Macrocyclization strategies in polyketide and nonribosomal peptide biosynthesis

Abstract

Nonribosomal peptides and polyketides have attracted considerable attention in basic and applied research and have given rise to a multitude of therapeutic agents. The biological activity of many of these complex natural products, including for example the peptide antibiotics daptomycin and bacitracin or the polyketide anticancer agents epothilone and geldanamycin, specifically relies on the macrocyclization of linear acyl chains that form the backbone of these highly valuable molecules. The construction of the linear acyl precursors is accomplished by modular protein templates that follow comparable assembly line logic. As an enzymatic key step, macrocyclization is introduced after the consecutive condensation of amino acid or acyl-CoA building blocks by dedicated catalysts, and the mature product is released from the biosynthetic machinery. The diverse chain termination strategies of nonribosomal peptide and polyketide assembly lines, the structures and mechanisms of the versatile macrocyclization catalysts, and chemoenzymatic approaches for the development of new therapeutics are the focus of this review. Further, it is illustrated that macrocyclization is not restricted to secondary metabolites, but represents a commonly found structural motif of other biologically active proteins and peptides.