Cytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis.
Cytochrome P450 metabolism of the post-lanosterol intermediates explains enigmas of cholesterol synthesis.
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DOI：
10.1038/srep28462
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发表时间：
2016-06-23
影响因子：
4.6
通讯作者：
Rozman D
中科院分区：
文献类型：
--
作者：
Ačimovič J;Goyal S;Košir R;Goličnik M;Perše M;Belič A;Urlep Ž;Guengerich FP;Rozman D
胆固醇合成是最古老的代谢途径之一，由Bloch和Kandutch-Russell分支组成。在羊毛甾醇之后，两个分支的甾醇被提议专用于胆固醇。我们挑战这个教条的数学建模和实验证据。用基于教科书胆固醇合成途径的数学模型无法解释cAMP反应元件调节剂tau（Crem τ）基因敲除小鼠睾丸中的固醇谱。我们的模型的不同之处在于包括虚拟甾醇代谢酶分支的途径。我们测试的假设，从细胞色素P450（P450）超家族的酶可以参与非经典反应的催化。我们发现，胆固醇代谢酶可以在体外代谢多种固醇，建立新的分支点的胆固醇合成。总之，胆固醇合成的甾醇可以被进一步氧化成不专门用于胆固醇生产的代谢产物。此外，CYP 7A 1，CYP 11 A1，CYP 27 A1和CYP 46 A1是更广泛的胆固醇合成网络的一部分。
Cholesterol synthesis is among the oldest metabolic pathways, consisting of the Bloch and Kandutch-Russell branches. Following lanosterol, sterols of both branches are proposed to be dedicated to cholesterol. We challenge this dogma by mathematical modeling and with experimental evidence. It was not possible to explain the sterol profile of testis in cAMP responsive element modulator tau (Crem τ) knockout mice with mathematical models based on textbook pathways of cholesterol synthesis. Our model differs in the inclusion of virtual sterol metabolizing enzymes branching from the pathway. We tested the hypothesis that enzymes from the cytochrome P450 (CYP) superfamily can participate in the catalysis of non-classical reactions. We show that CYP enzymes can metabolize multiple sterols in vitro, establishing novel branching points of cholesterol synthesis. In conclusion, sterols of cholesterol synthesis can be oxidized further to metabolites not dedicated to production of cholesterol. Additionally, CYP7A1, CYP11A1, CYP27A1, and CYP46A1 are parts of a broader cholesterol synthesis network.