Chlorinated Natural Products and Related Halogenases

Halogenated compounds are well‐known for their diverse bioactivities and wide applications in pharmaceutical industry, chemical engineering and other fields. Novel halometabolites isolated from nature inspire scientists to synthesize these “chance compounds”, which were, however, usually hampered by the extreme catalytic conditions and severe selectivity challenges. In the past several decades, enzymatic reactions have been brought into attention for their efficiency, selectivity, and mild reaction conditions. Synthetic biology which is in compliance with the laws of nature to a large extent shed light on the rational biosynthesis of halogenated compounds. This article summarizes several representative categories of halogenated natural products and halogenases to seek clues to the relationship between the structures and halogenase mechanisms. Some types of halogenase convert the basic building blocks to diverse early intermediates during natural product biosynthetic processes, while others are involved in the late tailoring steps to afford the final structures of halogenated molecules. The broad substrate specificity and strong regioselectivity exhibited in some halogenases are irreplaceable advantages for biosynthesis. In addition, tremendous efforts and encouraging results enable us to engineer the enzymes or techniques to synthesize “unnatural” halogenated natural products. More reaction mechanisms and structural data are expected to be revealed exponentially in this rapid growing realm.