The flavin-containing monooxygenase 2 gene (FMO2) of humans, but not of other primates, encodes a truncated, nonfunctional protein
The flavin-containing monooxygenase 2 gene (FMO2) of humans, but not of other primates, encodes a truncated, nonfunctional protein
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DOI：
10.1074/jbc.273.46.30599
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发表时间：
1998-11-13
影响因子：
4.8
通讯作者：
Phillips, IR
中科院分区：
文献类型：
--
作者：
Dolphin, CT;Beckett, DJ;Phillips, IR
黄素单加氧酶(FMOS)是一种依赖于NADPH的黄素酶，可催化多种药物和外源化合物中杂原子中心的氧化。FMO2是哺乳动物中发现的五种形式的酶之一，主要在肺中表达，与其他FMO不同的是，它可以催化某些伯烷基胺的N-氧化。我们在这里描述了人类FMO2的cDNA的分离和鉴定。序列分析表明，人类主要的Fmo2等位基因编码一种多肽，与其他哺乳动物的同源蛋白相比，其C末端缺少氨基酸残基。异源表达表明，截短的多肽具有催化失活作用。在包括大猩猩和黑猩猩在内的近亲灵长类动物的FMO2基因中不存在导致截短多肽的无义突变，这是472密码子的C->；T转换，因此肯定是在人和潘支系分化后出现在人类谱系中的。讨论了在人类群体中固定突变的可能机制，以及在人类中失去功能性FMO2的潜在意义。
Flavin-containing monooxygenases (FMOs) are NADPH-dependent flavoenzymes 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 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.