Terminal oxidant-supported P450 reactions alleviate the need for substrate binding to initiate catalysis by chemically generating “compound I.” This allows investigation of the innate substrate range of the enzyme active site. Using iodosylbenzene as the oxidant, CYP153A6, a medium-chain terminal alkane hydroxylase, exhibits methanol formation in the presence of methane demonstrating that P450-mediated methane hydroxylation is possible.