[4Fe-4S]-mediated proton-coupled electron transfer enables the efficient degradation of chloroalkenes by reductive dehalogenases

Reductive dehalogenases (RDases) are key enzymes involved in the degradation of organohalide compounds. Despite extensive experi-mental and computational studies, the catalytic mechanism of RDases remains unclear. We show here that the proximal [4Fe-4S]1+ cluster of the reductive dehalogenase PceA can mediates a proton-coupled electron transfer (PCET) process to quench the substrate radical. Such [4Fe-4S]1+-mediated PCET process is enhanced by both exchange and super-exchange interactions. The participation of [4Fe-4S]1+ in mediating a PCET process in RDases is unexpected, though well known in reducing Co(II). In addition, in RDases the Arg305 residue acts as an efficient proton donor for the PCET reactions. The deprotonated Tyr246 serves to maintain the favorable conformation of Arg305 during catalysis, and sustains its proton donation ability, which is requested during the PCET reaction. Such a novel mechanism enables the efficient detoxification of chloroalkene pollutants by the reductive dehalogenase PceA. These results highlight the critical role of the proximal [4Fe-4S]