Stereoselective Carbene Transfer and Cascade Activity by Short-Peptide-Based Cross-β Amyloids

Enzymes with specific cofactors serve as catalytic machinery with remarkable stereoselectivity for various chemical transformations, facilitating diverse reaction networks in extant biology. A three-dimensional structure with multiple residues exposed in the active site facilitates stereoselective reactions. However, how early protein folds facilitate stereoselective catalytic transformations remains an open question. In this work, the catalytic potential of short-peptide-based amyloids is explored in the presence of hemin as a cofactor to perform complex and challenging carbene transfer reactions under equilibrium and nonequilibrium conditions. Short peptide fragments demonstrate a stereoselective cyclopropanation reaction and mimic hydrolase activity to subsequently degrade its catalytic product, providing negative feedback toward the assembly process via cyclopropanation-hydrolysis cascade reaction. These results underpin the broader potential of short-peptide-based assemblies complexed with hemin as minimalistic, yet powerful catalytic systems to enable diverse and practically relevant chemical transformations. Further, this work underscores the catalytic diversity of the short peptides with notable stereoselectivity, which opens up the possibilities for devising methodologies for wider applications.