streptomyces griseus relC mutant.J.Bacteriol.1990,172(7):4008-4016
[91]Braeken K,Moris M,Daniels R,et al.New horizons for(p)ppGpp in bacterial and plant physiology.Trends Microbiol.2006,14(1):45-54
[92]Hesketh A,Chen WJ,Ryding J,et al.The global role of ppGpp synthesis in morphological differentiation and antibiotic production in Streptomyces coelicolor A3(2).Genome Biol.2007,8(8):R161
[93]Sola-Landa A,Moura RS,and Martin JF.The two-component PhoR-PhoP system controls both primary metabolism and secondary metabolite biosynthesis in Streptomyces lividans.Proe.Natl.Acad.Sci.U.S.A.2003,100(10):6133-6138
[94]Chouayekh H and Virolle MJ.The polyphosphate kinase plays a negative role in the control of antibiotic production in Streptomyces lividans.Mol.Microbiol.2002,43(4):919-930
[95]Liu W and Hulett FM.Comparison of PhoP binding to the tuaA promoter with PhoP binding to other Pho-regulon promoters establishes a Bacillus subtilis Pho core binding site.Microbiology.1998,144(Pt 5) 1443-1450
[96]Torriani-Gorini A(1994) The Pho regulon of Escherichia coli.In Phosphate in microorganisms,ASM Press,Washington,D.C
[97]Susstrunk U,Pidoux J,Taubert S,et al.Pleiotropic effects of cAMP on germination,antibiotic biosynthesis and morphological development in Streptomyces coelicolor.Mol.Microbiol.1998,30(1):33-46
[98]Bruckner R and Titgemeyer F.Carbon catabolite repression in bacteria:choice of the carbon source and autoregulatory limitation of sugar utilization.FEMS Microbiol.Lett.2002,209(2):141-148
[99]Busby S and Ebright RH.Transcription activation by catabolite activator protein (CAP).J.Mol.Biol.1999,293(2):199-213
[100]Marschall C,Labrousse V,Kreimer M,et al.Molecular analysis of the regulation of csiD,a carbon starvation-inducible gene in Escherichia coli that is exclusively dependent on sigma s and requires activation by cAMP-CRP.J.Mol.Biol.1998,276(2):339-353
[101]Castanie-Cornet MP and J WF.Escherichia coli acid resistance:cAMP receptor protein and a 20 bp cis-acting sequence control pH and stationary phase expression of the gadA and gadBC glutamate decarboxylase genes.Microbiology.2001,709-715
[102]Soutourina O,Kolb A,Krin E,et al.Multiple control of flagellum biosynthesis in Escherichia coli:role of H-NS protein and the cyclic AMP-catabolite activator protein complex in transcription of the flhDC master operon.J.Bacteriol.1999,181(24):7500-7508
[103]Derouaux A,Dehareng D,Lecocq E,et al.Crp of Streptomyces coelicolor is the third transcription factor of the large CRP-FNR superfamily able to bind cAMP.Biochem.Biophys.Res.Commun.2004,325(3):983-990
[104]Piette A,Derouaux A,Gerkens P,et al.From dormant to germinating spores of Streptomyces coelicolor A3(2):new perspectives from the crp null mutant.J.Proteome.Res.2005,4(5):1699-1708
[105]Guthrie EP,Flaxman CS,White J,et al.A response-regulator-like activator of antibiotic synthesis from Streptomyces coelicolor A3(2) with an amino-terminal domain that lacks a phosphorylation pocket.Microbiology.1998,144(Pt 3) 727-738
[106]Hesketh A,Bucca G,Laing E,et al.New pleiotropic effects of eliminating a rare tRNA from Streptomyces coelicolor,revealed by combined proteomic and transcriptomic analysis of liquid cultures.BMC.Genomics.2007,8 261
[107]Eccleston M,Ali RA,Seyler R,et al.Structural and genetic analysis of the BldB protein of Streptomyces coelicolor.J.Bacteriol.2002,184(15):4270-4276
[108]Elliot MA,Bibb MJ,Buttner MJ,et al.BldD is a direct regulator of key developmental genes in Streptomyces coelicolor A3(2).Mol.Microbiol.2001,40(1):257-269
[109]Bignell DR,Lau LH,Colvin KR,et al.The putative anti-anti-sigma factor BldG is post-translationally modified by phosphorylation in Streptomyces coelicolor.FEMS Microbiol.Lett.2003,225(1):93-99
[110]Hunt AC,Servin-Gonzalez L,Kelemen GH,et al.The bldC developmental locus of Streptomyces coelicolor encodes a member of a family of small DNA-binding proteins related to the DNA-binding domains of the MerR family.J.Bacteriol.2005,187(2):716-728
[111]Wietzorrek A and Bibb M.A novel family of proteins that regulates antibiotic production in streptomycetes appears to contain an OmpR-like DNA-binding fold.Mol.Microbiol.1997,25(6):1181-1184
[112]Horinouchi S.AfsR as an integrator of signals that are sensed by multiple serine/threonine kinases in Streptomyces coelicolor A3(2).J.Ind.Microbiol.Biotechnol.2003,30(8):462-467
[113]Tanaka A,Takano Y,Ohnishi Y,et al.AfsR recruits RNA polymerase to the afsS promoter:a model for transcriptional activation by SARPs.J.Mol.Biol.2007,369(2):322-333
[114]Wilson DJ,Xue Y,Reynolds KA,et al.Characterization and analysis of the PikD regulatory factor in the pikromycin biosynthetic pathway of Streptomyces venezuelae.J.Bacteriol.2001,183(11):3468-3475
[115]Sekurova ON,Brautaset T,Sletta H,et al.In vivo analysis of the regulatory genes in the nystatin biosynthetic gene cluster of Streptomyces noursei ATCC 11455 reveals their differential control over antibiotic biosynthesis.J.Bacteriol.2004,186(5):1345-1354
[116]Carmody M,Byrne B,Murphy B,et al.Analysis and manipulation of amphotericin biosynthetic genes by means of modified phage KC515 transduction techniques.Gene.2004,343(1):107-115
[117]Campelo AB and Gil JA.The candicidin gene cluster from Streptomyces griseus IMRU 3570.Microbiology.2002,148(Pt 1):51-59
[118]Rascher A,Hu Z,Viswanathan N,et al.Cloning and characterization of a gene cluster for geldanamycin production in Streptomyces hygroscopicus NRRL 3602.FEMS Microbiol.Lett.2003,218(2):223-230
[119]Knirschova R,Novakova R,Feckova L,et al.Multiple regulatory genes in the salinomycin biosynthetic gene cluster of Streptomyces albus CCM 4719.Folia Microbiol.(Praha).2007,52(4):359-365
[120]Anderson TB,Brian P,and Champness WC.Genetic and transcriptional analysis of absA,an antibiotic gene cluster-linked two-component system that regulates multiple antibiotics in Streptomyces coelicolor.Mol.Microbiol.2001,39(3):553-566
[121]Sheeler NL,MacMillan SV,and Nodwell JR.Biochemical activities of the absA two-component system of Streptomyces coelicolor.J.Bacteriol.2005,187(2):687-696
[122]Ryding NJ,Anderson TB,and Champness WC.Regulation of the Streptomyces coelicolor calcium-dependent antibiotic by absA,encoding a cluster-linked two-component system.J.Bacteriol.2002,184(3):794-805
[123]McKenzie NL and Nodwell JR.Phosphorylated AbsA2 negatively regulates antibiotic production in Streptomyces coelicolor through interactions with pathway-specific regulatory gene promoters.J.Bacteriol.2007,189(14):5284-5292
[124]Sheldon PJ,Busarow SB,and Hutchinson CR.Mapping the DNA-binding domain and target sequences of the Streptomyces peucetius daunorubicin biosynthesis regulatory protein,Dnrl.Mol.Microbiol.2002,44(2):449-460
[125]Madduri K and Hutchinson CR.Functional characterization and transcriptional analysis of the dnrRl locus,which controls daunorubicin biosynthesis in Streptomyces peucetius.J.Bacteriol.1995,177(5):1208-1215
[126]Madduri K and Hutchinson CR.Functional characterization and transcriptional analysis of the dnrRl locus,which controls daunorubicin biosynthesis in Streptomyces peucetius.J.Bacteriol.1995,177(5):1208-1215
[127]Stratigopoulos G and Cundliffe E.Expression analysis of the tylosin-biosynthetic gene cluster:pivotal regulatory role of the tylQ product.Chem.Biol.2002,9(1):71-78
[128]Edo K,Mizugaki M,Koide Y,et al.The Structure of Neocarzinostatin Chromophore Possessing a Novel Bicyclo[7.3.0]dodecadiyne System.Tetrahedron Lett.1985,(26):331-340
[129]May DL,Theresa S.Dunne,Marshall M.Siegel,et al.Calichemicins,a novel family of antitumor antibiotics.1.Chemistry and partial structure of calichemicin.gamma.Ⅱ.J.Am.Chem.Soc.1987,109 3464-3466
[130]jerzy G,george D,gary G,et al.Esperamicins,a novel class of potent antitumor antibiotics.3.Structures of esperamicins A 1,A2,and Alb.J.Am.Chem.Soc.1987,109 3462-3464
[131]Jerzy G,j on C,George D,etal.Esperamicins,a novel class of potent antitumor antibiotics.2.Structure of esperamicin X.J.Am.Chem.Soc.1987,109 3461-3462
[132]Oku N,Matsunaga S,and Fusetani N.Shishijimicins A-C,novel enediyne antitumor antibiotics from the ascidian Didemnum proliferum(1).J.Am.Chem Soc.2003,125(8):2044-2045
[133]Davies J,Wang H,Taylor T,et al.Uncialamycin,a new enediyne antibiotic.Org.Lett.2005,7(23):5233-5236
[134]Stassinopoulos A,Ji J,Gao X,et al.Solution structure of a two-base DNA bulge complexed with an enediyne cleaving analog.Science.1996,272(5270):1943-1946
[135]Dziegielewski J and Beerman TA.Cellular responses to the DNA strand-scission enediyne C-1027 can be independent of ATM,ATR,and DNA-PK kinases.J.Biol Chem.2002,277(23):20549-20554
[136]Schor NF,Tyurina YY,Fabisiak JP,et al.Selective oxidation and externalization of membrane phosphatidylserine:Bcl-2-induced potentiation of the final common pathway for apoptosis.Brain Res.1999,831(1-2):125-130
[137]Jones GB and Fouad FS.Designed enediyne antitumor agents.Curr.Pharm.Des.2002,8(27):2415-2440
[138]Sievers EL,Appelbaum FR,Spielberger RT,et al.Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy:a phase I study of an anti-CD33 calicheamicin immunoconjugate.Blood.1999,93(11):3678-3684
[139]Du L and Shen B.Biosynthesis of hybrid peptide-polyketide natural products.Curr.Opin.Drug Discov.Devel.2001,4(2):215-228
[140]Hopwood DA.Genetic Contributions to Understanding Polyketide Synthases.Chem Rev.1997,97(7):2465-2498
[141]Cane DE,Walsh CT,and Khosla C.Harnessing the biosynthetic code:combinations,permutations,and mutations.Science.1998,282(5386):63-68
[142]Strohl WR.Biochemical engineering of natural product biosynthesis pathways.Metab Eng.2001,3(1):4-14
[143]Staunton J and Weissman KJ.Polyketide biosynthesis:a millennium review.Nat.Prod.Rep.2001,18(4):380-416
[144]Hopwood DA and Wright HM.CDA is a new chromosomally-determined antibiotic from Streptomyces coelicolor A3(2).J.Gen.Microbiol.1983,129(12):3575-3579
[145]He XM and Liu HW.Formation of unusual sugars:mechanistic studies and biosynthetic applications.Annu.Rev.Biochem.2002,71 701-754
[146]Trefzer A,Salas JA,and Bechthold A.Genes and enzymes involved in deoxysugar biosynthesis in bacteria.Nat.Prod.Rep.1999,16(3):283-299
[147]Decker H,Gaisser S,Pelzer S,et al.A general approach for cloning and characterizing dNDP-glucose dehydratase genes from actinomycetes.FEMS Microbiol.Lett.1996,141(2-3):195-201
[148]Sakata N,Ikeno S,Hori M,et al.Cloning and nucleotide sequencing of the antitumor antibiotic C-1027 apoprotein gene.Biosci.Biotechnol.Biochem.1992,56(10):1592-1595
[149]Ross EW,Joachim A,Theodore RH,et al.The Gene calC Encodes for a Non-Heme Iron Metalloprotein Responsible for Calicheamicin Self-Resistance in Micromonospora.J.Am.Chem.Soc..2000,122 1556-1557
[150]Ahlert J,Shepard E,Lomovskaya N,et al.The calicheamicin gene cluster and its iterative type I enediyne PKS.Science.2002,297(5584):1173-1176
[151]Thorson JS,Shen B,Whitwam RE,et al.Enediyne Biosynthesis and Self-Resistance:A Progress Report.Bioorg.Chem.1999,27 172-188
[152]Zazopoulos E,Huang K,Staffa A,et al.A genomics-guided approach for discovering and expressing cryptic metabolic pathways.Nat.Biotechnol.2003,21(2):187-190
[153]Shen B.Polyketide biosynthesis beyond the type Ⅰ,Ⅱ and Ⅲ polyketide synthase paradigms.Curr.Opin.Chem Biol.2003,7(2):285-295
[154]Liu W,Ahlert J,Gao Q,et al.Rapid PCR amplification of minimal enediyne polyketide synthase cassettes leads to a predictive familial classification model.Proc.Natl.Acad.Sci.U.S.A.2003,100(21):11959-11963
[155]Wenzel SC and Muller R.Formation of novel secondary metabolites by bacterial multimodular assembly lines:deviations from textbook biosynthetic logic.Curr.Opin.Chem Biol.2005,9(5):447-458
[156]Zhang J,Van Lanen SG,Ju J,et al.A phosphopantetheinylating polyketide synthase producing a linear polyene to initiate enediyne antitumor antibiotic biosynthesis.Proc.Natl.Acad.Sci.U.S A.2008,105(5):1460-1465
[157]Kennedy DR,Gawron LS,Ju J,et al.Single chemical modifications of the C-1027 enediyne core,a radiomimetic antitumor drug,affect both drug potency and the role of ataxia-telangiectasia mutated in cellular responses to DNA double-strand breaks.Cancer Res.2007,67(2):773-781
[158]Kennedy DR,Ju J,Shen B,et al.Designer enediynes generate DNA breaks,interstrand cross-links,or both,with concomitant changes in the regulation of DNA damage responses.Proc.Natl.Acad.Sci.U.S.A.2007,104(45):17632-17637
[159]胡云峰.(2005).中国协和医科大学硕士研究生学位论文.
[2]Zhen YS,Ming XY,Yu B,et al.A new macromolecular antitumor antibiotic,C-1027.Ⅲ.Antitumor activity.J.Antibiot.(Tokyo).1989,42(8):1294-1298
[3]Shao RG and Zhen YS.Enediyne anticancer antibiotic lidamycin:chemistry,biology and pharmacology.Anticancer Agents Med.Chem.2008,8(2):123-131
[4]Dedon PC and Goldberg IH.Free-radical mechanisms involved in the formation of sequence-dependent bistranded DNA lesions by the antitumor antibiotics bleomycin,neocarzinostatin,and calicheamicin.Chem Res.Toxicol.1992,5(3):311-332
[5]Smith AL and Nicolaou KC.The enediyne antibiotics.J.Med.Chem.1996,39(11):2103-2117
[6]Maeda H,Edo K,and Ishida NE(1997) Neocarzinostatin:The Past,Present,and Future of an Anticancer Drug.,Springer-Verlag,NY
[7]Bross PF,Beitz J,Chen G,et al.Approval summary:gemtuzumab ozogamicin in relapsed acutemyeloid leukemia.Clin.Cancer Res.2001,7 1490-1496
[8]Liu W,Christenson SD,Standage S,et al.Biosynthesis of the enediyne antitumor antibiotic C-1027.Science.2002,297(5584):1170-1173
[9]Lin S,Van Lanen SG,and Shen B.Regiospecific chlorination of (S)-beta-tyrosyl-S-carrier protein catalyzed by SgcC3 in the biosynthesis of the enediyne antitumor antibiotic C-1027.J.Am.Chem Soc.2007,129(41):12432-12438
[10]Van Lanen SG,Lin S,Dorrestein PC,et al.Substrate specificity of the adenylation enzyme SgcC1 involved in the biosynthesis of the enediyne antitumor antibiotic C-1027.J.Biol Chem.2006,281(40):29633-29640
[11]Van Lanen SG,Lin S,and Shen B.Biosynthesis of the enediyne antitumor antibiotic C-1027 involves a new branching point in chorismate metabolism.Proc.Natl.Acad.Sci.U.S.A.2008,105(2):494-499
[12]Van Lanen SG,Dorrestein PC,Christenson SD,et al.Biosynthesis of the beta-amino acid moiety of the enediyne antitumor antibiotic C-1027 featuring beta-amino acyl-S-carrier protein intermediates.J.Am.Chem Soc.2005,127(33):11594-11595
[13]Murrell JM,Liu W,and Shen B.Biochemical characterization of the SgcA1alpha-D-glucopyranosyl-1-phosphate thymidylyltransferase from the enediyne antitumor antibiotic C-1027 biosynthetic pathway and overexpression of sgcA1 in Streptomyces globisporus to improve C-1027 production.J.Nat.Prod.2004,67(2):206-213
[14]Christenson SD,Wu W,Spies MA,et al.Kinetic analysis of the 4-methylideneimidazole-5-one-containing tyrosine aminomutase in enediyne antitumor antibiotic C-1027 biosynthesis.Biochemistry.2003,42(43):12708-12718
[15]Christenson SD,Liu W,Toney MD,et al.A novel 4-methylideneimidazole-5-one-containing tyrosine aminomutase in enediyne antitumor antibiotic C-1027 biosynthesis.J.Am.Chem Soc.2003,125(20):6062-6063
[16]Christianson CV,Montavon TJ,Van Lanen SG,et al.The structure of L-tyrosine 2,3-aminomutase from the C-1027 enediyne antitumor antibiotic biosynthetic pathway.Biochemistry.2007,46(24):7205-7214
[17]Bibb MJ.Regulation of secondary metabolism in streptomycetes.Curr.Opin.Microbiol.2005,8(2):208-215
[18]Fernandez-Moreno MA,Caballero JL,Hopwood DA,et al.The act cluster contains regulatory and antibiotic export genes,direct targets for translational control by the bldA tRNA gene of Streptomyces.Cell.1991,66(4):769-780
[19]Arias P,Fernandez-Moreno MA,and Malpartida F.Characterization of the pathway-specific positive transcriptional regulator for actinorhodin biosynthesis in Streptomyces coelicolor A3(2) as a DNA-binding protein.J.Bacteriol.1999,181(22):6958-6968
[20]Retzlaff L and Distler J.The regulator of streptomycin gene expression,StrR,of Streptomyces griseus is a DNA binding activator protein with multiple recognition sites.Mol.Microbiol.1995,18(1):151-162
[21]Tomono A,Tsai Y,Yamazaki H,et al.Transcriptional control by A-factor of strR,the pathway-specific transcriptional activator for streptomycin biosynthesis in Streptomyces griseus.J.Bacteriol.2005,187(16):5595-5604
[22]Furuya K and Hutchinson CR.The DnrN protein of Streptomyces peucetius,a pseudo-response regulator,is a DNA-binding protein involved in the regulation of daunorubicin biosynthesis.J.Bacteriol.1996,178(21):6310-6318
[23]Furuya K and Hutchinson CR.The DrrC protein of Streptomyces peucetius,a UvrA-like protein,is a DNA-binding protein whose gene is induced by daunorubicin.FEMS Microbiol.Lett.1998,168(2):243-249
[24]Stutzman-Engwall KJ,Otten SL,and Hutchinson CR.Regulation of secondary metabolism in Streptomyces spp.and overproduction of daunorubicin in Streptomyces peucetius.J.Bacteriol.1992,174(1):144-154
[25]Gallo MA,Ward J,and Hutchinson CR.The dnrM gene in Streptomyces peucetius contains a naturally occurring frameshift mutation that is suppressed by another locus outside of the daunorubicin-production gene cluster.Microbiology.1996,142(Pt 2)269-275
[26]Otten SL,Olano C,and Hutchinson CR.The dnrO gene encodes a DNA-binding protein that regulates daunorubicin production in Streptomyces peucetius by controlling expression of the dnrN pseudo response regulator gene.Microbiology.2000,146(Pt 6)1457-1468
[27]Otten SL,Ferguson J,and Hutchinson CR.Regulation of daunorubicin production in Streptomyces peucetius by the dnrR2 locus.J.Bacteriol.1995,177(5):1216-1224
[28]Bate N,Stratigopoulos G,and Cundliffe E.Differential roles of two SARP-encoding regulatory genes during tylosin biosynthesis.Mol.Microbiol.2002,43(2):449-458
[29]Bate N,Bignell DR,and Cundliffe E.Regulation of tylosin biosynthesis involving 'SARP-helper' activity.Mol.Microbiol.2006,62(1):148-156
[30]Bate N,Butler AR,Gandecha AR,et al.Multiple regulatory genes in the tylosin biosynthetic cluster of Streptomyces fradiae.Chem Biol.1999,6(9):617-624
[31]Bignell DR,Bate N,and Cundliffe E.Regulation of tylosin production:role of a TylP-interactive ligand.Mol.Microbiol.2007,63(3):838-847
[32]Stratigopoulos G,Gandecha AR,and Cundliffe E.Regulation of tylosin production and morphological differentiation in Streptomyces fradiae by TylP,a deduced gamma-butyrolactone receptor.Mol.Microbiol.2002,45(3):735-744
[33]Stratigopoulos G,Bate N,and Cundliffe E.Positive control of tylosin biosynthesis:pivotal role of TylR.Mol.Microbiol.2004,54(5):1326-1334
[34]Kuscer E,Coates N,Challis I,et al.Roles of rapH and rapG in positive regulation of rapamycin biosynthesis in Streptomyces hygroscopicus.J.Bacteriol.2007,189(13):4756-4763
[35]Sambrook J and Russell DW(2001) Molecular Cloning:a Laboratory Manual,3rd edn.,Cold Spring Harbor Laboratory.,Cold Spring Harbor,NY
[36]Zhao CY,Wang YF,L R,et al.Microbiological assay of lidamycin.Chinese Journal of Antibiotics.2005,30 535-537
[37]Hu JL,Xue YC,Xie MY,et al.A new macromolecular antitumor antibiotic,C-1027.I.Discovery,taxonomy of producing organism,fermentation and biological activity.J.Antibiot.(Tokyo).1988,41(11):1575-1579
[38]Bierman M,Logan R,O'Brien K,et al.Plasmid cloning vectors for the conjugal transfer of DNA from Escherichia coli to Streptomyces spp.Gene.1992,116(1):43-49
[39]Hong B,Phornphisutthimas S,Tilley E,et al.Streptomycin production by Streptomyces griseus can be modulated by a mechanism not associated with change in the adpA component of the A-factor cascade.Biotechnol.Lett.2007,29(1):57-64
[40]Liu W,Nonaka K,Nie L,et al.The neocarzinostatin biosynthetic gene cluster from Streptomyces carzinostaticus ATCC 15944 involving two iterative type Ⅰ polyketide synthases.Chem.Biol.2005,12(3):293-302
[41]Van Lanen SG,Oh T J,Liu W,et al.Characterization of the maduropeptin biosynthetic gene cluster from Actinomadura madurae ATCC 39144 supporting a unifying paradigm for enediyne biosynthesis.J.Am.Chem Soc.2007,129(43):13082-13094
[42]Liu W and Shen B.Genes for production of the enediyne antitumor antibiotic C-1027 in Streptomyces globisporus are clustered with the cagA gene that encodes the C-1027 apoprotein.Antimicrob.Agents Chemother.2000,44(2):382-392
[43]Eustaquio AS,Li SM,and Heide L.NovG,a DNA-binding protein acting as a positive regulator of novobiocin biosynthesis.Microbiology.2005,151(Pt 6):1949-1961
[44]Thamm S and Distler J.Properties of C-terminal truncated derivatives of the activator,StrR,of the streptomycin biosynthesis in Streptomyces griseus.FEMS Microbiol.Lett.1997,149(2):265-272
[45]Gallegos MT,Schleif R,Bairoch A,et al.Arac/XylS family of transcriptional regulators.Microbiol.Mol.Biol.Rev.1997,61(4):393-410
[46]Geistlich M,Losick R,Turner JR,et al.Characterization of a novel regulatory gene governing the expression of a polyketide synthase gene in Streptomyces ambofaciens.Mol.Microbiol.1992,6(14):2019-2029
[47]Perez-Llarena FJ,Liras P,Rodriguez-Garcia A,et al.A regulatory gene(ccaR)required for cephamycin and clavulanic acid production in Streptomyces clavuligerus:amplification results in overproduction of both beta-lactam compounds.J.Bacteriol.1997,179(6):2053-2059
[48]Chater KF and Bruton CJ.Resistance,regulatory and production genes for the antibiotic methylenomycin are clustered.EMBO J.1985,4(7):1893-1897
[49]Champness WC(2000) Actinomycete development,antibiotic production,and phylogeny:questions and challenges.In Prokaryotic Development,American Society for Microbiology,Washington DC
[50]Femandez-Moreno MA,Martinez E,Caballero JL,et al.DNA sequence and functions of the actVI region of the actinorhodin biosynthetic gene cluster of Streptomyces coelicolor A3(2).J.Biol Chem.1994,269(40):24854-24863
[51]Sevcikova B and Kormanec J.Differential production of two antibiotics of Streptomyces coelicolor A3(2),actinorhodin and undecylprodigiosin,upon salt stress conditions.Arch.Microbiol.2004,181(5):384-389
[52]Tang L,Grimm A,Zhang YX,et al.Purification and characterization of the DNA-binding protein DnrI,a transcriptional factor of daunorubicin biosynthesis in Streptomyces peucetius.Mol.Microbiol.1996,22(5):801-813
[53]Huang J,Shi J,Molle V,et al.Cross-regulation among disparate antibiotic biosynthetic pathways of Streptomyces coelicolor.Mol.Mierobiol.2005,58(5):1276-1287
[54]Horinouchi S.A microbial hormone,A-factor,as a master switch for morphological differentiation and secondary metabolism in Streptomyees griseus.Front Biosci.2002,7d2045-d2057
[55]Nihira T.(2008) Virginiamycin:biosynthetic pathway and its regulation,with special emphasis on the genetic aspects and autoregulator-dependent regulation.In Microbial Secondary Metabolites:Biosynthesis,Genetics and Regulation.,Research Signpost,Kerala,India
[56]Yamada Y(1999) Autoregulatory faetors and regulation of antibiotic production in Streptomyces:in microbial signaling and communication.,Society for General Microbiology,Cambridge University Press,Cambridge,UK
[57]Natsume R,Ohnishi Y,Senda T,et al.Crystal structure of a gamma-butyrolactone autoregulator receptor protein in Streptomyees coelicolor A3(2).J.Mol.Biol.2004, 336(2):409-419
[58]Yamazaki H,Tomono A,Ohnishi Y,et al.DNA-binding specificity of AdpA,a transcriptional activator in the A-factor regulatory cascade in Streptomyces griseus.Mol.Microbiol.2004,53(2):555-572
[59]Kato JY,Miyahisa I,Mashiko M,et al.A single target is sufficient to account for the biological effects of the A-factor receptor protein of Streptomyces griseus.J.BacterioL 2004,186(7):2206-2211
[60]Yamazaki H,Ohnishi Y,and Horinouchi S.An A-factor-dependent extracytoplasmic function sigma factor(sigma(AdsA)) that is essential for morphological development in Streptomyces griseus.J.Bacteriol.2000,182(16):4596-4605
[61]Yamazaki H,Ohnishi Y,and Horinouchi S.Transcriptional switch on of ssgA by A-factor,which is essential for spore septum formation in Streptomyces griseus.J.Bacteriol.2003,185(4):1273-1283
[62]Yamazaki H,Takano Y,Ohnishi Y,et al.amfR,an essential gene for aerial mycelium formation,is a member of the AdpA regulon in the A-factor regulatory cascade in Streptomyces griseus.Mol.Microbiol.2003,50(4):1173-1187
[63]Kato JY,Chi WJ,Ohnishi Y,et al.Transcriptional control by A-factor of two trypsin genes in Streptomyces griseus.J.Bacteriol.2005,187(1):286-295
[64]Higashi T,Iwasaki Y,Ohnishi Y,et al.A-factor and phosphate depletion signals are transmitted to the grixazone biosynthesis genes via the pathway-specific transcriptional activator GriR.J.Bacteriol.2007,189(9):3515-3524
[65]Natsume R,Takeshita R,Sugiyama M,et al.Crystallization of CprB,an autoregulator-receptor protein from Streptomyces coelicolor A3(2).Acta Crystallogr.D.Biol.Crystallogr.2003,59(Pt 12):2313-2315
[66]Kawachi R,Akashi T,Kamitani Y,et al.Identification of an AfsA homologue(BarX)from Streptomyces virginiae as a pleiotropic regulator controlling autoregulator biosynthesis,virginiamycin biosynthesis and virginiamycin M1 resistance.Mol.Microbiol.2000,36(2):302-313
[67]Nakano H,Takehara E,Nihira T,et al.Gene replacement analysis of the Streptomyces virginiae barA gene encoding the butyrolactone autoregulator receptor reveals that BarA acts as a repressor in virginiamycin biosynthesis.J.Bacteriol.1998,180(13):3317-3322
[68]Akashi T,Blinova IN,Efremenkova OV,et al(1984) Development regulators in Streptomyces coelicolor A3(2).In Izvestiya Akademii Nauk SSSR Seriya Biologicheskaya MM Shemyakin,Institute of Bioorganic Chemistry,Moscow
[69]Takano E,Nihira T,Hara Y,et al.Purification and structural determination of SCB1,a gamma-butyrolactone that elicits antibiotic production in Streptomyces coelicolor A3(2).J.Biol.Chem.2000,275(15):11010-11016
[70]Takano E,Chakraburtty R,Nihira T,et al.A complex role for the gamma-butyrolactone SCB1 in regulating antibiotic production in Streptomyces coelicolor A3(2).Mol.Microbiol.2001,41(5):1015-1028
[71]Takano E,Kinoshita H,Mersinias V,et al.A bacterial hormone(the SCB 1) directly controls the expression of a pathway-specific regulatory gene in the cryptic type Ⅰpolyketide biosynthetic gene cluster of Streptomyces coelicolor.Mol.Microbiol.2005,56(2):465-479
[72]Kitani S,Yamada Y,and Nihira T.Gene replacement analysis of the butyrolactone autoregulator receptor(FarA) reveals that FarA acts as a Novel regulator in secondary metabolism of Streptomyces lavendulae FRI-5.J.Bacteriol.2001,183(14):4357-4363
[73]Bentley SD,Chater KF,Cerdeno-Tarraga AM,et al.Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2).Nature.2002,417(6885):141-147
[74]Ikeda H,Ishikawa J,Hanamoto A,et al.Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis.Nat.Biotechnol.2003,21(5):526-531
[75]Folcher M,Gaillard H,Nguyen LT,et al.Pleiotropic functions of a Streptomyces pristinaespiralis autoregulator receptor in development,antibiotic biosynthesis,and expression of a superoxide dismutase.J.Biol.Chem.2001,276(47):44297-44306
[76]Li W,Liu G,and Tan H.Disruption of sabR affects nikkomycin biosynthesis and morphogenesis in Streptomyces ansochromogenes.Biotechnol.Lett.2003,25(18):1491-1497
[77]Engel P,Scharfenstein LL,Dyer JM,et al.Disruption of a gene encoding a putative gamma-butyrolactone-binding protein in Streptomyces tendae affects nikkomycin production.Appl.Microbiol.Biotechnol.2001,56(3-4):414-419
[78]Onaka H,Nakagawa T,and Horinouchi S.Involvement of two A-factor receptor homologues in Streptomyces coelicolor A3(2) in the regulation of secondary metabolism and morphogenesis.Mol.Microbiol.1998,28(4):743-753
[79]Gust B,Challis GL,Fowler K,et al.PCR-targeted Streptomyces gene replacement identifies a protein domain needed for biosynthesis of the sesquiterpene soil odor geosmin.Proc.Natl.Acad.Sci.U.S.A.2003,100(4):1541-1546
[80]Recio E,Colinas A,Rumbero A,et al.PI factor,a novel type quorum-sensing inducer elicits pimaricin production in Streptomyces natalensis.J.Biol.Chem.2004,279(40):41586-41593
[81]Anton N,Mendes MV,Martin JF,et al.Identification of PimR as a positive regulator of pimaricin biosynthesis in Streptomyces natalensis.J.Bacteriol.2004,186(9):2567-2575
[82]Magnusson LU,Farewell A,and Nystrom T.ppGpp:a global regulator in Escherichia coli.Trends Microbiol.2005,13(5):236-242
[83]Chakraburtty R and Bibb M.The ppGpp synthetase gene(relA) of Streptomyces coelicolor A3(2) plays a conditional role in antibiotic production and morphological differentiation.J.Bacteriol.1997,179(18):5854-5861
[84]Sun J,Hesketh A,and Bibb M.Functional analysis of relA and rshA,two relA/spoT homologues of Streptomyces coelicolor A3(2).J.Bacteriol.2001,183(11):3488-3498
[85]Hesketh A,Sun J,and Bibb M.Induction of ppGpp synthesis in Streptomyces coelicolor A3(2) grown under conditions of nutritional sufficiency elicits actⅡ-ORF4transcription and actinorhodin biosynthesis.Mol.Microbiol.2001,39(1):136-144
[86]Kelly KS,Ochi K,and Jones GH.Pleiotropic effects of a relC mutation in Streptomyces antibioticus.J.Bacteriol.1991,173(7):2297-2300
[87]Ochi K.A rel mutation abolishes the enzyme induction needed for actinomycin synthesis by Streptomyces antibioticus.Agric Biol Chem.1987,829-835
[88]Ochi K.Metabolic initiation of differentiation and secondary metabolism by Streptomyces griseus:significance of the stringent response(ppGpp) and GTP content in relation to A factor.J.Bacteriol.1987,169(8):3608-3616
[89]Ochi K.A relaxed(rel) mutant of Streptomyces coelicolor A3(2) with a missing ribosomal protein lacks the ability to accumulate ppGpp,A-factor and prodigiosin,J.Gen.Microbiol.1990,136(12):2405-2412
[90]Ochi K.Streptomyces relC mutants with an altered ribosomal protein ST-L11 and genetic analysis of a Streptomyces griseus relC mutant.J.Bacteriol.1990,172(7):4008-4016
[91]Braeken K,Moris M,Daniels R,et al.New horizons for(p)ppGpp in bacterial and plant physiology.Trends Microbiol.2006,14(1):45-54
[92]Hesketh A,Chen WJ,Ryding J,et al.The global role of ppGpp synthesis in morphological differentiation and antibiotic production in Streptomyces coelicolor A3(2).Genome Biol.2007,8(8):R161
[93]Sola-Landa A,Moura RS,and Martin JF.The two-component PhoR-PhoP system controls both primary metabolism and secondary metabolite biosynthesis in Streptomyces lividans.Proe.Natl.Acad.Sci.U.S.A.2003,100(10):6133-6138
[94]Chouayekh H and Virolle MJ.The polyphosphate kinase plays a negative role in the control of antibiotic production in Streptomyces lividans.Mol.Microbiol.2002,43(4):919-930
[95]Liu W and Hulett FM.Comparison of PhoP binding to the tuaA promoter with PhoP binding to other Pho-regulon promoters establishes a Bacillus subtilis Pho core binding site.Microbiology.1998,144(Pt 5) 1443-1450
[96]Torriani-Gorini A(1994) The Pho regulon of Escherichia coli.In Phosphate in microorganisms,ASM Press,Washington,D.C
[97]Susstrunk U,Pidoux J,Taubert S,et al.Pleiotropic effects of cAMP on germination,antibiotic biosynthesis and morphological development in Streptomyces coelicolor.Mol.Microbiol.1998,30(1):33-46
[98]Bruckner R and Titgemeyer F.Carbon catabolite repression in bacteria:choice of the carbon source and autoregulatory limitation of sugar utilization.FEMS Microbiol.Lett.2002,209(2):141-148
[99]Busby S and Ebright RH.Transcription activation by catabolite activator protein (CAP).J.Mol.Biol.1999,293(2):199-213
[100]Marschall C,Labrousse V,Kreimer M,et al.Molecular analysis of the regulation of csiD,a carbon starvation-inducible gene in Escherichia coli that is exclusively dependent on sigma s and requires activation by cAMP-CRP.J.Mol.Biol.1998,276(2):339-353
[101]Castanie-Cornet MP and J WF.Escherichia coli acid resistance:cAMP receptor protein and a 20 bp cis-acting sequence control pH and stationary phase expression of the gadA and gadBC glutamate decarboxylase genes.Microbiology.2001,709-715
[102]Soutourina O,Kolb A,Krin E,et al.Multiple control of flagellum biosynthesis in Escherichia coli:role of H-NS protein and the cyclic AMP-catabolite activator protein complex in transcription of the flhDC master operon.J.Bacteriol.1999,181(24):7500-7508
[103]Derouaux A,Dehareng D,Lecocq E,et al.Crp of Streptomyces coelicolor is the third transcription factor of the large CRP-FNR superfamily able to bind cAMP.Biochem.Biophys.Res.Commun.2004,325(3):983-990
[104]Piette A,Derouaux A,Gerkens P,et al.From dormant to germinating spores of Streptomyces coelicolor A3(2):new perspectives from the crp null mutant.J.Proteome.Res.2005,4(5):1699-1708
[105]Guthrie EP,Flaxman CS,White J,et al.A response-regulator-like activator of antibiotic synthesis from Streptomyces coelicolor A3(2) with an amino-terminal domain that lacks a phosphorylation pocket.Microbiology.1998,144(Pt 3) 727-738
[106]Hesketh A,Bucca G,Laing E,et al.New pleiotropic effects of eliminating a rare tRNA from Streptomyces coelicolor,revealed by combined proteomic and transcriptomic analysis of liquid cultures.BMC.Genomics.2007,8 261
[107]Eccleston M,Ali RA,Seyler R,et al.Structural and genetic analysis of the BldB protein of Streptomyces coelicolor.J.Bacteriol.2002,184(15):4270-4276
[108]Elliot MA,Bibb MJ,Buttner MJ,et al.BldD is a direct regulator of key developmental genes in Streptomyces coelicolor A3(2).Mol.Microbiol.2001,40(1):257-269
[109]Bignell DR,Lau LH,Colvin KR,et al.The putative anti-anti-sigma factor BldG is post-translationally modified by phosphorylation in Streptomyces coelicolor.FEMS Microbiol.Lett.2003,225(1):93-99
[110]Hunt AC,Servin-Gonzalez L,Kelemen GH,et al.The bldC developmental locus of Streptomyces coelicolor encodes a member of a family of small DNA-binding proteins related to the DNA-binding domains of the MerR family.J.Bacteriol.2005,187(2):716-728
[111]Wietzorrek A and Bibb M.A novel family of proteins that regulates antibiotic production in streptomycetes appears to contain an OmpR-like DNA-binding fold.Mol.Microbiol.1997,25(6):1181-1184
[112]Horinouchi S.AfsR as an integrator of signals that are sensed by multiple serine/threonine kinases in Streptomyces coelicolor A3(2).J.Ind.Microbiol.Biotechnol.2003,30(8):462-467
[113]Tanaka A,Takano Y,Ohnishi Y,et al.AfsR recruits RNA polymerase to the afsS promoter:a model for transcriptional activation by SARPs.J.Mol.Biol.2007,369(2):322-333
[114]Wilson DJ,Xue Y,Reynolds KA,et al.Characterization and analysis of the PikD regulatory factor in the pikromycin biosynthetic pathway of Streptomyces venezuelae.J.Bacteriol.2001,183(11):3468-3475
[115]Sekurova ON,Brautaset T,Sletta H,et al.In vivo analysis of the regulatory genes in the nystatin biosynthetic gene cluster of Streptomyces noursei ATCC 11455 reveals their differential control over antibiotic biosynthesis.J.Bacteriol.2004,186(5):1345-1354
[116]Carmody M,Byrne B,Murphy B,et al.Analysis and manipulation of amphotericin biosynthetic genes by means of modified phage KC515 transduction techniques.Gene.2004,343(1):107-115
[117]Campelo AB and Gil JA.The candicidin gene cluster from Streptomyces griseus IMRU 3570.Microbiology.2002,148(Pt 1):51-59
[118]Rascher A,Hu Z,Viswanathan N,et al.Cloning and characterization of a gene cluster for geldanamycin production in Streptomyces hygroscopicus NRRL 3602.FEMS Microbiol.Lett.2003,218(2):223-230
[119]Knirschova R,Novakova R,Feckova L,et al.Multiple regulatory genes in the salinomycin biosynthetic gene cluster of Streptomyces albus CCM 4719.Folia Microbiol.(Praha).2007,52(4):359-365
[120]Anderson TB,Brian P,and Champness WC.Genetic and transcriptional analysis of absA,an antibiotic gene cluster-linked two-component system that regulates multiple antibiotics in Streptomyces coelicolor.Mol.Microbiol.2001,39(3):553-566
[121]Sheeler NL,MacMillan SV,and Nodwell JR.Biochemical activities of the absA two-component system of Streptomyces coelicolor.J.Bacteriol.2005,187(2):687-696
[122]Ryding NJ,Anderson TB,and Champness WC.Regulation of the Streptomyces coelicolor calcium-dependent antibiotic by absA,encoding a cluster-linked two-component system.J.Bacteriol.2002,184(3):794-805
[123]McKenzie NL and Nodwell JR.Phosphorylated AbsA2 negatively regulates antibiotic production in Streptomyces coelicolor through interactions with pathway-specific regulatory gene promoters.J.Bacteriol.2007,189(14):5284-5292
[124]Sheldon PJ,Busarow SB,and Hutchinson CR.Mapping the DNA-binding domain and target sequences of the Streptomyces peucetius daunorubicin biosynthesis regulatory protein,Dnrl.Mol.Microbiol.2002,44(2):449-460
[125]Madduri K and Hutchinson CR.Functional characterization and transcriptional analysis of the dnrRl locus,which controls daunorubicin biosynthesis in Streptomyces peucetius.J.Bacteriol.1995,177(5):1208-1215
[126]Madduri K and Hutchinson CR.Functional characterization and transcriptional analysis of the dnrRl locus,which controls daunorubicin biosynthesis in Streptomyces peucetius.J.Bacteriol.1995,177(5):1208-1215
[127]Stratigopoulos G and Cundliffe E.Expression analysis of the tylosin-biosynthetic gene cluster:pivotal regulatory role of the tylQ product.Chem.Biol.2002,9(1):71-78
[128]Edo K,Mizugaki M,Koide Y,et al.The Structure of Neocarzinostatin Chromophore Possessing a Novel Bicyclo[7.3.0]dodecadiyne System.Tetrahedron Lett.1985,(26):331-340
[129]May DL,Theresa S.Dunne,Marshall M.Siegel,et al.Calichemicins,a novel family of antitumor antibiotics.1.Chemistry and partial structure of calichemicin.gamma.Ⅱ.J.Am.Chem.Soc.1987,109 3464-3466
[130]jerzy G,george D,gary G,et al.Esperamicins,a novel class of potent antitumor antibiotics.3.Structures of esperamicins A 1,A2,and Alb.J.Am.Chem.Soc.1987,109 3462-3464
[131]Jerzy G,j on C,George D,etal.Esperamicins,a novel class of potent antitumor antibiotics.2.Structure of esperamicin X.J.Am.Chem.Soc.1987,109 3461-3462
[132]Oku N,Matsunaga S,and Fusetani N.Shishijimicins A-C,novel enediyne antitumor antibiotics from the ascidian Didemnum proliferum(1).J.Am.Chem Soc.2003,125(8):2044-2045
[133]Davies J,Wang H,Taylor T,et al.Uncialamycin,a new enediyne antibiotic.Org.Lett.2005,7(23):5233-5236
[134]Stassinopoulos A,Ji J,Gao X,et al.Solution structure of a two-base DNA bulge complexed with an enediyne cleaving analog.Science.1996,272(5270):1943-1946
[135]Dziegielewski J and Beerman TA.Cellular responses to the DNA strand-scission enediyne C-1027 can be independent of ATM,ATR,and DNA-PK kinases.J.Biol Chem.2002,277(23):20549-20554
[136]Schor NF,Tyurina YY,Fabisiak JP,et al.Selective oxidation and externalization of membrane phosphatidylserine:Bcl-2-induced potentiation of the final common pathway for apoptosis.Brain Res.1999,831(1-2):125-130
[137]Jones GB and Fouad FS.Designed enediyne antitumor agents.Curr.Pharm.Des.2002,8(27):2415-2440
[138]Sievers EL,Appelbaum FR,Spielberger RT,et al.Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy:a phase I study of an anti-CD33 calicheamicin immunoconjugate.Blood.1999,93(11):3678-3684
[139]Du L and Shen B.Biosynthesis of hybrid peptide-polyketide natural products.Curr.Opin.Drug Discov.Devel.2001,4(2):215-228
[140]Hopwood DA.Genetic Contributions to Understanding Polyketide Synthases.Chem Rev.1997,97(7):2465-2498
[141]Cane DE,Walsh CT,and Khosla C.Harnessing the biosynthetic code:combinations,permutations,and mutations.Science.1998,282(5386):63-68
[142]Strohl WR.Biochemical engineering of natural product biosynthesis pathways.Metab Eng.2001,3(1):4-14
[143]Staunton J and Weissman KJ.Polyketide biosynthesis:a millennium review.Nat.Prod.Rep.2001,18(4):380-416
[144]Hopwood DA and Wright HM.CDA is a new chromosomally-determined antibiotic from Streptomyces coelicolor A3(2).J.Gen.Microbiol.1983,129(12):3575-3579
[145]He XM and Liu HW.Formation of unusual sugars:mechanistic studies and biosynthetic applications.Annu.Rev.Biochem.2002,71 701-754
[146]Trefzer A,Salas JA,and Bechthold A.Genes and enzymes involved in deoxysugar biosynthesis in bacteria.Nat.Prod.Rep.1999,16(3):283-299
[147]Decker H,Gaisser S,Pelzer S,et al.A general approach for cloning and characterizing dNDP-glucose dehydratase genes from actinomycetes.FEMS Microbiol.Lett.1996,141(2-3):195-201
[148]Sakata N,Ikeno S,Hori M,et al.Cloning and nucleotide sequencing of the antitumor antibiotic C-1027 apoprotein gene.Biosci.Biotechnol.Biochem.1992,56(10):1592-1595
[149]Ross EW,Joachim A,Theodore RH,et al.The Gene calC Encodes for a Non-Heme Iron Metalloprotein Responsible for Calicheamicin Self-Resistance in Micromonospora.J.Am.Chem.Soc..2000,122 1556-1557
[150]Ahlert J,Shepard E,Lomovskaya N,et al.The calicheamicin gene cluster and its iterative type I enediyne PKS.Science.2002,297(5584):1173-1176
[151]Thorson JS,Shen B,Whitwam RE,et al.Enediyne Biosynthesis and Self-Resistance:A Progress Report.Bioorg.Chem.1999,27 172-188
[152]Zazopoulos E,Huang K,Staffa A,et al.A genomics-guided approach for discovering and expressing cryptic metabolic pathways.Nat.Biotechnol.2003,21(2):187-190
[153]Shen B.Polyketide biosynthesis beyond the type Ⅰ,Ⅱ and Ⅲ polyketide synthase paradigms.Curr.Opin.Chem Biol.2003,7(2):285-295
[154]Liu W,Ahlert J,Gao Q,et al.Rapid PCR amplification of minimal enediyne polyketide synthase cassettes leads to a predictive familial classification model.Proc.Natl.Acad.Sci.U.S.A.2003,100(21):11959-11963
[155]Wenzel SC and Muller R.Formation of novel secondary metabolites by bacterial multimodular assembly lines:deviations from textbook biosynthetic logic.Curr.Opin.Chem Biol.2005,9(5):447-458
[156]Zhang J,Van Lanen SG,Ju J,et al.A phosphopantetheinylating polyketide synthase producing a linear polyene to initiate enediyne antitumor antibiotic biosynthesis.Proc.Natl.Acad.Sci.U.S A.2008,105(5):1460-1465
[157]Kennedy DR,Gawron LS,Ju J,et al.Single chemical modifications of the C-1027 enediyne core,a radiomimetic antitumor drug,affect both drug potency and the role of ataxia-telangiectasia mutated in cellular responses to DNA double-strand breaks.Cancer Res.2007,67(2):773-781
[158]Kennedy DR,Ju J,Shen B,et al.Designer enediynes generate DNA breaks,interstrand cross-links,or both,with concomitant changes in the regulation of DNA damage responses.Proc.Natl.Acad.Sci.U.S.A.2007,104(45):17632-17637
[159]胡云峰.(2005).中国协和医科大学硕士研究生学位论文.