+, protein or activity detected, - , protein or activity not detected, ?, not determined, -/ + protein or activity detected in a fraction of the samples. Adapted and modified from24,25. a Fetal-specific enzymes. b Adult-specific enzymes.
FMO1 possesses a very broad substrate specificity and can metabolize most soft nucleophiles it encounters, but its extrahepatic location (see below) minimizes its impact on drug clearance. FMO3 is the major form of the enzyme present in human liver. While it too has a wide substrate specificity in vitro, the enzyme participates significantly in the metabolic clearance of only a few drugs and xenobiotics, e.g., itopride, ranitidine, moclobemide, nicotine.40 However, FMO3 plays a major role in the conversion of the dietary breakdown product, trimethylamine, to trimethylamine N-oxide, and genetic defects in FMO3 are responsible for the rare metabolic disorder, trimethylaminuria.45 Genetic polymorphisms also render FMO2 largely nonfunctional in most human ethnic groups. Very little is known about the substrate specificity of FMO4 and FMO5.
Human FMOs are FAD-containing flavoproteins comprising 532-558 amino acids (i.e., 60-65 kDa proteins). Two glycine-rich motifs forming part of the Rossman folds for NADPH and FAD binding are found in the N-terminal half of the enzyme. The C-terminal portion is pronouncedly hydrophobic and may represent a membrane anchor domain. However, deletion of this hydrophobic region has generally been accompanied by loss of enzyme activity and crystallization of the protein has yet to be accomplished. Homology models based on soluble GSH reductase and/or phenylacetone monooxygenase may hold promise in the interim for visualizing some aspects of FMO structure.39
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