Modular Design of Small Enzymatic Reaction Networks Based on Reversible and Cleavable Inhibitors

Systems chemistry aims to mimic the functional behavior of living systems by constructing chemical reaction networks with well‐defined dynamic properties. Enzymes can play a key role in such networks, but there is currently no general and scalable route to the design and construction of enzymatic reaction networks. Here, we introduce reversible, cleavable peptide inhibitors that can link proteolytic enzymatic activity into simple network motifs. As a proof‐of‐principle, we show auto‐activation topologies producing sigmoidal responses in enzymatic activity, explore cross‐talk in minimal systems, design a simple enzymatic cascade, and introduce non‐inhibiting phosphorylated peptides that can be activated using a phosphatase.