In response to the alarming rise in antibiotic resistance, the search for new bioactive molecules has become a public health priority. Among the most promising leads are ribosomally-synthesized and post-translationally modified peptides (RiPPs), a diverse family of natural compounds with rich structural complexity and therapeutic potential.
In collaboration with a research team from Singapore and scientists from the EDyP laboratory at IRIG (CEA-Grenoble), researchers from the Metalloproteins Group of the IBS have elucidated how a radical SAM enzyme specifically recognizes its peptide substrate via a dedicated leader sequence. We also uncovered how the enzyme initiates a sophisticated radical-based chemistry that leads to the formation of intramolecular carbon–carbon bonds, resulting in macrocyclic structures known as cyclophanes. Their work further reveals the enzyme’s remarkable ability to sequentially recognize multiple ΩXR motifs within a single precursor peptide, enabling the formation of multiple distinct cycles. Moreover, by studying the structural and functional association between this enzyme and a partner oxygenase, they have identified a finely tuned mechanism that coordinates cyclophane formation and hydroxylation reactions through a dynamic interplay between the two enzymes.
These findings pave the way for the rational engineering of this enzyme to modify or expand its substrate scope, with the ultimate goal of screening non-natural compounds in the search for new antibiotics.
Peptide Recognition and Mechanism of the Radical S-Adenosyl-l-methionine Multiple Cyclophane Synthase ChlB. Ruel J, Nguyen TQN, Morishita Y, Usclat A, Martin L, Amara P, Kieffer-Jaquinod S, Stefanoiu MC, de la Mora E, Morinaka BI, Nicolet Y. J Am Chem Soc. 2025 May 12. doi : 10.1021/jacs.4c16004.
Contact : Yvain Nicolet (IBS/Metalloproteins Group)