Diverse classes of nonribosomal peptides are used as, or have inspired the development of, anticancer drugs. Examples include bleomycin, actinomycin D, romidepsin, epoxomicin, trabectidin and didemnin B. Biosynthetic engineering is a promising approach to the creation of novel nonribosomal peptide derivatives that can inform structure-activity relationships and may possess enhanced therapeutic properties. Moreover, it has the potential to be become a sustainable and scalable method for the production of nonribosomal peptide-based pharmaceuticals and agrochemicals. However, to develop broadly applicable biosynthetic engineering methods, a thorough understanding of the genetics, enzymology and evolution of nonribosomal peptide biosynthesis is required.
In this lecture, I will describe recent efforts to develop a better understanding of the biosynthesis of two classes of nonribosomal peptide-based anticancer drugs: bicyclic depsipeptide histone deacetylase inhibitors, exemplified by romidepsin, and epoxyketone proteasome inhibitors, exemplified by eponemycin (1-3). In both cases, these studies have identified conserved machinery for pharmacophore biosynthesis that interfaces with variable machinery for nonribosomal peptide assembly, revealing evolutionary strategies for biosynthetic diversification.