Efficient Lewis acid catalysis of an abiological reaction in a de novo protein scaffold

New enzyme catalysts are usually engineered by repurposing the active sites of natural proteins. Here we show that design and directed evolution can be used to transform a non-natural, functionally naive zinc-binding protein into highly catalyst for an abiological hetero-Diels–Alder reaction. The artificial metalloenzyme achieves >104 turnovers per site, exerts absolute control over reaction pathway product stereochemistry, displays catalytic proficiency (1/KTS = 2.9 × 1010 M?1) exceeds all previously characterized Diels–Alderases. These properties capitalize on effective Lewis acid catalysis, chemical strategy accelerating Diels–Alder reactions common in laboratory but so far unknown nature. Extension this approach other metal ions de novo scaffolds may propel field exciting new directions. A designed has been converted active, stereoselective Design were effectively harness catalysis create more proficient than reported