ThiF‐Like Enzyme Chemistry in Primary and Secondary Metabolism

ThiF‐like proteins are members of the widespread E1‐like enzyme superfamily. The eponymous ThiF enzyme was first described in thiamin biosynthesis as part of Escherichia coli 's primary metabolism, and homologous proteins have been subsequently discovered in secondary metabolism. These ThiF‐like enzymes are united in their defining ability to perform nucleotidylation of a carboxyl group to generate an activated, electrophilic intermediate, a feature it shares with the structurally related ubiquitin‐activating enzymes. From here, an array of different nucleophiles are used across distinct biosynthetic pathways to yield diverse structural scaffolds. In this review, we discuss various ThiF‐like enzymes that perform nucleotidylation to facilitate a diverse array of interesting and rare chemistry on different types of substrates, as well as showcase some of the shared structural features.