抗真菌活性水稻内生菌的筛选及美达霉素生物合成中糖基化机制研究
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摘要
微生物资源(无论是菌体本身还是其活性代谢产物)在农、林、医、药等各行业都有重要的利用价值,筛选更有应用价值的微生物资源或研究其天然代谢产物的生物合成途径是当今微生物资源开发利用的两大重要研究领域。在农业生防方面,选择更多、更好、性能稳定的、对寄主安全的、能作为外源基因载体的内生菌一直是生防工作者奋斗的目标；而作为有应用价值的抗生素类化合物,研究其合成代谢机制则是进行抗生素结构和活性优化的基础,展开这两方面的研究具有重要的现实意义。
该文从两个方面展开了研究工作：(一)以开发生防内生菌为目的,分离到一株对多种农业病原真菌有抑制作用的水稻内生细菌CHM-1 (Bacillus licheniformis CHM-1),对其分类地位、抑菌活性、内生定殖、防病效果与寄主的关系进行了研究；(二)对链霉菌AM-7161 (Streptomyces sp. AM-7161)产生的芳香聚酮类抗生素美达霉素(Medermycin)生物合成途径的糖基化现象从分子水平上进行研究。具体工作内容如下：
(一)具有抑制植物病原真菌活性的水稻内生细菌分离及相关性质研究：
(1)在多年水稻和油菜轮作的田块取样,分离多株内生细菌,筛选出对几种重要的植物病原真菌抑制活性最强的CHM-1菌株；
(2)通过离体、活体的植物病原真菌抑制作用的测定,初步探讨了该菌株对几种植物病原真菌的抑制作用及作用机理,并进行了对玉米小斑病(Bipolaris.maydis)、水稻纹枯病(Rhizoctonia solani)活体防效测定,发现CHM-1菌株对玉米小斑病和水稻纹枯病的防治效果分别为70.22%、62.79%；
(3)从形态学特征、生理生化反应、代谢类型、分子生物学等各个水平对CHM-1进行了分类鉴定,初步鉴定为一株解淀粉芽孢杆菌(Bacillus licheniformis CHM-1);
(4)为了将其作为候选的生防菌株开发利用,本文利用双抗标记法研究CHM-1在水稻和油菜内的定殖作用,发现其在水稻和油菜内的定殖不仅不会给两种作物带来危害,反而对其具有明显的促生作用。
(二)聚酮抗生素美达霉素生物合成途径中糖基化修饰的研究：
(1)通过同源性分析确定：链霉菌AM-7161的美达霉素生物合成基因簇中存在6个与脱氧六碳糖合成相关的糖基合成酶基因(med-ORF14、15、16、17、19、20)以及一个与C—糖基转移酶基因同源的基因med-OKF8。推测这7个基因完成美达霉素结构中安哥拉糖胺的合成以及C—糖苷键的形成：
(2)通过构建这7个基因的共表达系统,在宿主天蓝色链霉菌B135 (Streptomyces coelicolorB135)提供糖基受体的情况下,进行共表达系统的异源表达,或在一个通用天蓝色链霉菌细胞((Streptomyces coelicolor CH999)中进行异源表达,同时与产生糖基供体的菌株B135进行共培养(即单菌株培养或双菌株共培养),并通过LC/MS检测发酵产物,发现这7个基因的共表达可以导致聚酮糖基受体(由宿主体内积累的或共培养体系中另一个菌株提供)转化成带有糖基的结构,说明这7个基因共同参与脱氧糖胺的合成和转移过程；
(3)利用PCR-Targeting介导的链霉菌基因突变操作系统(RedirectTM)将med-OKF8从美达霉素完整的生物合成基因簇中敲掉,获得了突变基因簇,进行异源表达,获得突变菌株；然后再克隆med-OKF8连接到链霉菌表达型载体上,经过原生质体转化导入突变基因簇异源表达细胞,获得回补菌株。通过LC/MS产物分析野生型菌株、突变菌株及互补菌株的发酵产物,发现在med-ORF8敲掉的突变株中确实没有美达霉素的产生,而在回补菌株中,又检测出了美达霉素的存在,这说明med-ORF8在美达霉素的C-糖基化过程中是必不可少的基因：
(4)本文构建了五个有关,ned-ORF8基因的原核表达体系,从中筛选出了最优化的表达体系,并进行了诱导条件的探索,确定了med-ORF8高效可溶性表达的体系和诱导条件,这为下一步弄清楚,ned-ORF8的底物识别特异性以及酶学性质研究奠定基础。
Many microorganisms with biological activity against pathogenic organisms could accumulate a vast number of bioactive compounds with structural and functional diversity. Isolation of more new microbes with potential application in crop protection and clinical therapy and elucidation of biosynthetic mechanism of bioactive natural products have been of great interest.
The present study focused on two aspects:firstly, in order to get more microbes possessing the powerful characteristics such as stability, high effect and safety to hosts when used to control fungal diseases on crops, an endophytic bacteria from the rice with strong antifungal activity was screened and identified, and its colonized action and effect on the hosts were also studied; Secondly, in order to elucidate the mechanism of C-glycosylation of an aromatic antibiotic medermycin with antibacterial and antitumor activity, the function of several medermycin biosynthetic genes related to C-glycosylation was investigated:
1.Here, several endophytic bacterial strains were isolated from the field rotated by rice and cole for many years.Among the isolated strains, CHM-1 was found to have the highest antifungal activity. The inhibitory effect of CHM-1 and its action mechanism on several kinds of plant pathogenic fungi were investigated by in vivo and in vitro tests, and the control efficacy was also determined against Bipolaris maydis and Rhizoctonia solani in vitro. On the basis of the comprehensive taxonomic data from morphological, physiological and biochemical characteristics, and 16S rDNA sequence analysis, CHM-1 was identified to be Bacillus licheniformis. In order to develop CHM-1 as a candidate for biocontrol in agriculture, the colonized action of this isolate was further probed in rice and cole by double-resistance tag. The results showed that CHM-1 has no any harm to the investigated plant hosts, and promotes strongly the growth of hosts.
2.In the biosynthetic gene cluster of medermycin, there are six genes (med-ORF14,15,16,17, 19,20) proposed to encode glycosylsynthases and one C-glycosyltransferase-homologous gene med-ORF8,which are proposed for the glycosyl-synthesis and-transferring of a novel angolasamine during medermycin biosynthesis. A multigene coexpression system containing 7 genes as above was introduced into a streptomyces host which could offer a sugar acceptor. The LC/MS analysis on the resultant metabolites revealed that this coexpression system could covert the sugar acceptor into a glycosylated structure.Knock out and complementation experiments of med-ORF8 using PCR-Targeting RedirectTM technology indicated that med-ORF8 is an indispensable gene in the process of C-glycosylation of medermycin. But substrate specificity and enzymatic properties of Med-ORF8 remains obscured. Therefore, in order to obtain Med-ORF8 protein enough for further enzymatic characterization in vitro, several prokaryotic expression systems concerned with med-ORF8 gene were established, then an optimized system was screened to express efficiently soluble Med-ORF8 protein.
该文从两个方面展开了研究工作：(一)以开发生防内生菌为目的,分离到一株对多种农业病原真菌有抑制作用的水稻内生细菌CHM-1 (Bacillus licheniformis CHM-1),对其分类地位、抑菌活性、内生定殖、防病效果与寄主的关系进行了研究；(二)对链霉菌AM-7161 (Streptomyces sp. AM-7161)产生的芳香聚酮类抗生素美达霉素(Medermycin)生物合成途径的糖基化现象从分子水平上进行研究。具体工作内容如下：
(一)具有抑制植物病原真菌活性的水稻内生细菌分离及相关性质研究：
(1)在多年水稻和油菜轮作的田块取样,分离多株内生细菌,筛选出对几种重要的植物病原真菌抑制活性最强的CHM-1菌株；
(2)通过离体、活体的植物病原真菌抑制作用的测定,初步探讨了该菌株对几种植物病原真菌的抑制作用及作用机理,并进行了对玉米小斑病(Bipolaris.maydis)、水稻纹枯病(Rhizoctonia solani)活体防效测定,发现CHM-1菌株对玉米小斑病和水稻纹枯病的防治效果分别为70.22%、62.79%；
(3)从形态学特征、生理生化反应、代谢类型、分子生物学等各个水平对CHM-1进行了分类鉴定,初步鉴定为一株解淀粉芽孢杆菌(Bacillus licheniformis CHM-1);
(4)为了将其作为候选的生防菌株开发利用,本文利用双抗标记法研究CHM-1在水稻和油菜内的定殖作用,发现其在水稻和油菜内的定殖不仅不会给两种作物带来危害,反而对其具有明显的促生作用。
(二)聚酮抗生素美达霉素生物合成途径中糖基化修饰的研究：
(1)通过同源性分析确定：链霉菌AM-7161的美达霉素生物合成基因簇中存在6个与脱氧六碳糖合成相关的糖基合成酶基因(med-ORF14、15、16、17、19、20)以及一个与C—糖基转移酶基因同源的基因med-OKF8。推测这7个基因完成美达霉素结构中安哥拉糖胺的合成以及C—糖苷键的形成：
(2)通过构建这7个基因的共表达系统,在宿主天蓝色链霉菌B135 (Streptomyces coelicolorB135)提供糖基受体的情况下,进行共表达系统的异源表达,或在一个通用天蓝色链霉菌细胞((Streptomyces coelicolor CH999)中进行异源表达,同时与产生糖基供体的菌株B135进行共培养(即单菌株培养或双菌株共培养),并通过LC/MS检测发酵产物,发现这7个基因的共表达可以导致聚酮糖基受体(由宿主体内积累的或共培养体系中另一个菌株提供)转化成带有糖基的结构,说明这7个基因共同参与脱氧糖胺的合成和转移过程；
(3)利用PCR-Targeting介导的链霉菌基因突变操作系统(RedirectTM)将med-OKF8从美达霉素完整的生物合成基因簇中敲掉,获得了突变基因簇,进行异源表达,获得突变菌株；然后再克隆med-OKF8连接到链霉菌表达型载体上,经过原生质体转化导入突变基因簇异源表达细胞,获得回补菌株。通过LC/MS产物分析野生型菌株、突变菌株及互补菌株的发酵产物,发现在med-ORF8敲掉的突变株中确实没有美达霉素的产生,而在回补菌株中,又检测出了美达霉素的存在,这说明med-ORF8在美达霉素的C-糖基化过程中是必不可少的基因：
(4)本文构建了五个有关,ned-ORF8基因的原核表达体系,从中筛选出了最优化的表达体系,并进行了诱导条件的探索,确定了med-ORF8高效可溶性表达的体系和诱导条件,这为下一步弄清楚,ned-ORF8的底物识别特异性以及酶学性质研究奠定基础。
Many microorganisms with biological activity against pathogenic organisms could accumulate a vast number of bioactive compounds with structural and functional diversity. Isolation of more new microbes with potential application in crop protection and clinical therapy and elucidation of biosynthetic mechanism of bioactive natural products have been of great interest.
The present study focused on two aspects:firstly, in order to get more microbes possessing the powerful characteristics such as stability, high effect and safety to hosts when used to control fungal diseases on crops, an endophytic bacteria from the rice with strong antifungal activity was screened and identified, and its colonized action and effect on the hosts were also studied; Secondly, in order to elucidate the mechanism of C-glycosylation of an aromatic antibiotic medermycin with antibacterial and antitumor activity, the function of several medermycin biosynthetic genes related to C-glycosylation was investigated:
1.Here, several endophytic bacterial strains were isolated from the field rotated by rice and cole for many years.Among the isolated strains, CHM-1 was found to have the highest antifungal activity. The inhibitory effect of CHM-1 and its action mechanism on several kinds of plant pathogenic fungi were investigated by in vivo and in vitro tests, and the control efficacy was also determined against Bipolaris maydis and Rhizoctonia solani in vitro. On the basis of the comprehensive taxonomic data from morphological, physiological and biochemical characteristics, and 16S rDNA sequence analysis, CHM-1 was identified to be Bacillus licheniformis. In order to develop CHM-1 as a candidate for biocontrol in agriculture, the colonized action of this isolate was further probed in rice and cole by double-resistance tag. The results showed that CHM-1 has no any harm to the investigated plant hosts, and promotes strongly the growth of hosts.
2.In the biosynthetic gene cluster of medermycin, there are six genes (med-ORF14,15,16,17, 19,20) proposed to encode glycosylsynthases and one C-glycosyltransferase-homologous gene med-ORF8,which are proposed for the glycosyl-synthesis and-transferring of a novel angolasamine during medermycin biosynthesis. A multigene coexpression system containing 7 genes as above was introduced into a streptomyces host which could offer a sugar acceptor. The LC/MS analysis on the resultant metabolites revealed that this coexpression system could covert the sugar acceptor into a glycosylated structure.Knock out and complementation experiments of med-ORF8 using PCR-Targeting RedirectTM technology indicated that med-ORF8 is an indispensable gene in the process of C-glycosylation of medermycin. But substrate specificity and enzymatic properties of Med-ORF8 remains obscured. Therefore, in order to obtain Med-ORF8 protein enough for further enzymatic characterization in vitro, several prokaryotic expression systems concerned with med-ORF8 gene were established, then an optimized system was screened to express efficiently soluble Med-ORF8 protein.
引文
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