抗生素糖基转移酶系统发育及催化机理分析
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摘要
糖基化反应是由糖基转移酶催化完成的,它对于抗生素等生物次级代谢产物发挥其生物活性有着十分重要的影响。在一些有着特殊性质的抗生素糖基转移酶(AGt)的催化下,各种初级代谢中不常见的脱氧糖基被连接到抗生素糖苷配基上,使其能够很好地发挥生物功能。本文对目前收集到的所有AGt氨基酸序列进行全面细致的相似性搜索,并利用邻接法、最大似然法和Bayesian法对GT-1成员进行系统发育分析。构建的系统发育树显示,多烯大环内酯AGt与其它聚酮AGt存在比较明显的进化差异,却更接近一些真核来源的糖基转移酶,结合多种序列分析手段推测其可能是来自真核的水平基因转移的产物。以上结论同时得到了基于结构数据的系统发育分析结果的支持。蛋白三维结构的比对揭示了Gtf-蛋白与MurG蛋白之间存在的进化关联,后者是一种参与细菌细胞壁形成的重要糖基转移酶。根据Gtf-蛋白系统发育分析结果,整个糖肽类抗生素生物合成基因簇之间的进化关系也得到了推测。另一方面,基于以结构比对为基础的氨基酸序列比对结果,本文对多个糖基转移酶中结构同源位点的氨基酸残基的功能进行分析,并对其作用机理进行推测。此外,考虑到聚酮AGt与Gtf-蛋白都是GT-1成员,且这两种抗生素糖苷配基合成模式十分相似的事实,文中提出了AGt与其糖苷配基合成酶之间可能存在进化关联的观点。文中也对非GT-1 AGt进行了简单分类,并对其进化来源进行了探讨,分析结果显示它们的祖先蛋白很可能来自各种初级代谢所需的蛋白。
Catalyzed by a family of enzymes called glycosyltransferases, glycosylation reactions are essential for the bioactivities of secondary metabolites such as antibiotics. Due to the special characters of antibiotic glycosyltransferases (AGts), antibiotics can function by attaching some unusual deoxy-sugars to their aglycons. Comprehensive similarity searches on the amino acid sequences of AGts have been performed. This paper reconstructed the molecular phylogeny of AGts with neighbor-joining, maximum-likelihood and Bayesian methods of phylogenetic inference. The phylogenetic trees show a distinct separation of polyene macrolide (PEM) AGts and other polyketide AGts. The former are more like eukaryotic glycosyltransferases and were deduced to be the results of horizontal gene transfer (HGT) from eukaryotes. This conclusion was also supported by structure-based phylogenetic analysis. Protein tertiary structural comparison indicated that some glycopeptide AGts (Gtf-proteins) have a close evolutionary relationship with MurGs, essential glycosyltransferases involved in maturation of bacterial cell walls. The evolutionary relationship of glycopeptide antibiotic biosynthetic gene clusters was speculated according to the phylogenetic analysis of Gtf-proteins. Based on the structural alignment of glycosyltransferases, the structurally homologous sites were detected, whose biological functions were also presumed. Considering the fact that polyketide AGts and Gtf-proteins are all GT-1 members and their aglycon acceptor biosynthetic patterns are very similar, this paper deduced that AGts and the synthases of their aglycon acceptors have some evolutionary relevancy. Finally, the evolutionary origins of AGts that do not fall under GT-1 (non-GT1 AGts) were discussed, suggesting that their ancestral proteins appear to be derived from various proteins responsible for primary metabolisms.
Catalyzed by a family of enzymes called glycosyltransferases, glycosylation reactions are essential for the bioactivities of secondary metabolites such as antibiotics. Due to the special characters of antibiotic glycosyltransferases (AGts), antibiotics can function by attaching some unusual deoxy-sugars to their aglycons. Comprehensive similarity searches on the amino acid sequences of AGts have been performed. This paper reconstructed the molecular phylogeny of AGts with neighbor-joining, maximum-likelihood and Bayesian methods of phylogenetic inference. The phylogenetic trees show a distinct separation of polyene macrolide (PEM) AGts and other polyketide AGts. The former are more like eukaryotic glycosyltransferases and were deduced to be the results of horizontal gene transfer (HGT) from eukaryotes. This conclusion was also supported by structure-based phylogenetic analysis. Protein tertiary structural comparison indicated that some glycopeptide AGts (Gtf-proteins) have a close evolutionary relationship with MurGs, essential glycosyltransferases involved in maturation of bacterial cell walls. The evolutionary relationship of glycopeptide antibiotic biosynthetic gene clusters was speculated according to the phylogenetic analysis of Gtf-proteins. Based on the structural alignment of glycosyltransferases, the structurally homologous sites were detected, whose biological functions were also presumed. Considering the fact that polyketide AGts and Gtf-proteins are all GT-1 members and their aglycon acceptor biosynthetic patterns are very similar, this paper deduced that AGts and the synthases of their aglycon acceptors have some evolutionary relevancy. Finally, the evolutionary origins of AGts that do not fall under GT-1 (non-GT1 AGts) were discussed, suggesting that their ancestral proteins appear to be derived from various proteins responsible for primary metabolisms.
引文
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