Over the past 60 years over 4000 natural products have been discovered which contain halogen substituents, and this number is increasing rapidly.¹ However, it was only 9 years ago that elegant work by van Pée identified the first regiospecific ‘halogenase’ that was dedicated to a biosynthetic pathway.² A unique GWXWXIP sequence motif present in this flavin-dependent halogenase (FDH) has enabled the annotation of ~730 sequence homologues (which were previously thought to be flavin-dependent monoxygenases of unknown function) in a vast number of bacterial and environmental DNA samples. The FAD cofactor present in these enzymes is used to oxidize a halide ion (X-) to the corresponding hypohalous acid (HOX), which in turn is directed by a highly conserved active site Lys to react regiospecifically with a substrate.³ Although the catalytic machinery used to generate an ‘X+’ equivalent is highly conserved, the FDH family nonetheless reacts with an astonishing array of functional groups. One such enzyme is CmlS, a FDH responsible for generating a dichloracetyl group in the biosynthesis of the antibiotic chloramphenicol.⁴ Recent work on CmlS will be presented.

References: (1) Gribble Chemosphere 2003, 52, 289; (2) Keller, Angew Chem Int Ed Engl 2000, 39, 2300; (3) Neumann, Chem Biol 2008, 15, 99; (4) Piraee, Microbiology 2004, 150, 85.