Nat. Chem. (2019)

Flavin-dependent halogenases (FDHs), which catalyze the formation of carbon–halogen bonds, are most often of bacterial or fungal origin and are typically selective for either chlorine or bromine. Seeking new FDHs, Gkotsi et al. performed a sequence alignment of all characterized FDHs, from which they identified a previously unappreciated conserved sequence motif. Genome mining with this motif as a probe led them to focus on the halogenase VirX1 from a cyanobacteria-infecting virus. In vitro, VirX1 exhibited an unusual preference for iodide donors over chloride or bromide, along with promiscuous activity for numerous organic acceptor substrates. The structure of VirX1 is overall similar to those of other FDHs, but has an especially wide opening to an already expanded substrate-binding cavity, enabling it to accommodate larger halides and a broad scope of substrates. Although certain other halogenases exhibit some level of iodination ability, VirX1 represents the first example of a halogenase with such a preference. This specialized activity of VirX1, coupled with its broad substrate scope, provides a new potential biocatalytic route to iodine-containing compounds.