珍珠膜海绵共附生微生物PKS与NRPS的筛选与模块结构研究
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摘要
本论文从开发海洋药物及探询药源问题出发,针对我国沿海特殊来源的微生物——海洋生物附生细菌开展了一系列的探索性研究。我们通过抗菌、细胞毒的筛选,从分离到的364株海洋细菌中获得42株具有抗菌活性的海洋细菌,12株具有细胞毒活性的海洋细菌。对12株具有细胞毒活性的细菌菌株进行了16SrRNA系统发生学分析,它们分别属于Agrobacterium,Pseudoalteromons,Bacillus,Paracoccus,Rheinheimera,Aerococcus,Exiguobacterium和Alteromonas 8个属。同时,对这12株具有细胞毒活性的细菌菌株进行进一步的多聚酮合酶(PKSⅠ型)和非核糖体肽合成酶(NRPS)的筛选,得到了4株含有PKSⅠ型的KS结构域或NPRS的A结构域的海洋细菌,为从聚酮和非核糖体肽等生物合成途径去深入研究其次生代谢产物提供了基因学的证据。
以海洋微生物Pseudoalteromons sp.NJ632作为研究对象,运用Genome-walking策略对已获得KS片段的上、下游区域进行了部分的步移得到了一段约为10 Kb大小的连续的核苷酸序列,对其中疑似PKS的开放阅读框(ORF)进行了PKS模件中结构域的分析。结果显示,我们获得了包括ketosynthase(KS),acyltransferase(AT),dehydratase(DH),ketoreductase(KR),cyclization(Cy)在内的一个相对完整的PKS模件。在我们获得的PKS模件的结构中,除了常见的PKS相关结构域外,还发现了结构域cyclization(Cy),这在以往的报道中极少见到。这也暗示在NJ6-3-2中有可能存在一个PKS/NRPS杂合的,且结构非常特殊的杂合基因簇。
以海洋微生物Pseudoalteromons sp.NJ631作为研究对象,首次成功的构建并保存了其基因组文库,并对文库质量做了相应的鉴定,保证了文库的完整性。在此基础上,进一步用来自于其本身的酮基合酶基因(KS)制备探针,对2880个单克隆进行了杂交筛选,获得了14个阳性克隆子,分别标记为:AE1,BG2,CA1,CB6,DD12,DH5,FA11,GC10,GD7,GG4,KG10,LD8,MH9,OA5。运用“染色体步移”策略,对这14个阳性重组子上所插入的NJ6-3-1的基因组DNA片段进行简单的排序,并结合相应的酶切片段,最终确定,阳性克隆子BG2,GG4最有可能是14个阳性克隆子最外侧的两个克隆子,采用鸟枪法(Shot Gun Sequencing)对阳性克隆子BG2,GG4进行了大片段测序,获得了一条约为60 Kb的,连续的DNA序列。通过生物信息学分析,对其中所包含的20个开放阅读框(ORF)进行了逐一的功能注释。对疑似PKS或NRPS的三个ORF(ORF14,ORF15和ORF19)运用在线软件“NPRS-PKS”对其PKS或NRPS的结构域进行了预测。最终,获得了一个包括终止结构域“TE”在内的,由7个连续模件组成的,完整的,NRPS/PKS杂合生物合成基因簇,命名为“NJ631 NPRS-PKS生物合成基因簇”。运用NRPS A结构域底物特异性预测法则,我们成功的对获得的NJ631NRPS/PKS杂合生物合成基因簇中4个A结构域(A_2,A_3,A_4,A_5)进行了其各自的特异性底物的预测。结果显示,4个A结构域(A_2,A_3,A_4,A_5)各自特异性结合的氨基酸为:Glu/Gln,Ser,Ser-D,Aeo。
为了制备Pseudoalteromons sp.NJ631的NRPS-PKS基因簇中KS结构域的特异性抗体,同时也进行A结构域的底物特异性酶活检测,我们采用已商品化的pET表达系统(pET-28a)构建了分别含有KS、A1、A2、A3、A4、A5结构域的表达质粒pZPKS2、pZPA12、pZPA22、pZPA32、pZPA42、pZPA52。异源表达结果显示,我们成功的在大肠杆菌BL21(DE3)中超量表达了KS、A1、A3和A4结构域,为今后的KS结构域的特异性抗体制备和A结构域的底物特异性酶活检测提供了必要条件。
本论文从海洋生物附生微生物的分离开始,进行了其代谢产物生物活性(抗菌、细胞毒)和功能基因(PKS、NRPS)筛选以及活性菌株的分子鉴定;运用Genome-walking策略对分离得到的活性菌Pseudoalteromons sp.NJ632中的PKS模件进行了初步的研究,同时,通过文库构建、筛选、测序,采用反向遗传学的手段初步揭示了活性菌Pseudoalteromons sp.NJ631中存在一个NRPS/PKS杂合的生物合成途径,并对合成途径中的A结构域的底物特异性进行了预测:最后,对获得的“NJ631 NRPS-PKS生物合成途径”中的核心结构域进行了异源表达的尝试。这项工作不仅完善了一套进行海洋微生物活性天然产物研究的系统方法,为开发具有药用潜力的天然化合物建立模型,也为海洋微生物作为海洋活性物质的药源提供新的依据。本工作在海洋微生物活性天然产物的研究中尽管尚处于初级阶段,但在整个课题的研究中取得了实质性进展,对后续研究也起到了启发和推动的作用。
This research was focused on exploring marine natural products of medical potentiality and their origin.The studies of bioactive metabolites from marine bacteria associated with marine organisms along the coast in China were carried out. Through screening of antimicrobial and cytotoxic activities,the results showed that 42 isolates had antimicrobial activity and 12 isolates had cytotoxicity.Molecular phylogenetic analysis of marine bacteria with cytotoxicity based on 16S rRNA sequences indicated that they were belong to the genera Aerococcus,Agrobacterium, Alteromona,Bacillus,Exiguobacterium,Paracoccus,Pseudoalteromons, Rheinheimera.Furthermore,marine bacteria with cytotoxicity were also screened for PKS I and NRPS genes which could be responsible for bioactive secondary metabolites biosynthesis,4 strains having KS domain or A domain were obtained, which provide strong evidence that marine bioactive bacteria can produce natural products through PKS and NRPS pathways.
In order to further confirm the existence of PKS cluster in Pseudoalteromons sp. NJ632,genomic walking was used to amplify the flanking genomic DNA sequence to a KS sequence obtained from NJ632 by PCR amplification.A 10-kb continuous DNA sequence was obtained by five stepwise walking to upstream and downstream of KS fragment,respectively.The open reading frames(ORFs) were predicted and screened large multi-domain megasynthase involved in the biosynthesis of PKS.The results showed a relatively complete PKS module comprised of distinct core and auxiliary catalytic domains was obtained.Core catalytic domains include ketosynthase(KS) domain,acyltransferase(AT) domain,auxiliary domains include ketoreductase(KR), dehydratase(DH).Moreover,another auxiliary domain,cyclization(Cy),is also present in our gene walking sequence,which is generally present in NPRS module. For consideration of the existence of NRPS A domain also found in NJ632,it is suggested that there may exist a mixed or hybrid PKS/NRPS multienzyme system in the Pseudoalteromonas sp.NJ632,which could synthesize secondary metabolite with hydrid structure.
In order to confirm a putative NRPS/PKS gene cluster from marine sponge associated bacterium with cytotoxic activity and elucidate the gene structural information.The genomic library of marine sponge Hymeniacidon perleve associated bacterium Pseudoalteromons.sp NJ631 is constructed using pCC1FOS fosmid.The 2880 colonies from the fosmid library were screened by hybridizing with the digoxigenin(DIG)-labeled fragment of the KS domain from PCR amplification of Pseudoalteromons sp.NJ631 genomic DNA.The results showed 14 positive clones were identified and annotated AE1,BG2,CA1,CB6,DD12,DH5,FA11,GC10,GD7, GG4,KG10,LD8,MH9,OA5,respectively.To ensure that two clones we selected to sequence located both sides of these overlapping clones,additional chromosomal walking from this locus was carried out,eventually leading to two clones,BG2 and GG4 located both sides of all of positive clones.The genome of clones BG2 and GG4 were sequenced using genome shotgun method.According to analysis of sequence,a 60-kb continuous DNA region covered by overlapping fosmids BG2 and GG4 was obtained.The ORF and BlastX analysis of this large DNA fragment indicated that there are three big ORFs,ORF14,ORF15和ORF19,encoding proteins with similarities to amino acid adenylation,beta-ketoacyl synthase,and nonribosomal peptide synthase,respectively,from different organisms.The results gave us a clue there could be PKS or NRPS modules in three ORFs.Further analysis demonstrates three ORFs encoding two NPRS modules,one PKS modules and three NRPS modules.Finally,a NRPS/PKS gene cluster annotated "NJ631 NPRS-PKS" and containing seven modules was obtained.Using the specificity-conferring selection rule,the substrate specificity of four A(A_2,A_3,A_4,A_5) domains were successfully predicted,and the amino acids of the substrate specificity were Glu/Gln,Ser,Ser-D, Aeo,respectively.
To raise ployclonal antibodies using KS protein produced in E.coli as antigen and test the substrate specificity of A domains from NJ631 NRPS-PKS cluster,a series of expression vector,pZPKS2、pZPA12、pZPA22、pZPA32、pZPA42、pZPA52, containing KS、A1、A2、A3、A4、A5 domains were successfully constructed using pET system(pET-28a),respectively.The expression of the target DNA was induced by the addition of 1 mM IPTG to the bacterial culture.The results showed KS、A1、A3 and A4 domains were over expressed in E.coli,successfully,which provide strong foundation for raising ployclonal antibodies using KS protein and testing the substrate specificity of A domains.
This study was started with isolation of marine bacteria associated with marine organisms,continued with bioactive(antibacteria and cytotoxicity) and functional genes(PKS and NRPS) screening and bacteria identification.Then,the bacterium with bioactivity,Pseudoalteromons sp.NJ632,was further confirmed the existence of PKS cluster using genomic walking.At the same time,a NRPS/PKS gene cluster annotated "NJ631 NPRS-PKS" and containing seven modules was obtained in Pseudoalteromons sp.NJ631 using a series of methods containing the construction of genomic DNA library,screening,analysis.Finally,core domains contianing KS and A domain in NRPS/PKS gene cluster of Pseudoalteromons sp.NJ631 were tried to express in E.coli.Through these works,the integrated approach to explore the potential of marine bacteria for the production of bioactive metabolites was established and some new evidences of marine microorganisms as medical origin were provided.
以海洋微生物Pseudoalteromons sp.NJ632作为研究对象,运用Genome-walking策略对已获得KS片段的上、下游区域进行了部分的步移得到了一段约为10 Kb大小的连续的核苷酸序列,对其中疑似PKS的开放阅读框(ORF)进行了PKS模件中结构域的分析。结果显示,我们获得了包括ketosynthase(KS),acyltransferase(AT),dehydratase(DH),ketoreductase(KR),cyclization(Cy)在内的一个相对完整的PKS模件。在我们获得的PKS模件的结构中,除了常见的PKS相关结构域外,还发现了结构域cyclization(Cy),这在以往的报道中极少见到。这也暗示在NJ6-3-2中有可能存在一个PKS/NRPS杂合的,且结构非常特殊的杂合基因簇。
以海洋微生物Pseudoalteromons sp.NJ631作为研究对象,首次成功的构建并保存了其基因组文库,并对文库质量做了相应的鉴定,保证了文库的完整性。在此基础上,进一步用来自于其本身的酮基合酶基因(KS)制备探针,对2880个单克隆进行了杂交筛选,获得了14个阳性克隆子,分别标记为:AE1,BG2,CA1,CB6,DD12,DH5,FA11,GC10,GD7,GG4,KG10,LD8,MH9,OA5。运用“染色体步移”策略,对这14个阳性重组子上所插入的NJ6-3-1的基因组DNA片段进行简单的排序,并结合相应的酶切片段,最终确定,阳性克隆子BG2,GG4最有可能是14个阳性克隆子最外侧的两个克隆子,采用鸟枪法(Shot Gun Sequencing)对阳性克隆子BG2,GG4进行了大片段测序,获得了一条约为60 Kb的,连续的DNA序列。通过生物信息学分析,对其中所包含的20个开放阅读框(ORF)进行了逐一的功能注释。对疑似PKS或NRPS的三个ORF(ORF14,ORF15和ORF19)运用在线软件“NPRS-PKS”对其PKS或NRPS的结构域进行了预测。最终,获得了一个包括终止结构域“TE”在内的,由7个连续模件组成的,完整的,NRPS/PKS杂合生物合成基因簇,命名为“NJ631 NPRS-PKS生物合成基因簇”。运用NRPS A结构域底物特异性预测法则,我们成功的对获得的NJ631NRPS/PKS杂合生物合成基因簇中4个A结构域(A_2,A_3,A_4,A_5)进行了其各自的特异性底物的预测。结果显示,4个A结构域(A_2,A_3,A_4,A_5)各自特异性结合的氨基酸为:Glu/Gln,Ser,Ser-D,Aeo。
为了制备Pseudoalteromons sp.NJ631的NRPS-PKS基因簇中KS结构域的特异性抗体,同时也进行A结构域的底物特异性酶活检测,我们采用已商品化的pET表达系统(pET-28a)构建了分别含有KS、A1、A2、A3、A4、A5结构域的表达质粒pZPKS2、pZPA12、pZPA22、pZPA32、pZPA42、pZPA52。异源表达结果显示,我们成功的在大肠杆菌BL21(DE3)中超量表达了KS、A1、A3和A4结构域,为今后的KS结构域的特异性抗体制备和A结构域的底物特异性酶活检测提供了必要条件。
本论文从海洋生物附生微生物的分离开始,进行了其代谢产物生物活性(抗菌、细胞毒)和功能基因(PKS、NRPS)筛选以及活性菌株的分子鉴定;运用Genome-walking策略对分离得到的活性菌Pseudoalteromons sp.NJ632中的PKS模件进行了初步的研究,同时,通过文库构建、筛选、测序,采用反向遗传学的手段初步揭示了活性菌Pseudoalteromons sp.NJ631中存在一个NRPS/PKS杂合的生物合成途径,并对合成途径中的A结构域的底物特异性进行了预测:最后,对获得的“NJ631 NRPS-PKS生物合成途径”中的核心结构域进行了异源表达的尝试。这项工作不仅完善了一套进行海洋微生物活性天然产物研究的系统方法,为开发具有药用潜力的天然化合物建立模型,也为海洋微生物作为海洋活性物质的药源提供新的依据。本工作在海洋微生物活性天然产物的研究中尽管尚处于初级阶段,但在整个课题的研究中取得了实质性进展,对后续研究也起到了启发和推动的作用。
This research was focused on exploring marine natural products of medical potentiality and their origin.The studies of bioactive metabolites from marine bacteria associated with marine organisms along the coast in China were carried out. Through screening of antimicrobial and cytotoxic activities,the results showed that 42 isolates had antimicrobial activity and 12 isolates had cytotoxicity.Molecular phylogenetic analysis of marine bacteria with cytotoxicity based on 16S rRNA sequences indicated that they were belong to the genera Aerococcus,Agrobacterium, Alteromona,Bacillus,Exiguobacterium,Paracoccus,Pseudoalteromons, Rheinheimera.Furthermore,marine bacteria with cytotoxicity were also screened for PKS I and NRPS genes which could be responsible for bioactive secondary metabolites biosynthesis,4 strains having KS domain or A domain were obtained, which provide strong evidence that marine bioactive bacteria can produce natural products through PKS and NRPS pathways.
In order to further confirm the existence of PKS cluster in Pseudoalteromons sp. NJ632,genomic walking was used to amplify the flanking genomic DNA sequence to a KS sequence obtained from NJ632 by PCR amplification.A 10-kb continuous DNA sequence was obtained by five stepwise walking to upstream and downstream of KS fragment,respectively.The open reading frames(ORFs) were predicted and screened large multi-domain megasynthase involved in the biosynthesis of PKS.The results showed a relatively complete PKS module comprised of distinct core and auxiliary catalytic domains was obtained.Core catalytic domains include ketosynthase(KS) domain,acyltransferase(AT) domain,auxiliary domains include ketoreductase(KR), dehydratase(DH).Moreover,another auxiliary domain,cyclization(Cy),is also present in our gene walking sequence,which is generally present in NPRS module. For consideration of the existence of NRPS A domain also found in NJ632,it is suggested that there may exist a mixed or hybrid PKS/NRPS multienzyme system in the Pseudoalteromonas sp.NJ632,which could synthesize secondary metabolite with hydrid structure.
In order to confirm a putative NRPS/PKS gene cluster from marine sponge associated bacterium with cytotoxic activity and elucidate the gene structural information.The genomic library of marine sponge Hymeniacidon perleve associated bacterium Pseudoalteromons.sp NJ631 is constructed using pCC1FOS fosmid.The 2880 colonies from the fosmid library were screened by hybridizing with the digoxigenin(DIG)-labeled fragment of the KS domain from PCR amplification of Pseudoalteromons sp.NJ631 genomic DNA.The results showed 14 positive clones were identified and annotated AE1,BG2,CA1,CB6,DD12,DH5,FA11,GC10,GD7, GG4,KG10,LD8,MH9,OA5,respectively.To ensure that two clones we selected to sequence located both sides of these overlapping clones,additional chromosomal walking from this locus was carried out,eventually leading to two clones,BG2 and GG4 located both sides of all of positive clones.The genome of clones BG2 and GG4 were sequenced using genome shotgun method.According to analysis of sequence,a 60-kb continuous DNA region covered by overlapping fosmids BG2 and GG4 was obtained.The ORF and BlastX analysis of this large DNA fragment indicated that there are three big ORFs,ORF14,ORF15和ORF19,encoding proteins with similarities to amino acid adenylation,beta-ketoacyl synthase,and nonribosomal peptide synthase,respectively,from different organisms.The results gave us a clue there could be PKS or NRPS modules in three ORFs.Further analysis demonstrates three ORFs encoding two NPRS modules,one PKS modules and three NRPS modules.Finally,a NRPS/PKS gene cluster annotated "NJ631 NPRS-PKS" and containing seven modules was obtained.Using the specificity-conferring selection rule,the substrate specificity of four A(A_2,A_3,A_4,A_5) domains were successfully predicted,and the amino acids of the substrate specificity were Glu/Gln,Ser,Ser-D, Aeo,respectively.
To raise ployclonal antibodies using KS protein produced in E.coli as antigen and test the substrate specificity of A domains from NJ631 NRPS-PKS cluster,a series of expression vector,pZPKS2、pZPA12、pZPA22、pZPA32、pZPA42、pZPA52, containing KS、A1、A2、A3、A4、A5 domains were successfully constructed using pET system(pET-28a),respectively.The expression of the target DNA was induced by the addition of 1 mM IPTG to the bacterial culture.The results showed KS、A1、A3 and A4 domains were over expressed in E.coli,successfully,which provide strong foundation for raising ployclonal antibodies using KS protein and testing the substrate specificity of A domains.
This study was started with isolation of marine bacteria associated with marine organisms,continued with bioactive(antibacteria and cytotoxicity) and functional genes(PKS and NRPS) screening and bacteria identification.Then,the bacterium with bioactivity,Pseudoalteromons sp.NJ632,was further confirmed the existence of PKS cluster using genomic walking.At the same time,a NRPS/PKS gene cluster annotated "NJ631 NPRS-PKS" and containing seven modules was obtained in Pseudoalteromons sp.NJ631 using a series of methods containing the construction of genomic DNA library,screening,analysis.Finally,core domains contianing KS and A domain in NRPS/PKS gene cluster of Pseudoalteromons sp.NJ631 were tried to express in E.coli.Through these works,the integrated approach to explore the potential of marine bacteria for the production of bioactive metabolites was established and some new evidences of marine microorganisms as medical origin were provided.
引文
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