链霉菌胞外多糖139A生物合成基因簇克隆和鉴定的研究
摘要
链霉菌Streptomces 139能够分泌一种新型胞外多糖139A，该多糖由半乳糖、阿拉伯糖、甘露糖、岩藻糖、木糖、鼠李糖、半乳糖醛酸和葡萄糖以克分子数比19∶16∶5.0∶5.0∶4.0∶3.0∶3.0∶2.0组成，其重复单元的结构已经确定。经药效学研究表明该多糖具有明显的抗类风湿性关节炎的作用且毒性极低，可能发展为临床应用的全新药物。为了通过组合生物学途径获得139A的各种新型衍生物以进一步提高药效和产量，因此对其生物合成基因簇进行了深入研究。
尽管微生物胞外多糖(EPS)表现出很少的共同特性，但由重复单元组成的多糖的生物合成途径基本相同，甚至和脂多糖(LPS)的O-抗原以及一些荚膜多糖(CPS)的生物合成途径也很相似，即通过糖基转移酶将单糖从核苷酸糖顺序性转移而装配到脂类载体上形成重复单元，随后是这些重复单元的聚合和输出，形成细胞表面多糖。近年来已从G~+和G~-分离鉴定出多个EPS生物合成基因簇，这些基因簇的组成相似，都包括参与调控、核苷酸糖前体的合成、糖基转移、聚合和输出、修饰等功能的基因。
为研究多糖139A的生物合成，首要策略是克隆多糖139A生物合成途径中最为关键的基因，即催化第一步糖基转移反应的引导糖基转移酶基因。首先，我们以大肠杆菌-链霉菌穿梭cosmid pOJ446为载体，构建了Streptomces 139的基因组文库。我们根据其他几个微生物种属的已知引导糖基转移酶氨基酸序列的两个保守区域，结合链霉菌密码子使用偏向性设计出简并引物，用PCR方法从Streptomces 139总DNA扩增到一大小约为300bp的DNA片段，序列分析发现其蛋白序列与引导糖基转移酶具有较高的同源性，并含有A、B和C 3个保守区，表明它是引导糖基转移酶基因的一部分。以PCR产物为探针筛选基因组文库，共得到27个阳性转化子，Southern杂交结果证明其中17个重组cosmids都含有4.0kb的阳性条带。重组cosmids经酶切、电泳、拼接，结果表明我们克隆了Streptomces 139的染色体上大约65kb的区域，并且引导糖基转移酶基因(ste 5)被定位在一条4.0kb BamHI片段上。
从17个阳性克隆中选择引导糖基转移酶基因居中的pLY501进行DNA测序，总共大小为31.3kb(GenBank登录号为：AY131229)，它们的G+C含量高达73％并且密码子第
Streptomyces 139 has been identified to produce a new exopolysaccharide designated EPS 139A that shows anti-rheumatic arthritis activity remarkable in vivo. Qualitative and quantitative sugar analysis showed that the EPS 139A consisted of galactose, arabinose, mannose, fucose, xylose, rhamnose, galacturonic acid and glucose with a molar ratio of 19:16:5.0:5.0:4.0:3.0:3.0:2.0. It is possible that 139 A could be developed to be a new drug in the future. For increasing yield and modification the structure of 139 A with the combinatorial biosynthetic pathway, study of biosynthesis gene cluster for 139 A has been carried out.
In recent years, several EPS gene clusters have been identified in Gram-positive and Gram-negative bacteria. Genes involved in regulation, nucleotide sugar precursor synthesis, glycosyl transfer, polymerization and export are found in EPS gene clusters. These clusters constitute complex machinery with the biosynthesis of LPSs or CPSs. The repeating polysaccharide units are assembled at a phosphorylated lipid carrier by glycosyltransferases, subsequently polymerized to be a high molecular weight EPS and exported to the cell surface.
The strategy of studying EPS 139A biosynthesis is to clone the key gene in the EPS biosynthesis pathway, i.e. the priming glycosyltransferase gene catalyzing the first step of nucleotide sugar transfer. According to the homologous regions of several identified priming glycosyltransferases and taking into account information on Streptomyces codon usage degenerate primers were designed. A distinctive PCR product with the expected size of 0.3 kb was amplified from Streptomyces 139 total genomic DNA. Sequence analysis showed that it is a part of the putative priming glycosyltransferase gene and contains the predicted conserved domain A, B and C. To isolate the EPS 139A gene cluster, a Streptomyces 139 genomic library was constructed with the E. coli-Streptomyces shuttle vector pOJ446. A Streptomyces 139 genomic library was screened by colony hybridization with the PCR-amplified 0.3 kb fragment as a probe, 17 positive colonies were isolated, and the the ste gene cluster for exopolysaccharide biosynthesis in approximately 65 kb chromosomal region of Streptomyces 139 were localized.
尽管微生物胞外多糖(EPS)表现出很少的共同特性，但由重复单元组成的多糖的生物合成途径基本相同，甚至和脂多糖(LPS)的O-抗原以及一些荚膜多糖(CPS)的生物合成途径也很相似，即通过糖基转移酶将单糖从核苷酸糖顺序性转移而装配到脂类载体上形成重复单元，随后是这些重复单元的聚合和输出，形成细胞表面多糖。近年来已从G~+和G~-分离鉴定出多个EPS生物合成基因簇，这些基因簇的组成相似，都包括参与调控、核苷酸糖前体的合成、糖基转移、聚合和输出、修饰等功能的基因。
为研究多糖139A的生物合成，首要策略是克隆多糖139A生物合成途径中最为关键的基因，即催化第一步糖基转移反应的引导糖基转移酶基因。首先，我们以大肠杆菌-链霉菌穿梭cosmid pOJ446为载体，构建了Streptomces 139的基因组文库。我们根据其他几个微生物种属的已知引导糖基转移酶氨基酸序列的两个保守区域，结合链霉菌密码子使用偏向性设计出简并引物，用PCR方法从Streptomces 139总DNA扩增到一大小约为300bp的DNA片段，序列分析发现其蛋白序列与引导糖基转移酶具有较高的同源性，并含有A、B和C 3个保守区，表明它是引导糖基转移酶基因的一部分。以PCR产物为探针筛选基因组文库，共得到27个阳性转化子，Southern杂交结果证明其中17个重组cosmids都含有4.0kb的阳性条带。重组cosmids经酶切、电泳、拼接，结果表明我们克隆了Streptomces 139的染色体上大约65kb的区域，并且引导糖基转移酶基因(ste 5)被定位在一条4.0kb BamHI片段上。
从17个阳性克隆中选择引导糖基转移酶基因居中的pLY501进行DNA测序，总共大小为31.3kb(GenBank登录号为：AY131229)，它们的G+C含量高达73％并且密码子第
Streptomyces 139 has been identified to produce a new exopolysaccharide designated EPS 139A that shows anti-rheumatic arthritis activity remarkable in vivo. Qualitative and quantitative sugar analysis showed that the EPS 139A consisted of galactose, arabinose, mannose, fucose, xylose, rhamnose, galacturonic acid and glucose with a molar ratio of 19:16:5.0:5.0:4.0:3.0:3.0:2.0. It is possible that 139 A could be developed to be a new drug in the future. For increasing yield and modification the structure of 139 A with the combinatorial biosynthetic pathway, study of biosynthesis gene cluster for 139 A has been carried out.
In recent years, several EPS gene clusters have been identified in Gram-positive and Gram-negative bacteria. Genes involved in regulation, nucleotide sugar precursor synthesis, glycosyl transfer, polymerization and export are found in EPS gene clusters. These clusters constitute complex machinery with the biosynthesis of LPSs or CPSs. The repeating polysaccharide units are assembled at a phosphorylated lipid carrier by glycosyltransferases, subsequently polymerized to be a high molecular weight EPS and exported to the cell surface.
The strategy of studying EPS 139A biosynthesis is to clone the key gene in the EPS biosynthesis pathway, i.e. the priming glycosyltransferase gene catalyzing the first step of nucleotide sugar transfer. According to the homologous regions of several identified priming glycosyltransferases and taking into account information on Streptomyces codon usage degenerate primers were designed. A distinctive PCR product with the expected size of 0.3 kb was amplified from Streptomyces 139 total genomic DNA. Sequence analysis showed that it is a part of the putative priming glycosyltransferase gene and contains the predicted conserved domain A, B and C. To isolate the EPS 139A gene cluster, a Streptomyces 139 genomic library was constructed with the E. coli-Streptomyces shuttle vector pOJ446. A Streptomyces 139 genomic library was screened by colony hybridization with the PCR-amplified 0.3 kb fragment as a probe, 17 positive colonies were isolated, and the the ste gene cluster for exopolysaccharide biosynthesis in approximately 65 kb chromosomal region of Streptomyces 139 were localized.
引文
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