cDNA cloning of mouse and human cholesterol 25-hydroxylases, polytopic membrane proteins that synthesize a potent oxysterol regulatory of lipid metabolism
cDNA cloning of mouse and human cholesterol 25-hydroxylases, polytopic membrane proteins that synthesize a potent oxysterol regulatory of lipid metabolism
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DOI：
10.1074/jbc.273.51.34316
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发表时间：
1998-12-18
影响因子：
4.8
通讯作者：
Russell, DW
中科院分区：
文献类型：
--
作者：
Lund, EG;Kerr, TA;Russell, DW
氧化甾醇调节胆固醇和脂类代谢相关基因的表达，并作为胆固醇分解代谢的中间产物。其中调节作用最强的氧固醇是25-羟基胆固醇，其生物合成酶还没有被分离出来。在这里，我们报道了从小鼠和人的胆固醇25-羟基酶cDNA的克隆，编码的酶是分别由298和272个氨基酸组成的多孔膜蛋白，其中包含对催化活性至关重要的组氨酸残基簇。与大多数其他类固醇羟基酶不同，胆固醇25-羟基酶不是细胞色素P450，而是利用双铁辅助因子催化疏水底物羟化的一小类酶的成员。胆固醇25-羟基酶基因没有内含子，在人类中，它位于染色体10q23上。小鼠基因在多个组织中低水平表达。胆固醇25-羟基酶在转基因细胞中的表达减少了醋酸盐对胆固醇的生物合成，并抑制了固醇调节元件结合蛋白-1和-2的裂解，这些数据表明，胆固醇25-羟基酶可以通过合成辅助抑制因子来调节脂质代谢，从而阻止固醇调节元件结合蛋白的加工，最终导致基因转录的抑制。
Oxysterols regulate the expression of genes involved in cholesterol and Lipid metabolism and serve as intermediates in cholesterol catabolism. Among the most potent of regulatory oxysterols is 25-hydroxycholesterol, whose biosynthetic enzyme has not yet been isolated. Here, we report the cloning of cholesterol 25-hydroxylase cDNAs from the mouse and human, The encoded enzymes are polytopic membrane proteins of 298 and 272 amino acids, respectively, which contain clusters of histidine residues that are essential for catalytic activity. Unlike most other sterol hydroxylases, cholesterol 25-hydroxylase is not a cytochrome P450, but rather it is a member of a small family of enzymes that utilize diiron cofactors to catalyze the hydroxylation of hydrophobic substrates. The cholesterol 25-hydroxylase gene lacks introns, and in the human it is located on chromosome 10q23. The murine gene is expressed at low levels in multiple tissues. Expression of cholesterol 25-hydroxylase in transfected cells reduces the biosynthesis of cholesterol from acetate and suppresses the cleavage of sterol regulatory element binding protein-1 and -2, The data suggest that cholesterol 25-hydroxylase has the capacity to play an important role in regulating lipid metabolism by synthesizing a co-repressor that blocks sterol regulatory element binding protein processing and ultimately leads to inhibition of gene transcription.