Institute of Biomedical Chemistry, 10 Building 8, Pogodinskaya Street, 119121 Moscow, Russia.
Institute of Bioorganic Chemistry NASB, 5 Building 2, V.F. Kuprevich Street, 220141 Minsk, Belarus.
Molecules. 2021 Apr 13;26(8):2237. doi: 10.3390/molecules26082237.
Widespread pathologies such as atherosclerosis, metabolic syndrome and cancer are associated with dysregulation of sterol biosynthesis and metabolism. Cholesterol modulates the signaling pathways of neoplastic transformation and tumor progression. Lanosterol 14-alpha demethylase (cytochrome P450(51), CYP51A1) catalyzes one of the key steps in cholesterol biosynthesis. The fairly low somatic mutation frequency of CYP51A1, its druggability, as well as the possibility of interfering with cholesterol metabolism in cancer cells collectively suggest the clinical importance of CYP51A1. Here, we show that the natural flavonoid, luteolin 7,3'-disulfate, inhibits CYP51A1 activity. We also screened baicalein and luteolin, known to have antitumor activities and low toxicity, for their ability to interact with CYP51A1. The K values were estimated using both a surface plasmon resonance optical biosensor and spectral titration assays. Unexpectedly, in the enzymatic activity assays, only the water-soluble form of luteolin-luteolin 7,3'-disulfate-showed the ability to potently inhibit CYP51A1. Based on molecular docking, luteolin 7,3'-disulfate binding suggests blocking of the substrate access channel. However, an alternative site on the proximal surface where the redox partner binds cannot be excluded. Overall, flavonoids have the potential to inhibit the activity of human CYP51A1 and should be further explored for their cholesterol-lowering and anti-cancer activity.
广泛存在的病理学，如动脉粥样硬化、代谢综合征和癌症，与固醇生物合成和代谢的失调有关。胆固醇调节着肿瘤转化和肿瘤进展的信号通路。羊毛甾醇 14α-脱甲基酶（细胞色素 P450(51)，CYP51A1）催化胆固醇生物合成中的关键步骤之一。CYP51A1 的体细胞突变频率相当低，具有可成药性，以及干扰癌细胞中胆固醇代谢的可能性，这些都共同表明 CYP51A1 的临床重要性。在这里，我们表明天然类黄酮，木樨草素 7,3'-二硫酸盐，抑制 CYP51A1 的活性。我们还筛选了黄芩素和木樨草素，它们已知具有抗肿瘤活性和低毒性，以研究它们与 CYP51A1 相互作用的能力。使用表面等离子体共振光学生物传感器和光谱滴定测定法估算 K 值。出乎意料的是，在酶活性测定中，只有水溶性形式的木樨草素-木樨草素 7,3'-二硫酸盐-显示出有效抑制 CYP51A1 的能力。基于分子对接，木樨草素 7,3'-二硫酸盐的结合表明阻断了底物进入通道。然而，不能排除在近表面结合氧化还原伴侣的替代位点。总的来说，类黄酮有可能抑制人 CYP51A1 的活性，应进一步探索其降低胆固醇和抗癌活性。
