Principles of small molecule activation by metalloenzymes as exemplified by the soluble methane monooxygenase from Methylococcus capsulatus (Bath) *

Many metalloenzymes activate small molecules in a manner that is unique to natural systems. In this Perspective we discuss the soluble methane monooxygenase protein system from Methylococcus capsulatus (Bath), which uses a mixed-function oxidase to convert methane selectively to methanol. Through a series of biophysical studies, theoretical calculations, synthetic model studies and mechanistic biochemical experiments, the respective roles of the carboxylate-bridged non-heme diiron center and the protein environment in controlling the enzyme mechanism have been delineated. These results are used to identify themes common among metalloenzymes that activate small molecules and to identify future directions for the study of this protein system.