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首页> 外文期刊>The journal of physical chemistry, B. Condensed matter, materials, surfaces, interfaces & biophysical >How Does the Reductase Help To Regulate the Catalytic Cycle of Cytochrome P450 3A4 Using the Conserved Water Channel?
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How Does the Reductase Help To Regulate the Catalytic Cycle of Cytochrome P450 3A4 Using the Conserved Water Channel?

机译：还原酶如何利用节水通道帮助调节细胞色素P450 3A4的催化周期？

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摘要

Water molecules play a major role in the P450 catalytic cycle. Here, we locate the preferred water pathways and their gating mechanisms for the human cytochrome P450 3A4 (CYP3A4) and elucidate the role of the cytochrome P450 reductase (CPR) in turning on and activating these water channels. We perform explicit solvent molecular dynamic simulations of CYP3A4, unbound and bound to two substrates, and with and without the flavin mononucleotide (FMN)-binding domain of CPR. We observe in/out passage of water molecules via a water-specific and conserved channel (aqueduct) located between the active site and the heme proximal side. We find that the aqueduct gating mechanism is mediated by R375, the conserved arginine that salt bridges with the heme 7-propionate. When R375 rotates, it opens the aqueduct and establishes a connection between a cluster of active site water molecules network and the bulk solvent. The aqueduct region overlaps with the CPR binding-site to CYP3A4. Indeed, we find that when the FMN domain of CPR binds to CYP3A4, the aqueduct fully opens up, thereby allowing a flow of water molecules. The aqueduct's opening can permit proton transfer, shuttling the protons to the active site through ordered water molecules. In addition, the expulsion of water molecules via the aqueduct contributes to substrate binding. As such, the CPR binding has a function: it triggers the aqueduct's opening and thereby enables a proton shuttle pathway, which is needed for the dioxygen activation. This mechanism could be a general paradigm in P450s.
机译：水分子在P450催化循环中起主要作用。在这里，我们找到了人类细胞色素P450 3A4（CYP3A4）的优选水途径及其门控机制，并阐明了细胞色素P450还原酶（CPR）在开启和激活这些水通道中的作用。我们执行CYP3A4的显式溶剂分子动力学模拟，未结合和结合到两个底物上，带有和不带有CPR的黄素单核苷酸（FMN）结合域。我们观察到水分子通过位于活性位点和血红素近端之间的水特异性且保守的通道（渡槽）进入/流出通道。我们发现渡槽门控机制是由R375介导的，R375是盐与血红素7-丙酸酯桥接的保守精氨酸。当R375旋转时，它会打开渡槽并在一组活性位点水分子网络和大量溶剂之间建立连接。渡槽区域与CPR与CYP3A4的结合位点重叠。实际上，我们发现当CPR的FMN域与CYP3A4结合时，渡槽完全打开，从而允许水分子流动。渡槽的开口可以允许质子转移，通过有序的水分子将质子穿梭到活性位点。另外，水分子通过渡槽排出有助于底物结合。因此，CPR绑定具有功能：它触发渡槽的打开，从而启用质子穿梭路径，这是双氧激活所必需的。这种机制可能是P450的一般范例。

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