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 flavoenzymes that catalyze the oxidation of heteroatom centers in numerous drugs and xenobiotics. FMO2, or "pulmonary" 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 certain primary alkylamines. We describe here the isolation and characterization of cDNAs for human FMO2. Analysis of the sequence of the cDNAs and of a section of the corresponding gene revealed that the major FMO2 allele of humans encodes a polypeptide that, compared with the orthologous protein of other mammals, lacks 64 amino acid residues from its C terminus. Heterologous expression of the cDNA revealed that the truncated polypeptide was catalytically inactive. The nonsense mutation that gave rise to the truncated polypeptide, a C --> T transition in codon 472, is not present in the FMO2 gene of closely related primates, including gorilla and chimpanzee, and must therefore have arisen in the human lineage after the divergence of the Homo and Pan clades. Possible mechanisms for the fixation of the mutation in the human population and the potential significance of the loss of functional FMO2 in humans are discussed.
Dolphin
C T
CT
Laboratory of Molecular Biology, Department of Biochemistry, Queen Mary and Westfield College, University of London, London E1 4NS, United Kingdom.
Beckett
D J
DJ
Janmohamed
A
A
Cullingford
T E
TE
Smith
R L
RL
Shephard
E A
EA
Phillips
I R
IR
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002384:Catalysis; D018389:Codon, Nonsense; D018388:Codon, Terminator; D006801:Humans; D008252:Macaca fascicularis; D008969:Molecular Sequence Data; D010105:Oxygenases / Q000235:genetics*; D002679:Pan troglodytes; D012333:RNA, Messenger / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism
D018389:Codon, Nonsense; D018388:Codon, Terminator; D012333:RNA, Messenger; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D012260:Ribonucleases