Dap1/PGRMC1 binds and regulates cytochrome P450 enzymes
Dap1/PGRMC1 binds and regulates cytochrome P450 enzymes
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DOI：
10.1016/j.cmet.2006.12.009
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发表时间：
2007-02-01
期刊：
影响因子：
29
通讯作者：
Espenshade, Peter J.
中科院分区：
文献类型：
--
作者：
Hughes, Adam L.;Powell, David W.;Espenshade, Peter J.
细胞色素P450酶是一种依赖于血红素的单加氧酶，在人体生理中起着核心作用。尽管P450酶影响许多生理过程，但电子供体P450氧化还原酶和细胞色素b5是已知的唯一与ER微粒体P450相互作用并调节其活性的蛋白质。在这里，我们报告了Dap1/PGRMC1是酵母和人类ER P450功能所必需的。我们证明了S.pombe Dap1是一种血红素蛋白，它结合并正向调节Cyp51A1和Cyp61A1，这两个P450是固醇生物合成所必需的。同样，人PGRMC1的缺失会降低Cyp51A1的活性，阻止胆固醇的合成，并增加有毒类固醇中间体的产生。PGRMC1稳定地与另外三个家族的Cyp5lAll和人P450结合，其中包括代谢药物化合物的CYP3A4。这些发现表明，PGRMC1是P450活性所必需的，并提示PGRMC1功能的个体间差异可能影响多个生化途径和药物代谢。
Cytochrome P450 enzymes are heme-dependent monoxygenases that play a central role in human physiology. Despite the numerous physiological processes that P450 enzymes impact, the electron donors P450 oxidoreductase and cytochrome b5 are the only proteins known to interact with and modulate the activity of ER microsomal P450s. Here, we report that Dap1/ PGRMC1 is required for ER P450 function in yeast and humans. We show that S. pombe Dap1 is a hemoprotein that binds and positively regulates Cyp51A1 and Cyp61A1, two P450s required for sterol biosynthesis. Similarly, loss of human PGRMC1 reduces activity of Cyp51A1, blocking cholesterol synthesis and increasing production of toxic sterol intermediates. PGRMC1 stably binds Cyp5lAll and human P450s from three additional families including Cyp3A4, which metabolizes pharmaceutical compounds. These findings demonstrate that PGRMC1 is required for P450 activity and suggest that interindividual variation in PGRMC1 function may impact multiple biochemical pathways and drug metabolism.