Flavin transferase ApbE: From discovery to applications

ApbE is a unique, membrane-bound enzyme which covalently attaches a flavin cofactor to specific target proteins. This irreversible post-translational modification is crucial for proper functioning of various bacterial proteins. ApbEs have also been identified in archaea and eukaryotes. This review summarizes current knowledge on the structural and mechanistic properties of this unique protein-modifying enzyme and its recent applications. The relatively small flavin transferase is typically anchored to the outer membrane of bacteria and possesses a conserved flavin-binding domain and a catalytic domain. It recognizes a specific sequence motif of its target proteins, resulting in flavinylation of a threonine or serine. For flavinylation, it depends on magnesium and utilizes FAD as substrate to attach the FMN moiety to the target protein, analogous to phosphorylation. ApbE-mediated flavinylation supports critical bacterial respiratory and metabolic pathways. Recently, ApbE was also shown to be a versatile tool for selectively modifying proteins. Using the flavin-tagging approach, proteins can be decorated with FMN or other flavins. Furthermore, it was demonstrated that ApbE can be employed to turn natural noncovalent flavoproteins into covalent flavoproteins. In summary, ApbE is crucial for the maturation of various flavoproteins by catalyzing covalent flavinylation. While great progress has been made in understanding the role and mode of action of ApbE, there are still many bacterial proteins predicted to be flavinylated by ApbE for which their role is enigmatic. Also, exploration of the potential of ApbE as protein modification tool has just begun. Clearly, future research will generate new ApbE-related insights and applications.