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首页> 外文期刊>Toxicology: An International Journal Concerned with the Effects of Chemicals on Living Systems >Species-specific differences in the inhibition of human and zebrafish 11β-hydroxysteroid dehydrogenase 2 by thiram and organotins
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Species-specific differences in the inhibition of human and zebrafish 11β-hydroxysteroid dehydrogenase 2 by thiram and organotins

机译：锡兰和有机锡对人和斑马鱼11β-羟类固醇脱氢酶2抑制作用的物种特异性差异

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摘要

Dithiocarbamates and organotins can inhibit enzymes by interacting with functionally essential sulfhydryl groups. Both classes of chemicals were shown to inhibit human 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), which converts active cortisol into inactive cortisone and has a role in renal and intestinal electrolyte regulation and in the feto-placental barrier to maternal glucocorticoids. In fish, 11β-HSD2 has a dual role by inactivating glucocorticoids and generating the major androgen 11-ketotestosterone. Inhibition of this enzyme may enhance glucocorticoid and diminish androgen effects in fish. Here, we characterized 11β-HSD2 activity of the model species zebrafish. A comparison with human and mouse 11β-HSD2 revealed species-specific substrate preference. Unexpectedly, assessment of the effects of thiram and several organotins on the activity of zebrafish 11β-HSD2 showed weak inhibition by thiram and no inhibition by any of the organotins tested. Sequence comparison revealed the presence of an alanine at position 253 on zebrafish 11β-HSD2, corresponding to cysteine-264 in the substrate-binding pocket of the human enzyme. Substitution of alanine-253 by cysteine resulted in a more than 10-fold increased sensitivity of zebrafish 11β-HSD2 to thiram. Mutating cysteine-264 on human 11β-HSD2 to serine resulted in 100-fold lower inhibitory activity. Our results demonstrate significant species differences in the sensitivity of human and zebrafish 11β-HSD2 to inhibition by thiram and organotins. Site-directed mutagenesis revealed a key role of cysteine-264 in the substrate-binding pocket of human 11β-HSD2 for sensitivity to sulfhydryl modifying agents.
机译：二硫代氨基甲酸酯和有机锡可以通过与功能必需的巯基基团相互作用来抑制酶。这两类化学物质均显示抑制人11β-羟类固醇脱氢酶2（11β-HSD2）的作用，后者将活性皮质醇转化为无活性可的松，并在肾脏和肠道电解质调节以及对母体糖皮质激素的胎儿胎盘屏障中起作用。在鱼类中，11β-HSD2通过使糖皮质激素失活并产生主要的雄激素11-酮睾酮而具有双重作用。抑制这种酶可能会增强糖皮质激素并减少鱼类中的雄激素作用。在这里，我们表征了模型物种斑马鱼的11β-HSD2活性。与人和小鼠11β-HSD2的比较揭示了物种特异性底物偏好。出乎意料的是，对锡拉姆和几种有机锡对斑马鱼11β-HSD2活性的影响进行评估显示，锡拉姆的抑制作用较弱，而所测试的任何有机锡都没有抑制作用。序列比较显示在斑马鱼11β-HSD2的253位上存在丙氨酸，对应于人酶底物结合口袋中的半胱氨酸-264。半胱氨酸取代丙氨酸253导致斑马鱼11β-HSD2对硫胺素的敏感性提高了10倍以上。将人11β-HSD2上的半胱氨酸264突变为丝氨酸会导致抑制活性降低100倍。我们的研究结果表明，人类和斑马鱼11β-HSD2对thiram和有机锡的抑制作用的敏感性存在显着的物种差异。定点诱变揭示了半胱氨酸264在人11β-HSD2的底物结合口袋中对于巯基修饰剂的敏感性具有关键作用。

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