Enzymatic halogenation: enzyme mining, mechanisms, and implementation in reaction cascades
Regioselective halogenation of organic compounds using non-toxic halide salts and oxygen in aqueous media at ambient temperatures – a tough task for conventional chemical synthesis. However, thousands of halogenated natural products are formed by biosynthesis under such conditions without the need for reagents like molecular chlorine or bromine. Nature has evolved a variety of different enzymes able to halogenate their substrates by using Cl−, Br−, I− or even F− ions. In many cases, these reactions are highly regioselective and may address even electronically disfavoured positions. Unsurprisingly, the interest in halogenases continuously increases in the context of green chemistry to use them as biocatalysts for chemical synthesis. This review focusses on the class of flavin-dependent halogenases and their applications, while insights on their structure and mechanism are being discussed. Recent progress in utilising these enzymes for incorporation of halogen substituents in complex natural products by enzyme catalysis or fermentation is highlighted. Modification of the produced organohalogen compounds, for example in chemoenzymatic one-pot reaction cascades are described. Since the narrow substrate scope of flavin-dependent halogenases is still a crucial bottleneck, the current progress to obtain optimised and tailor-made biocatalysts by directed evolution of this enzyme class is highlighted.