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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Investigation of structure and function of a catalytically efficient variant of the human flavin-containing monooxygenase form 3.

To characterize the contribution of amino acid 360 to the functional activity of the human flavin-containing monooxygenase form 3 ( FMO3) and form 1 (FMO1) in the oxygenation of drugs and chemicals, we expressed four FMO3 variants (i.e., Ala(360)-FMO3, His(360)-FMO3, Gln(360)-FMO3, and Pro(360)-FMO3) and one FMO1 variant (i.e., Pro(360)-FMO1) and compared them to wild-type enzymes (Leu(360)-FMO3 and His(360)-FMO1, respectively). The amino acid substitutions were introduced into wild-type FMO3 or FMO1 cDNA by site-directed mutagenesis. The thermal stability of variants of Leu(360) FMO3 was also studied, and the thermal stability was significantly different from that of wild-type FMO3. The influence of different substrates to modulate the catalytic activity of FMO3 variants was also examined. Selective functional substrate activity was determined with mercaptoimidazole, chlorpromazine, and 10-[(N,N-dimethylaminopentyl)-2-(trifluoromethyl)]phenothiazine. Compared with wild-type FMO3, the Ala(360)-FMO3 and His(360)-FMO3 variants were less catalytically efficient for mercaptoimidazole S-oxygenation. N-Oxygenation of chlorpromazine was significantly less catalytically efficient for His(360)-FMO3 compared with wild-type FMO3. Human Pro(360)-FMO1 was significantly more catalytically efficient at S-oxygenating mercaptoimidazole and chlorpromazine compared with wild-type FMO1. The data support the mechanism that the Pro(360) loci affect thermal stability of FMO3. Because different amino acids at position 360 affect substrate oxygenation in a unique fashion compared with that of FMO3 stimulation, we conclude that the mechanism of stimulation of FMO3 is distinct from that of enzyme catalysis. A molecular model of human FMO3 was also constructed to help explain the results. The increase in catalytic efficiency observed for Pro(360) in human FMO3 was also observed when the His of FMO1 was replaced by Pro at loci 360.[1]


  1. Investigation of structure and function of a catalytically efficient variant of the human flavin-containing monooxygenase form 3. Borb??s, T., Zhang, J., Cerny, M.A., Lik??, I., Cashman, J.R. Drug Metab. Dispos. (2006) [Pubmed]
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