Enabling desaturation of lactones by reversible catalytic activity of ‘ene’-reductases

Abstract

An engineered old yellow enzyme lactone dehydrogenase (OYE1_LD), which can reversibly catalyze the formation of CC bonds and facilitate the conversion of lactones and ketones into their α,β-unsaturated counterparts, is reported. The synthesis of various naturally active unsaturated carbonyl compounds proceeds without external oxidants or cofactors, showing compatibility with diverse functional groups and high conversion efficiency. Mechanistic and reactivity studies indicate that mutations lead to a reduced distance between key active residues and the substrate, thereby enhancing the reaction. The methodology was also successfully extended to the synthesis of chromone derivatives and various pharmaceutically relevant molecules. The findings of this study pave the way for biocatalyzing a novel non-natural dehydrogenation reaction and suggest potential applications in the synthesis of natural products derived from aromatic heterocycles.