Clinicile Puls Medica, Bucharest, Romania.
Department of Medical Biochemistry, Faculty of Medicine, Near East University, Nicosia, Cyprus.
J Mol Recognit. 2023 Sep;36(9):e3050. doi: 10.1002/jmr.3050. Epub 2023 Aug 9.
The interactions of the classic phytohormones gibberellic acid (gibberellin A , GA ) and abscisic acid (dormin, ABA), which antagonistically regulate several developmental processes and stress responses in higher plants, with human placental glutathione S-transferase P1-1 (hpGSTP1-1), an enzyme that plays a role in endo- or xenobiotic detoxification and regulation of cell survival and apoptosis, were investigated. The inhibitory potencies of ABA and GA against hpGSTP1, as well as the types of inhibition and the kinetic parameters, were determined by making use of both enzyme kinetic graphs and SPSS nonlinear regression models. The structural basis for the interaction between hpGSTP1-1 and phytohormones was predicted with the aid of molecular docking simulations. The IC values of ABA and GA were 5.3 and 5.0 mM, respectively. Both phytohormones inhibited hpGSTP1-1 in competitive manner with respect to the cosubstrates GSH and CDNB. When ABA was the inhibitor at [CDNB] -[GSH] and at [GSH] -[CDNB] , V , K , and K values were statistically estimated to be 205 ± 16 μmol/min-mg protein, 1.32 ± 0.18 mM, 1.95 ± 0.25 mM and 175 ± 6 μmol/min-mg protein, 0.85 ± 0.06 mM, 1.85 ± 0.16 mM, respectively. On the other hand, the kinetic parameters V , K , and K obtained with GA at [CDNB] -[GSH] and at [GSH] -[CDNB] were found to be 303 ± 14 μmol/min-mg protein, 1.77 ± 0.13 mM, 3.38 ± 0.26 mM and 249 ± 7 μmol/min-mg protein, 1.43 ± 0.07 mM, 2.89 ± 0.19 mM, respectively. Both phytohormones had the potential to engage in hydrogen-bonding and electrostatic interactions with the key residues that line the G- and H-sites of the enzyme's catalytic center. Inhibitory actions of ABA/GA on hpGSTP1-1 may guide medicinal chemists through the structure-based design of novel antineoplastic agents. It should be noted, however, that the same interactions may also render fetuses vulnerable to the potentially toxic effects of xenobiotics and noxious endobiotics.
经典植物激素赤霉素（GA）和脱落酸（ABA，休眠素）相互作用，拮抗调节高等植物的几个发育过程和应激反应，与人类胎盘谷胱甘肽 S-转移酶 P1-1（hpGSTP1-1）相互作用，该酶在内外源毒物解毒和细胞存活和凋亡调节中起作用。利用酶动力学图和 SPSS 非线性回归模型确定了 ABA 和 GA 对 hpGSTP1 的抑制效力、抑制类型和动力学参数。借助分子对接模拟预测了 hpGSTP1-1 与植物激素相互作用的结构基础。ABA 和 GA 的 IC 值分别为 5.3 和 5.0 mM。两种植物激素均以竞争性方式抑制 hpGSTP1-1 对共底物 GSH 和 CDNB 的作用。当 ABA 是抑制剂时，[CDNB] -[GSH] 和 [GSH] -[CDNB]时，V、K 和 K 值分别统计估计为 205 ± 16 μmol/min-mg protein、1.32 ± 0.18 mM、1.95 ± 0.25 mM 和 175 ± 6 μmol/min-mg protein、0.85 ± 0.06 mM、1.85 ± 0.16 mM。另一方面，用 GA 在 [CDNB] -[GSH]和 [GSH] -[CDNB]时获得的动力学参数 V、K 和 K 分别为 303 ± 14 μmol/min-mg protein、1.77 ± 0.13 mM、3.38 ± 0.26 mM 和 249 ± 7 μmol/min-mg protein、1.43 ± 0.07 mM、2.89 ± 0.19 mM。两种植物激素都有可能与酶催化中心 G-和 H-位点的关键残基形成氢键和静电相互作用。ABA/GA 对 hpGSTP1-1 的抑制作用可能指导药物化学家通过基于结构的新型抗肿瘤药物设计。然而，应该注意的是，相同的相互作用也可能使胎儿容易受到外源性毒物和内源性毒物的潜在毒性影响。
