Chemoenzymatic Design of Acidic Lipopeptide Hybrids: New Insights into the Structure-Activity Relationship of Daptomycin and A54145

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• 作者：Florian Kopp ; Jan Grü ; newald ; Christoph Mahlert ; Mohamed A. Marahiel
• 刊名：Biochemistry
• 出版年：2006
• 出版时间：September 5, 2006
• 年：2006
• 卷：45
• 期：35
• 页码：10474 - 10481
• 全文大小：1741K
• 年卷期：v.45,no.35(September 5, 2006)
• ISSN：1520-4995

文摘

The acidic lipopeptides, including the clinically approved antibiotic daptomycin, constitute aclass of structurally related branched cyclic peptidolactones and peptidolactams synthesized by nonribosomalpeptide synthetases (NRPSs). In this study, the excised peptide cyclases from A54145 and daptomycinNRPSs were shown to be able to catalyze the macrocyclization of peptide thioester substrates, whichwere chemically produced by solid phase peptide synthesis. Applying this chemoenzymatic strategy, wegenerated 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-activityrelationship 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. Asa robust macrocyclization catalyst, the peptide cyclase excised from A54145 synthetase is the first cyclaseof a branched cyclic lipopeptide, which catalyzes both macrolactonization and macrolactamization. Theresults presented herein illustrate the advantages of combining organic synthesis with natural productbiosynthetic enzymes to explore the interplay between structural features and biological activity.