Expanding the Horizon of Natural Products: The Role of Starter Units in Nonribosomal Lipopeptide Biosynthesis

Nonribosomal lipopeptides (NRLPs) are structurally complex natural products that play crucial ecological and biological roles. They are also valuable sources and lead structures for developing new pharmaceuticals. These compounds are typically synthesized using a molecular assembly machinery known as nonribosomal peptide synthetases (NRPSs) or hybrid polyketide synthases-NRPSs. Unlike conventional NRPS, NRLPs are characterized by a starter module that loads lipid chains and a substrate synthesis pathway that supplies the necessary substrates during the initiation stages. Unique lipid chains are critical determinants of the biological activity of NRLPs. Therefore, modifying these lipid chains through combinatorial biosynthesis holds great promise for unlocking their full therapeutic potential. Herein, we use the term "Starter Unit" to refer to the initial modules and lipoinitiation pathway involved in the lipid chain initiation process of NRLPs. This Review provides a comprehensive summary of recent advances in the combinatorial biosynthesis of starter units and offers insights into future directions for further development.