链霉菌LZ35菌株中沉默新安莎基因簇的激活和hygrocin生物合成研究
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摘要
耐药病原微生物和各种新型传染病的不断出现,迫使人们不断寻求新的药物。天然产物一直是新药发现的源泉,其中放线菌尤其是链霉菌产生的次级代谢产物是抗生素和其它药物的主要来源。基因组测序数据显示微生物中含有大量的次级代谢基因簇,其编码次级代谢产物的合成潜力远超过已发现代谢产物的数量,其中大部分次级代谢基因簇是沉默或低表达的,基因组挖掘的方法是发现这些基因簇代谢产物的有力工具。安莎霉素是一类主要由放线菌产生的结构独特的大环内酰胺类抗生素,具有显著的生物活性,如抗菌、抗肿瘤和酶抑制剂等。在后基因组时代,通过基因组挖掘发现微生物中新颖安莎代谢产物,为新药研究提供先导化合物,对新药创制具有重要意义。
本学位论文研究通过全基因组测序和生物信息学分析,从链霉菌LZ35菌株中发现3个安莎基因簇,包括安莎化合物geldanamycin生物合成基因簇(gdm)和hygrocin生物合成基因簇(hgc),以及一个结构未知的新安莎基因簇(nam)。分析nam生物合成基因簇,其可能编码一个新型8酮萘安莎化合物。在实验室条件下,优化发酵条件未能分离得到这一安莎化合物,推测nam基因簇是沉默的或其表达量低于检测限。我们采用了3条途径尝试激活这个沉默安莎基因簇表达：(1)在聚酮合酶基因前插入组成型表达ermEp*启动子,RT-PCR分析显示部分激活了基因簇表达,分离得到一个中间体4酮化合物。(2)分别敲除nam基因簇中TetR家族负调控因子,HPLC分析突变株发酵产物,与野生型相比未发现明显的代谢谱变化。(3)通过组成型过表达基因簇中LuxR家族调控因子Naml,全面激活了nam基因簇的表达,得到基因簇的编码产物neoansamycins。生物活性测定显示neoansamycin A对HeLa和HepG-2细胞的ICso均为10μM,具有中等的抗肿瘤活性。Neoansamycins生物合成中含有乙基丙二酰辅酶A和戊基丙二酰辅酶A两种不常见的延伸单元,阻断nam8基因终止了neoansamycins的产生,表明nam8基因可能与戊基丙二酰辅酶A的合成相关。基因nam7与rifemycin生物合成基因簇中rif-orf19同源,可能参与萘环的形成,阻断nam7基因终止了neoansamycins的产生,积累了一个可能是苯安莎的中间代谢产物。
Hygrocins是LZ35菌株产生的另一类萘安莎化合物,其生物合成机制尚未见报道。我们通过序列分析在基因组上定位了其生物合成基因簇,通过阻断hgcA基因进行了确认。对hgc基因簇开展了以下几方面的工作：(1)前体AHBA及乙基延伸单元的合成。表明hygrocin生物合成和其它次级代谢产物途径存在前体共享性,与geldanamycin生物合成途径共用起始单元AHBA,与其它生物合成途径共用延伸单元乙基丙二酰辅酶A。(2)酰胺合酶的功能验证。酰胺合酶是安莎类化合物特有的聚酮链释放和环化酶,在hgcF基因敲除突变株中分别回补其它安莎基因簇来源的酰胺合酶基因,结果ansalactam和divergolides基因簇的酰胺合酶可以环化hygrocin生物合成聚酮链,并产生新的hygrocin衍生物。(3)氧化后修饰基因功能的研究。通过对hgc基因簇中7个氧化还原酶基因敲除,确定了hgc2、hgc3和hgc4与hygrocin的生物合成相关。基因rif-orf19交叉回补实验,表明羟基化酶Hgc2可能参与hygrocin萘环形成；单氧化酶Hgc3可能通过Baeyer-Villiger氧化反应催化hygrocin C5/C6位的氧化断裂；P450氧化酶Hgc4负责催化hygrocin C7位的羟基化反应。(4) hygrocin生物合成调控的研究。通过基因敲除、回补及组成型过表达LAL家族调控基因hgcl,证明Hgc1是hygrocin生物合成途径的正调控因子。
综上,本学位论文研究通过基因组挖掘策略,从链霉菌LZ35菌株中发现了一类新骨架的安莎类化合物neoansamycins,一方面证明了由基因序列指导天然产物发现研究策略的可行性和有效性；另一方面证实了自然界微生物中还存在许多新骨架安莎的猜想。对hygrocins的生物合成研究,加深了我们对安莎生物合成机制的理解,为进一步通过组合生物学和合成生物学手段,理性改造获得更优良的安莎类先导化合物提供依据。
There is a constant need for new drugs to combat the increase of resistance of pathogenic microorganisms and infectious diseases. Natural products continue to provide a diverse and unique source of bioactive lead compounds for drug discovery. Actinomycetes and especially the genus Streptomyces are the main producers of secondary metabolites. Genomics data has revealed that most of microorganisms have the potential to produce a far larger number of natural products than have been isolated previously. In search for new drugs, the genome mining approach proved to be a powerful tool in the identification of cryptic secondary metabolite pathways. Ansamycins is a family of macrocyclic lactam compounds, mainly produced by Actinomycetes. These compounds demonstrate extensive biological and pharmaceutical activities, and are used as antibiotics, anticancer gents, and enzyme inhibitors. In the post-genome era, it's significant that genome mining for novel ansamycins to offer new lead compound for drugs.
Genome sequence of Streptomyces sp.LZ35has revealed three ansamycins biosynthetic gene clusters, two of which for producing geldanamycin and hygrocin, the other for producing cryptic ansamycin compounds. According to bioinformatics analysis, the cryptic ansamycin gene cluster is related to a new octaketide naphthalenic ansamycin compounds. Initially, we failed to isolate the compound by the optimization of culture conditions, maybe in the laboratory standard conditions, the cluster is either silent or expressed at a very low level. To trigger expression of the cluster, three different strategies were adopted in this work, respectively. The first one is introduction of a constitutive promoter ermEp*into the upstream of the polyketide synthase genes, RT-PCR analysis showed that the cluster is partially activated, and leading to the production of tetraketide intermediates. The second one is knocking out the TetR family negative regulators, the resulted mutant had no discernible effect on the metabolite profile. The third one is constitutive overexpression of the luxR family regulatory gene naml, transcriptional analysis showed total activation of the silent ansamycin biosynthetic genes, and led to the identification of three novel ansamycins, named neoansamycins. Interestingly, the neoansamycin A showed IC5010μM against the growth of HeLa and HepG2cell line, respectively, exhibiting moderate anti-tumor activity. The structure of neoansamycins contains an atypical extender unit, ethylnalonyl-CoA and pentalmalonyl-CoA, inactivation of nam8terminated the generation of neoansamycin, indcated that nam8maybe involved in the biosynthesis of pentalmalonyl-CoA. Nam7is homologous to Rif-orfl9, disruption of nam7gene resulted in neoansamycin elimination and concurrent production of a putative analog, maybe a derivative of neoansamycin with a benzenic ring system.
Hygrocin is another naphthalenic ansamycin compounds produced by strain LZ35and its biosynthesis have not been reported in the literature. We analyzed the sequence of hgc gene cluster and locate it in the genome, the cluster was confirmed by disruption of hgcA leading to no hygrocin production. We carried out the following work:(1) The biosynthesis of AHBA precursor and ethyhnalonyl-CoA extendr unit. The hygrocin biosynthetic pathway shared the precursor with other secondary metabolites pathway, such as the AHBA precursor in geldanamycin gene cluster, and ethylmabnyl-CoA extendr unit in other biosynthetic pathways in strain LZ35.(2) Amide synthase functional verification. Amide synthase is a key enzyme, which is respond for ansamycin cyclization and release from the PKS. We have investigated the substrate selectivity of amide synthase. In hgcF disruption mutant, cross-complementation of amide synthase gene from other ansamycin gene cluster, only the amide synthase gene from ansalactam and divergolides can replace the hgcF to release and cyclization hygrocin derivatives.(3) The genes involved in tailoring process. To investigate the roles of oxidase gene played in the hygrocin gene cluster, seven genes were inactivated, the hgc2, hgc3, hgc4disruption mutants abolished the production of hygrocin, confirming their involvement in the hygrocin biosynthesis. Cross-complementation of rif-orfl9indicated that the Hgc2may involvement in naphthalene ring formation in biosynthesis of hygrocin. The Hgc3functions in the oxidative cleavage C5/C6of hygrocin via a Baeyer-Viliger type oxidation reaction. The Hgc4encodes a cytochrome P450hydroxylases, involved in the hydroxylation of the hygrocin polyketide moiety at C7. Gene inactivation, complementation and constitutive overexpression indicated that Hgcl is a positive regulator for hygrocin biosynthesis.
In summary, we have identified a unique novel structural class of ansamycin named neoansamycins used genome mining strategy, which demonstrated that the feasibility and effectiveness of gene cluster and pathway analysis provide important information to guide isolation of compounds specified by particular gene clusters. And it also proved that many novel structural ansamycins produced by microbiology are waiting for us to exploit. The information of biosynthesis hygrocin presented here expands our knowledge of the biosynthesis of ansamycins, and pave the way for further rational engineering new ansamycin with combinatorial biosynthesis and synthetic biology.
本学位论文研究通过全基因组测序和生物信息学分析,从链霉菌LZ35菌株中发现3个安莎基因簇,包括安莎化合物geldanamycin生物合成基因簇(gdm)和hygrocin生物合成基因簇(hgc),以及一个结构未知的新安莎基因簇(nam)。分析nam生物合成基因簇,其可能编码一个新型8酮萘安莎化合物。在实验室条件下,优化发酵条件未能分离得到这一安莎化合物,推测nam基因簇是沉默的或其表达量低于检测限。我们采用了3条途径尝试激活这个沉默安莎基因簇表达：(1)在聚酮合酶基因前插入组成型表达ermEp*启动子,RT-PCR分析显示部分激活了基因簇表达,分离得到一个中间体4酮化合物。(2)分别敲除nam基因簇中TetR家族负调控因子,HPLC分析突变株发酵产物,与野生型相比未发现明显的代谢谱变化。(3)通过组成型过表达基因簇中LuxR家族调控因子Naml,全面激活了nam基因簇的表达,得到基因簇的编码产物neoansamycins。生物活性测定显示neoansamycin A对HeLa和HepG-2细胞的ICso均为10μM,具有中等的抗肿瘤活性。Neoansamycins生物合成中含有乙基丙二酰辅酶A和戊基丙二酰辅酶A两种不常见的延伸单元,阻断nam8基因终止了neoansamycins的产生,表明nam8基因可能与戊基丙二酰辅酶A的合成相关。基因nam7与rifemycin生物合成基因簇中rif-orf19同源,可能参与萘环的形成,阻断nam7基因终止了neoansamycins的产生,积累了一个可能是苯安莎的中间代谢产物。
Hygrocins是LZ35菌株产生的另一类萘安莎化合物,其生物合成机制尚未见报道。我们通过序列分析在基因组上定位了其生物合成基因簇,通过阻断hgcA基因进行了确认。对hgc基因簇开展了以下几方面的工作：(1)前体AHBA及乙基延伸单元的合成。表明hygrocin生物合成和其它次级代谢产物途径存在前体共享性,与geldanamycin生物合成途径共用起始单元AHBA,与其它生物合成途径共用延伸单元乙基丙二酰辅酶A。(2)酰胺合酶的功能验证。酰胺合酶是安莎类化合物特有的聚酮链释放和环化酶,在hgcF基因敲除突变株中分别回补其它安莎基因簇来源的酰胺合酶基因,结果ansalactam和divergolides基因簇的酰胺合酶可以环化hygrocin生物合成聚酮链,并产生新的hygrocin衍生物。(3)氧化后修饰基因功能的研究。通过对hgc基因簇中7个氧化还原酶基因敲除,确定了hgc2、hgc3和hgc4与hygrocin的生物合成相关。基因rif-orf19交叉回补实验,表明羟基化酶Hgc2可能参与hygrocin萘环形成；单氧化酶Hgc3可能通过Baeyer-Villiger氧化反应催化hygrocin C5/C6位的氧化断裂；P450氧化酶Hgc4负责催化hygrocin C7位的羟基化反应。(4) hygrocin生物合成调控的研究。通过基因敲除、回补及组成型过表达LAL家族调控基因hgcl,证明Hgc1是hygrocin生物合成途径的正调控因子。
综上,本学位论文研究通过基因组挖掘策略,从链霉菌LZ35菌株中发现了一类新骨架的安莎类化合物neoansamycins,一方面证明了由基因序列指导天然产物发现研究策略的可行性和有效性；另一方面证实了自然界微生物中还存在许多新骨架安莎的猜想。对hygrocins的生物合成研究,加深了我们对安莎生物合成机制的理解,为进一步通过组合生物学和合成生物学手段,理性改造获得更优良的安莎类先导化合物提供依据。
There is a constant need for new drugs to combat the increase of resistance of pathogenic microorganisms and infectious diseases. Natural products continue to provide a diverse and unique source of bioactive lead compounds for drug discovery. Actinomycetes and especially the genus Streptomyces are the main producers of secondary metabolites. Genomics data has revealed that most of microorganisms have the potential to produce a far larger number of natural products than have been isolated previously. In search for new drugs, the genome mining approach proved to be a powerful tool in the identification of cryptic secondary metabolite pathways. Ansamycins is a family of macrocyclic lactam compounds, mainly produced by Actinomycetes. These compounds demonstrate extensive biological and pharmaceutical activities, and are used as antibiotics, anticancer gents, and enzyme inhibitors. In the post-genome era, it's significant that genome mining for novel ansamycins to offer new lead compound for drugs.
Genome sequence of Streptomyces sp.LZ35has revealed three ansamycins biosynthetic gene clusters, two of which for producing geldanamycin and hygrocin, the other for producing cryptic ansamycin compounds. According to bioinformatics analysis, the cryptic ansamycin gene cluster is related to a new octaketide naphthalenic ansamycin compounds. Initially, we failed to isolate the compound by the optimization of culture conditions, maybe in the laboratory standard conditions, the cluster is either silent or expressed at a very low level. To trigger expression of the cluster, three different strategies were adopted in this work, respectively. The first one is introduction of a constitutive promoter ermEp*into the upstream of the polyketide synthase genes, RT-PCR analysis showed that the cluster is partially activated, and leading to the production of tetraketide intermediates. The second one is knocking out the TetR family negative regulators, the resulted mutant had no discernible effect on the metabolite profile. The third one is constitutive overexpression of the luxR family regulatory gene naml, transcriptional analysis showed total activation of the silent ansamycin biosynthetic genes, and led to the identification of three novel ansamycins, named neoansamycins. Interestingly, the neoansamycin A showed IC5010μM against the growth of HeLa and HepG2cell line, respectively, exhibiting moderate anti-tumor activity. The structure of neoansamycins contains an atypical extender unit, ethylnalonyl-CoA and pentalmalonyl-CoA, inactivation of nam8terminated the generation of neoansamycin, indcated that nam8maybe involved in the biosynthesis of pentalmalonyl-CoA. Nam7is homologous to Rif-orfl9, disruption of nam7gene resulted in neoansamycin elimination and concurrent production of a putative analog, maybe a derivative of neoansamycin with a benzenic ring system.
Hygrocin is another naphthalenic ansamycin compounds produced by strain LZ35and its biosynthesis have not been reported in the literature. We analyzed the sequence of hgc gene cluster and locate it in the genome, the cluster was confirmed by disruption of hgcA leading to no hygrocin production. We carried out the following work:(1) The biosynthesis of AHBA precursor and ethyhnalonyl-CoA extendr unit. The hygrocin biosynthetic pathway shared the precursor with other secondary metabolites pathway, such as the AHBA precursor in geldanamycin gene cluster, and ethylmabnyl-CoA extendr unit in other biosynthetic pathways in strain LZ35.(2) Amide synthase functional verification. Amide synthase is a key enzyme, which is respond for ansamycin cyclization and release from the PKS. We have investigated the substrate selectivity of amide synthase. In hgcF disruption mutant, cross-complementation of amide synthase gene from other ansamycin gene cluster, only the amide synthase gene from ansalactam and divergolides can replace the hgcF to release and cyclization hygrocin derivatives.(3) The genes involved in tailoring process. To investigate the roles of oxidase gene played in the hygrocin gene cluster, seven genes were inactivated, the hgc2, hgc3, hgc4disruption mutants abolished the production of hygrocin, confirming their involvement in the hygrocin biosynthesis. Cross-complementation of rif-orfl9indicated that the Hgc2may involvement in naphthalene ring formation in biosynthesis of hygrocin. The Hgc3functions in the oxidative cleavage C5/C6of hygrocin via a Baeyer-Viliger type oxidation reaction. The Hgc4encodes a cytochrome P450hydroxylases, involved in the hydroxylation of the hygrocin polyketide moiety at C7. Gene inactivation, complementation and constitutive overexpression indicated that Hgcl is a positive regulator for hygrocin biosynthesis.
In summary, we have identified a unique novel structural class of ansamycin named neoansamycins used genome mining strategy, which demonstrated that the feasibility and effectiveness of gene cluster and pathway analysis provide important information to guide isolation of compounds specified by particular gene clusters. And it also proved that many novel structural ansamycins produced by microbiology are waiting for us to exploit. The information of biosynthesis hygrocin presented here expands our knowledge of the biosynthesis of ansamycins, and pave the way for further rational engineering new ansamycin with combinatorial biosynthesis and synthetic biology.
引文
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