Identification and functional analysis of common human flavin-containing monooxygenase 3 genetic variants
Identification and functional analysis of common human flavin-containing monooxygenase 3 genetic variants
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DOI：
10.1124/jpet.106.112268
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发表时间：
2007-01-01
影响因子：
3.5
通讯作者：
Hines, Ronald N.
中科院分区：
文献类型：
--
作者：
Koukouritaki, Sevasti B.;Poch, Mark T.;Hines, Ronald N.
含黄素单加氧酶（FMO）对于许多治疗剂、环境毒物和营养物的处置是重要的。FMO 3，主要的成人肝脏FMO酶，表现出显着的个体间差异。在202名西班牙裔（墨西哥裔）、201名非洲裔美国人和200名非拉丁裔白人中测定了18个FMO 3单核苷酸多态性（SNP）频率。使用含有甲巯咪唑、三甲胺、舒林酸和乙撑硫脲的表达重组酶，新结构变体FMO 3 E24 D和K416 N显示出催化效率的适度变化，而第三种新变体FMO 3 N61 K基本上没有活性。后一种变体在非拉丁裔白人中的等位基因频率为5.2%，在非洲裔美国人中为3.5%，但在西班牙裔美国人中不存在。使用PHASE 2.1版推断单倍型，在非裔美国人中观察到最大的单倍型多样性，其次是非拉丁裔白人和西班牙裔。单倍型2A和2B由与同义结构变体连锁的超形态启动子SNP簇（-2650 C> G、-2543 T> A和-2177 G> C）组成，在西班牙裔人群中推断频率为27%，但在非拉丁裔白人和非洲裔美国人中仅为5%。与一个或多个亚型结构变体连锁的相同启动子SNP簇也在多个单倍型中推断，在非裔美国人研究组中的总频率为5.6%，但在其他两组中低于1%。亚纯单倍型H3 [ 15，167 G> A（E158 K）]、H5 B [-2650 C> G，15，167 G> A（E158 K），21，375 C> T（N285 N），21，443 A> G（E308 G）]和H6 [ 15，167 G> A（E158 K），21，375 C> T（N285 N）]在西班牙裔中为28%，在非拉丁裔白人中为23%，在非洲裔美国人中为24%。
Flavin- containing monooxygenases ( FMOs) are important for the disposition of many therapeutics, environmental toxicants, and nutrients. FMO3, the major adult hepatic FMO enzyme, exhibits significant interindividual variation. Eighteen FMO3 single- nucleotide polymorphism ( SNP) frequencies were determined in 202 Hispanics ( Mexican descent), 201 African Americans, and 200 non- Latino whites. Using expressed recombinant enzyme with methimazole, trimethylamine, sulindac, and ethylenethiourea, the novel structural variants FMO3 E24D and K416N were shown to cause modest changes in catalytic efficiency, whereas a third novel variant, FMO3 N61K, was essentially devoid of activity. The latter variant was present at an allelic frequency of 5.2% in non- Latino whites and 3.5% in African Americans, but it was absent in Hispanics. Inferring haplotypes using PHASE, version 2.1, the greatest haplotype diversity was observed in African Americans followed by non- Latino whites and Hispanics. Haplotype 2A and 2B, consisting of a hypermorphic promoter SNP cluster (- 2650C > G, - 2543T > A, and - 2177G > C) in linkage with synonymous structural variants was inferred at a frequency of 27% in the Hispanic population, but only 5% in non- Latino whites and African Americans. This same promoter SNP cluster in linkage with one or more hypomorphic structural variant also was inferred in multiple haplotypes at a total frequency of 5.6% in the AfricanAmerican study group but less than 1% in the other two groups. The sum frequencies of the hypomorphic haplotypes H3 [ 15,167G > A ( E158K)], H5B [- 2650C > G, 15,167G > A ( E158K), 21,375C > T (N285N), 21,443A > G ( E308G)], and H6 [ 15,167G > A ( E158K), 21,375C > T ( N285N)] was 28% in Hispanics, 23% in non- Latino whites, and 24% in African Americans.