THE FLAVIN-CONTAINING-MONOOXYGENASE-2 GENE (FMO2) OF HUMANS, BUT NOT OF OTHER PRIMATES, ENCODES A TRUNCATED, NONFUNCTIONAL PROTEIN

Flavin-containing monooxygenases (FMOs) are NADPH-dependent flavoenzym es that catalyze the oxidation of heteroatom centers in numerous drugs and xenobiotics. FMO2, or ''puhnonary'' FMO, one of five forms of the enzyme identified in mammals, is expressed predominantly in lung and differs from other FMOs in that it can catalyze the N-oxidation of cer tain primary alkylamines. We describe here the isolation and character ization of cDNAs for human FMO2. Analysis of the sequence of the cDNAs and of a section of the corresponding gene revealed that the major FM O2 allele of humans encodes a polypeptide that, compared with the orth ologous protein of other mammals, lacks 64 amino acid residues from it s C terminus. Heterologous expression of the cDNA revealed that the tr uncated polypeptide was catalytically inactive. The nonsense mutation that gave rise to the truncated polypeptide, a C -->T transition in co don 472, is not present in the FMO2 gene of closely related primates, including gorilla and chimpanzee, and must therefore have arisen in th e human lineage after the divergence of the Homo and Pan clades. Possi ble mechanisms for the fixation of the mutation in the human populatio n and the potential significance of the loss of functional FMO2 in hum ans are discussed.