Wu Wanying, Jiang Tianqing, Lin Haihui, Chen Chao, Wang Lingling, Wen Jikai, Wu Jun, Deng Yiqun
Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou 510642, China.
Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China.
Metabolites. 2023 Apr 27;13(5):601. doi: 10.3390/metabo13050601.
Human AKR 7A2 broadly participates in the metabolism of a number of exogenous and endogenous compounds. Azoles are a class of clinically widely used antifungal drugs, which are usually metabolized by CYP 3A4, CYP2C19, and CYP1A1, etc. in vivo. The azole-protein interactions that human AKR7A2 participates in remain unreported. In this study, we investigated the effect of the representative azoles (miconazole, econazole, ketoconazole, fluconazole, itraconazole, voriconazole, and posaconazole) on the catalysis of human AKR7A2. The steady-state kinetics study showed that the catalytic efficiency of AKR7A2 enhanced in a dose-dependent manner in the presence of posaconazole, miconazole, fluconazole, and itraconazole, while it had no change in the presence of econazole, ketoconazole, and voriconazole. Biacore assays demonstrated that all seven azoles were able to specifically bind to AKR7A2, among which itraconazole, posaconazole, and voriconazole showed the strongest binding. Blind docking predicted that all azoles were apt to preferentially bind at the entrance of the substrate cavity of AKR7A2. Flexible docking showed that posaconazole, located at the region, can efficiently lower the binding energy of the substrate 2-CBA in the cavity compared to the case of no posaconazole. This study demonstrates that human AKR7A2 can interact with some azole drugs, and it also reveals that the enzyme activity can be regulated by some small molecules. These findings will enable a better understanding of azole-protein interactions.
人类AKR 7A2广泛参与多种外源性和内源性化合物的代谢。唑类是一类临床上广泛使用的抗真菌药物，在体内通常由CYP 3A4、CYP2C19和CYP1A1等代谢。人类AKR7A2参与的唑类与蛋白质的相互作用尚未见报道。在本研究中，我们研究了代表性唑类药物（咪康唑、益康唑、酮康唑、氟康唑、伊曲康唑、伏立康唑和泊沙康唑）对人类AKR7A2催化作用的影响。稳态动力学研究表明，在泊沙康唑、咪康唑、氟康唑和伊曲康唑存在的情况下，AKR7A2的催化效率呈剂量依赖性增强，而在益康唑、酮康唑和伏立康唑存在的情况下则没有变化。Biacore分析表明，所有七种唑类都能够特异性结合AKR7A2，其中伊曲康唑、泊沙康唑和伏立康唑的结合力最强。盲对接预测所有唑类都倾向于优先结合在AKR7A2底物腔的入口处。柔性对接显示，与不存在泊沙康唑的情况相比，位于该区域的泊沙康唑可以有效降低底物2-CBA在腔内的结合能。本研究表明人类AKR7A2可以与一些唑类药物相互作用，同时也揭示了酶活性可以受到一些小分子的调节。这些发现将有助于更好地理解唑类与蛋白质的相互作用。
