A focus on unexpected surprises in RiPP natural product biosynthesis

Natural products are biologically active molecules made by living organisms that serve a vital role in the pharmaceutical industry and account for (or have inspired) nearly 75% of human medicines. For decades, natural product biosynthetic enzymes have challenged chemists and enzymologists to harness these powerful catalysts for the production and engineering of high-value, structurally-complex chemicals. As genome science has rapidly advanced over the past two decades, the ribosomally-synthesized and post-translationally modified peptide (RiPP) family of natural products have emerged as a promising target for detailed investigation. Recently, Zhang and co-workers (Y. Jia, Y. Han, X. Liu and Q. Zhang, <i>Chem. Sci.</i>, 2025, <b>16</b>, 10722, https://doi.org/10.1039/D5SC01546D) reported the characterization of thuricin CD (an antimicrobial RiPP) and revealed several unexpected surprises that have expanded our understanding of natural diversity in RiPP biosynthetic mechanisms. Their study calls for caution when making assumptions about these highly versatile biosynthetic pathways and highlights a need for detailed characterization of these pathways as a prelude to engineering applications.