Biosynthesis of Macrolactam BE-14106 Involves Two Distinct PKS Systems and Amino Acid Processing Enzymes for Generation of the Aminoacyl Starter Unit

摘要

BE-14106 is a macrocyclic lactam with an acyl sidechain previously identified in a marine-derived Strep-tomyces sp. The gene cluster for BE-14106 biosyn-thesis was cloned from a Streptomyces strain newlyisolated from marine sediments collected in theTrondheimsfjord (Norway). Bioinformatics and experi-mental analyses of the genes in the cluster suggestedan unusual mechanism for assembly of the molecule.Biosynthesis of the aminoacyl starter apparentlyinvolves the concerted action of a distinct polyketidesynthase (PKS) system and several enzymes thatactivate and process an amino acid. The resultingstarter unit is loaded onto a second PKS complex,which completes the synthesis of the macrolactamring. Gene inactivation experiments, enzyme assayswith heterologously expressed proteins, and feedingstudies supported the proposed model for the biosyn-thesis and provided new insights into the assembly ofmacrolactams with acyl side chain.