Dap1/PGRMC1 binds and regulates cytochrome P450 enzymes.

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作   者：

Hughes AL;  Powell DW;  Bard M;  Eckstein J;  Barbuch R;  Link AJ;  Espenshade PJ; 

作者机构：

USA.;  Johns Hopkins University School of Medicine;  Baltimore;  MD 21205;  Department of Cell Biology; 

关键词：

基因表达调控;  真菌;  膜蛋白质类;  Fungal;  Gene Expression Regulation;  裂殖酵母菌属;  Cholesterol;  Cytochrome P-450 Enzyme System;  血红素;  孕酮;  蛋白质结合;  受体;  胆固醇; 

期刊名称：

Cell metabolism

i s s n：

1550-4131

年卷期：

2007 年 5 卷 2 期

页   码：

143-149

页   码：

摘   要：

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 Cyp51A1 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.