Overall, this review highlights the structures, mechanisms and applications of flavin-dependent halogenases (FDHs) for future development of FDHs as potential biocatalysts. FDHs catalyze incorporation of halogen atoms into a broad range of substrates. The reactions involved in the production of various halogenated natural products which are important drugs. Typical substrates for FDHs include indole, pyrrole, phenolic and aliphatic compounds. In addition to organic substrates, all FDHs utilize reduced FAD (FADH), oxygen and halides as co-substrates. Structural studies reveal that FDHs all have similar FAD binding sites. However, FDHs have variations between the different isotypes including different recognition residues for substrate binding and some unique loop structures and conformations. These different structural differences suggest that variations in reaction catalysis exist. However, limited knowledge of the reaction mechanisms of FDHs is currently available. Various biocatalytic applications of FDHs have been explored. Further investigation of the catalytic reactions of FDHs is essential for improving enzyme engineering work to enable FDHs catalysis of challenging reactions.
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