Robust platform for de novo production of heterologous polyketides and nonribosomal peptides in Escherichia coli

Abstract

During the past decade, numerous gene clusters responsible for the biosynthesis of important natural products have been identified from a variety of organisms. Heterologous expression utilizing E. coli has been employed to provide proteins for mechanistic understanding and structural analyses. It was very recently shown that this system is also capable of de novo production of biologically active forms of heterologous nonribosomal peptides, echinomycin and triostin A, through the introduction of genes encoding modules responsible for their assembly into this model bacterial host. The superlative advantage of using E. coli as a heterologous host is the availability of a wealth of well-established molecular biological techniques for its genetic and metabolic manipulation. The platform described above which was developed in our laboratory is ideal for use in the production of metabolites found in marine and symbiotic bacteria that are not amenable to artificial cultivation. Development and tailoring of our system will allow for the design of these natural products and ultimately combinatorial yet rational modification of these compounds. This review focuses on the heterologous expression of biosynthetic gene clusters for the assembly of therapeutically potent compounds.