Pathway-Dependent Catalytic Activity of Short-Peptide-Based Metallozyme: From Promiscuous Activity to Cascade...

Many natural enzymes contain metal ions as cofactors in the active site for biological activity. However, the pathway of the introduction of metal ions in the earliest protein folds for the emergence of higher catalytic activity remains an intriguing open question. Herein, we demonstrate that pathway-dependent self-assembly of short-peptide-based metallozymes results in differences in catalytic activity. Short-peptide-based amyloids with solvent exposed arrays of colocalized catalytic units are able to bind highly soluble Cu²⁺ ions to demonstrate oxidase-like and RNase-like activity (promiscuity). Further, the metallozyme was able to exhibit higher hydrolase-oxidase cascade activity compared to the mixture of natural enzymes, esterase, and laccase. The collaboration between short-peptide-based amyloid microphases and metal ions suggests that metallozymes might have played a pivotal role in early metabolic processes and biopolymer evolution on the prebiotic earth.