Combinatorial biosynthesis of RiPPs: docking with marine life

•Observations from marine RiPP biosynthesis teaches us lessons about peptide combinatorial libraries.•Marine RiPP substrates contain mutable hypervariable cores, which are coupled with promiscuous posttranslational modification enzymes.•Marine RiPPs led to the discovery of conserved enzyme recognition sequences outside the core sequence, which serve as docking sites for the promiscuous biosynthetic enzymes.•Portability of recognition sequences allow modularity and enables hybridization of RiPP pathways.•Several unique posttranslational modifications were discovered in marine RiPPs. Ribosomally synthesized natural products are found in all forms of life. Their biosynthesis uses simple ribosomally synthesized peptides as starting materials that are transformed into complex structures via posttranslational modifications, enriched with elaborate chemical scaffolds that make them desirable as pharmacological tools. In addition, these natural products often exhibit combinatorial biosynthesis, making them attractive targets for engineering. An increasing knowledge of their biosynthetic machinery has provided key insights into their fascinating chemistry. Marine organisms have been a rich source of this class of natural products and here we review the lessons learned from marine life that enables exploitation of their potential for combinatorial engineering, opening up new routes for peptide-based drug discovery.