Donadio Stefano, Sosio Margherita, Stegmann Evi, Weber Tilmann, Wohlleben Wolfgang
Vicuron Pharmaceuticals, 21040 Gerenzano, Italy.
Mol Genet Genomics. 2005 Aug;274(1):40-50. doi: 10.1007/s00438-005-1156-3. Epub 2005 Jul 9.
The bal, cep, dbv, sta and tcp gene clusters specify the biosynthesis of the glycopeptide antibiotics balhimycin, chloroeremomycin, A40926, A47934 and teicoplanin, respectively. These structurally related compounds share a similar mechanism of action in their inhibition of bacterial cell wall formation. Comparative sequence analysis was performed on the five gene clusters. Extensive conserved synteny was observed between the bal and cep clusters, which direct the synthesis of very similar compounds but originate from two different species of the genus Amycolatopsis. All other cluster pairs show a limited degree of conserved synteny, involving biosynthetically functional gene cassettes: these include those involved in the synthesis of the carbon backbone of two non-proteinogenic amino acids; in the linkage of amino acids 1--3 and 4--7 in the heptapeptide; and in the formation of the aromatic cross-links. Furthermore, these segments of conserved synteny are often preceded by conserved intergenic regions. Phylogenetic analysis of protein families shows several instances in which relatedness in the chemical structure of the glycopeptides is not reflected in the extent of the relationship of the corresponding polypeptides. Coherent branchings are observed for all polypeptides encoded by the syntenous gene cassettes. These results suggest that the acquisition of distinct, functional genetic elements has played a significant role in the evolution of glycopeptide gene clusters, giving them a mosaic structure. In addition, the synthesis of the structurally similar compounds A40926 and teicoplanin appears as the result of convergent evolution.
bal、cep、dbv、sta和tcp基因簇分别负责糖肽抗生素巴龙霉素、氯埃博霉素、A40926、A47934和替考拉宁的生物合成。这些结构相关的化合物在抑制细菌细胞壁形成方面具有相似的作用机制。对这五个基因簇进行了比较序列分析。在bal和cep基因簇之间观察到广泛的保守同线性，它们指导合成非常相似的化合物，但起源于不同的枝顶孢属物种。所有其他基因簇对显示出有限程度的保守同线性，涉及生物合成功能基因盒：这些包括参与两种非蛋白质氨基酸碳骨架合成的基因盒；参与七肽中氨基酸1-3和4-7连接的基因盒；以及参与芳香族交联形成的基因盒。此外，这些保守同线性片段之前通常有保守的基因间区域。蛋白质家族的系统发育分析表明，在几个实例中，糖肽化学结构的相关性并未反映在相应多肽的关系程度上。对于由同线性基因盒编码的所有多肽都观察到了连贯的分支。这些结果表明，独特的功能性遗传元件的获得在糖肽基因簇的进化中发挥了重要作用，使其具有镶嵌结构。此外，结构相似的化合物A40926和替考拉宁的合成似乎是趋同进化的结果。
