Glutathione reductase (GR) is a homodimeric enzyme playing an important role in the regeneration of the central antioxidant molecule reduced glutathione (GSH) from oxidized glutathione (GSSG) at the expense of a molecule of NADPH. GSH scavenges and eliminates superoxide and hydroxyl radicals non-enzymatically or serves as an electron donor for several enzymes. Fluoxetine (FLU), a selective serotonin reuptake inhibitor, is widely prescribed in the treatment of major depressive disorder. Here, using enzyme kinetic studies and molecular docking simulations, we aimed at disclosing the mechanistic and structural aspects of the interaction between GR and FLU. Affecting enzyme activity in a dose-dependent manner, FLU was shown to be a moderately potent (IC₅₀ = 0.88 mM) inhibitor of GR. When the variable substrate was GSSG, the type of inhibition was linear mixed-type competitive (K_i = 279 ± 32 μM; α = 5.48 ± 1.29). When the variable substrate was NADPH, however, the type of inhibition was non-competitive (K_i = 879 ± 82 μM). The observed difference in inhibition types was attributed to the binding of FLU in the large intermonomer cavity of GR, where it hampered catalysis and interfered with substrate binding. Overall, although it is anticipated that long-term use of FLU leads to acquired GR deficiency, the inhibitory action of FLU on GR may be therapeutically exploited in anti-cancer research.

中文翻译：

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氟西汀对谷胱甘肽还原酶的抑制作用与人类健康和疾病的关系：动力学和对接研究的结合。

谷胱甘肽还原酶（GR）是一种同型二聚酶，在以氧化型谷胱甘肽（GSSG）为中心的抗氧化剂分子还原型谷胱甘肽（GSH）的再生中起着重要作用，而以NADPH分子为代价。GSH非酶清除和消除超氧化物和羟基自由基，或作为多种酶的电子供体。氟西汀（FLU）是一种选择性的5-羟色胺再摄取抑制剂，在治疗重度抑郁症中被广泛使用。在这里，使用酶动力学研究和分子对接模拟，我们旨在揭示GR和FLU之间相互作用的机理和结构方面。以剂量依赖的方式影响酶的活性，FLU被证明具有中等效力（IC ₅₀ = 0.88 mM）GR抑制剂。当可变底物为GSSG时，抑制类型为线性混合竞争型（K _i  = 279±32μM；α  = 5.48±1.29）。但是，当可变底物为NADPH时，抑制类型是非竞争性的（K _i  = 879±82μM）。在抑制类型上观察到的差异归因于FLU在GR的大分子单体腔中的结合，在那阻碍了催化并干扰了底物的结合。总体而言，尽管可以预期长期使用FLU会导致获得性GR缺乏，但在抗癌研究中可以通过治疗利用FLU对GR的抑制作用。