Advancements in protein engineering and organocatalysis have made it possible to create a new generation of hybrid catalysts which have the combined benefits of both enzymes and organocatalysts. Our study focuses on the Thiamine-diphosphate (ThDP)/ Carboxyethyl-Arginine Synthase (CEAS) catalytic pair, this pair forms an acyl-azolium adduct that has had a profound impact on the field of organocatalytic reaction discovery. The aim of this study is to design an analog cofactor which when paired with CEAS can catalyse the synthesis of a diverse range of complex cyclohexyl beta-lactones. Based on ancestral sequence reconstruction, a number of CEAS variants have been constructed, which will now be assessed for desirable activity using ThDP analogs. Computational and semi-rational design methods will then be used to improve the catalytic activity to more industrially relevant characteristics. Ultimately, we expect that this will show the potential of harnessing catalytic power and specificity of enzymes with the catalytic novelty and versatility of organocatalysts to perform reactions only currently possible in the laboratory.