Substrate specificity of flavin-containing monooxygenase 3 is altered by mutations in humans

초록

In previous studies, we found a siginificant correlation between the flavin-containing monooxygenase(FMO)catalyzed ranitidine N-oxidation activites and the presence of mutations in exon 4(Glu158Lys)and exon 7(Glu308Gly) of FMO3 gene in Korean volunteers. Results of the present study show that another mutation(Val257Met)in exon 6 of FMO3,which also occurs commonly(16.2% allele frequency)in our Korean population(n=197),is significantly correlated with the FMO catalysed caffeine N-1 detethylation but not with ranitidine N-oxidation activites. The exon 6 mutation in FMO3 was caused by a point mutation(G769A). The point mutation in FMO3 brings about a substitution of valine(Val)for methionine(Met)and transforms the secondary structure of FMO3 from a sheet to a helix structure. In a family study of a person carrying heterozygous nonsense mutation in exon 4(Gly148Stop)and heterozygous missense mutation in exon 6(Val257Met)of FMO3, the low FMO activity(N-1 detethylation of caffeine)could be explained by the inheritance of exon 6 mutation. These results suggest that differential changes in the secondary structure of FMO3 brought about by point mutations in the coding regions of FMO3(exon 4,6 and 7)may be responsible for the altered substrate specificity. Results further suggest that phenotyping people for their FMO3 activity may need to be conducted with several probe compounds of varying chemical structure that correlate with each mutation on the FMO3 gene.