Chemoenzymatic design of acidic lipopeptide hybrids: new insights into the structure-activity relationship of daptomycin and A54145.
Chemoenzymatic design of acidic lipopeptide hybrids: new insights into the structure-activity relationship of daptomycin and A54145.
复制标题
DOI：
10.1021/bi0609422
复制
发表时间：
2006-08
期刊：
影响因子：
2.9
通讯作者：
F. Kopp;J. Grünewald;C. Mahlert;M. Marahiel
中科院分区：
文献类型：
--
作者：
F. Kopp;J. Grünewald;C. Mahlert;M. Marahiel
酸性脂肽，包括临床批准的抗生素达托霉素，构成一类结构相关的支链环状肽内酯和肽内酰胺，由非核糖体肽合成酶（NRPS）合成。在这项研究中，从A54145和达托霉素NRPS切下的肽环化酶被证明能够催化肽硫酯底物的大环化，肽硫酯底物是通过固相肽合成化学产生的。应用这种化学酶策略，我们产生了A54145和达托霉素的衍生物以及两种化合物的杂合分子。衍生的环状分子的生物活性测定揭示了酸性脂肽家族的结构-活性关系的新见解。几个氨基酸位置，包括两个保守的天冬氨酸残基的一般重要性，被证实是抗生素效力的实质。作为一种强有力的大环化催化剂，从A54145合成酶切下的肽环化酶是支链环状脂肽的第一个环化酶，其催化大环内酯化和大环内酰胺化。本文所呈现的结果说明了将有机合成与天然产物生物合成酶相结合以探索结构特征与生物活性之间的相互作用的优势。
The acidic lipopeptides, including the clinically approved antibiotic daptomycin, constitute a class of structurally related branched cyclic peptidolactones and peptidolactams synthesized by nonribosomal peptide synthetases (NRPSs). In this study, the excised peptide cyclases from A54145 and daptomycin NRPSs were shown to be able to catalyze the macrocyclization of peptide thioester substrates, which were chemically produced by solid phase peptide synthesis. Applying this chemoenzymatic strategy, we generated derivatives of A54145 and daptomycin as well as hybrid molecules of both compounds. Bioactivity determination of the derived cyclic molecules revealed new insights into the structure-activity relationship of the acidic lipopeptide family. The general importance of several amino acid positions, including two conserved aspartic acid residues, was confirmed to be substantial for antibiotic potency. As a robust macrocyclization catalyst, the peptide cyclase excised from A54145 synthetase is the first cyclase of a branched cyclic lipopeptide, which catalyzes both macrolactonization and macrolactamization. The results presented herein illustrate the advantages of combining organic synthesis with natural product biosynthetic enzymes to explore the interplay between structural features and biological activity.