Artificial metalloenzymes in whole-cell catalysis: Toward hybrid metabolic systems

The application repertoire of industrial biotechnology is constrained by the reaction scope of natural biocatalysis, which covers only a fraction of the accessible chemical space. To expand the versatility of biomanufacturing, abiological organometallic catalysts can be integrated into synthetic biology in the form of artificial metalloenzymes (ArMs). ArMs have been developed for a broad range of new-to-nature reactions, and in recent years multiple examples of their successful implementation in vivo have been demonstrated. Nevertheless, whole-cell ArM catalysis remains at the stage of fundamental research, and hybrid metabolic systems incorporating ArMs have yet to be realized at scale. In this review, we summarize the recent advances in whole-cell ArM catalysis and outline the challenges associated with in vivo ArM incorporation. We highlight the additional complexity that arises when transitioning from simple whole-cell biotransformations to metabolic engineering with ArMs and discuss potential strategies to achieve efficient integration of ArMs into biosynthetic pathways.