Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University Olomouc, tř. 17. listopadu 12, 771 46, Olomouc, Czech Republic.
J Chem Inf Model. 2015 Mar 23;55(3):628-35. doi: 10.1021/ci500645k. Epub 2015 Feb 19.
Cholesterol is a widely researched component of biological membranes that significantly influences membrane properties. Human cytochrome P450 3A4 (CYP3A4) is an important drug-metabolizing enzyme, wherein the catalytic domain is attached to a membrane by an N-terminal α-helical transmembrane anchor. We analyzed the behavior of CYP3A4 immersed in a 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) membrane with various amounts of cholesterol. The presence of cholesterol caused ordering and thickening of the membrane and led to greater immersion and inclination of CYP3A4 toward the membrane. Cholesterol also lowered the flexibility of and tended to concentrate around membrane-immersed parts of CYP3A4. Further, the pattern of the CYP3A4 active-site access channels was altered in the presence of cholesterol. In summary, cholesterol in the membrane affected the positioning and structural features of CYP3A4, which in turn may have implications for the activity of this enzyme in various membranes and membrane parts with different cholesterol content.
胆固醇是生物膜中广泛研究的成分，对膜性质有重要影响。人类细胞色素 P450 3A4（CYP3A4）是一种重要的药物代谢酶，其催化结构域通过 N 端α-螺旋跨膜锚附着在膜上。我们分析了 CYP3A4 在含有不同胆固醇量的 1,2-二油酰基-sn-甘油-3-磷酸胆碱（DOPC）膜中的行为。胆固醇的存在导致膜的有序化和增厚，并使 CYP3A4 更多地浸入并倾斜向膜。胆固醇还降低了 CYP3A4 膜浸入部分的柔韧性，并倾向于集中在周围。此外，胆固醇的存在改变了 CYP3A4 活性部位进入通道的模式。总之，膜中的胆固醇影响 CYP3A4 的定位和结构特征，这可能对该酶在不同膜和具有不同胆固醇含量的膜部分中的活性产生影响。
