Molecular modelling and protein engineering of a C-terminally truncated human flavin-containing monooxygenase 3

Human flavin containing monooxygenase 3 is a drug-metabolizing enzyme involved in the oxidation of many drugs, chemicals and xenobiotics. It is predominantly expressed in the liver where its substrates, generally soft nucleophiles are transformed into more polar metabolites. The enzyme is attached to the smooth endoplasmic reticulum membrane, where its reduced flavin group binds molecular oxygen and readily performs nucleophilic attack on the substrates. To date the structure of hFMO3 has not been solved due to difficulties in the crystallization of microsomal, membrane-bound proteins. In the present study a molecular model of hFMO3 is constructed, exploited by in silico molecular dynamics experiments to identify the membrane anchor and used for the rational design of a soluble truncated hFMO3 enzyme.