AEM Accepts, published online ahead of print on 23 October 2009

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Appl. Environ. Microbiol. doi:10.1128/AEM.00744-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Insights into the evolution of macrolactam biosynthesis: cloning and comparative analysis of the biosynthetic gene cluster for a novel macrocyclic lactam ML-449

Hanne Jørgensen, Kristin F. Degnes, Alexander Dikiy, Espen Fjærvik, Geir Klinkenberg, and Sergey B. Zotchev^*

Department of Biotechnology, Norwegian University of Science and Technology, N-7491 Trondheim, Norway; Department of Industrial Biotechnology, SINTEF Materials and Chemistry, SINTEF, N-7034 Trondheim, Norway

^* To whom correspondence should be addressed. Email: sergey.zotchev{at}nt.ntnu.no.

A new compound designated ML-449 structurally similar to the known 20-membered macrolactam BE-14106 was isolated from a marine sediment-derived Streptomyces sp. Cloning and sequencing of the 83 kb ML-449 biosynthetic gene cluster revealed its high similarity to the BE-14106 gene cluster. Comparison of the respective biosynthetic pathways indicated that the difference in the compounds' structures stems from the incorporation of one extra acetate unit during the synthesis of the acyl side chain. A phylogenetic analysis of the -ketosynthase (KS) domains from polyketide synthases involved in the biosynthesis of macrolactams pointed to a common ancestry for the two clusters. Furthermore, the analysis demonstrated the formation of a macrolactam-specific subclade for the majority of the KS domains from several macrolactam biosynthetic gene clusters, indicating a closer relationship between macrolactam clusters than with the macrolactone clusters included in the analysis. Some KS domains from the ML-449, BE-14106 and salinilactam gene clusters did, however, show a closer relationship with KS domains from the polyene macrolide clusters, suggesting potential acquisition rather than duplication of certain PKS genes. Comparison of the ML-449, BE-14106, vicenistatin and salinilactam biosynthetic gene clusters indicated an evolutionary relationship between them and provided new insights into the processes governing the evolution of small-ring macrolactam biosynthesis.