Biosynthesis of coral settlement cue tetrabromopyrrole in marine bacteria by a uniquely adapted brominase-thioesterase enzyme pair

The majority of pharmaceuticals are inspired by natural product scaffolds that are functionalized by tailoring enzymes, such as halogenases. The degree of halogenation is an important determinant of natural product bioactivity, yet little is known regarding the molecular basis for the exquisite control exhibited by tailoring halogenases. Known pyrrole halogenases commonly perform up to two halogenations on the pyrrole. Our study of tetrabromopyrrole biosynthesis revealed a uniquely adapted halogenase-thioesterase enzyme pair that catalyzes an unprecedented series of halogenations on a pyrrole. Structural comparison of the pyrrole tetrahalogenase to a pyrrole dihalogenase revealed key residues involved in controlling the degree of halogenation. Our findings provide fundamental insights that might be applied in the rational design of biocatalysts toward directed biosynthesis of new chemicals.