光譜法和分子對(duì)接模擬技術(shù)研究托拉塞米與胃蛋白酶和胰蛋白酶的相互作用（英文）
發(fā)布時(shí)間：2018-10-20 17:43
【摘要】：托拉塞米(TOR)屬于吡啶磺酰脲類袢利尿劑,被廣泛有效地用于高血壓,心臟衰竭,慢性腎功能衰竭和肝臟疾病的治療。TOR在治療過程中易引起的不良反應(yīng)之一為輕微腸胃不適。然而,TOR與消化蛋白酶(胰蛋白酶和胃蛋白酶)分子間的相互作用鮮有報(bào)道。在模擬生理?xiàng)l件下,采用熒光光譜、紫外-可見吸收光譜、圓二色譜和分子對(duì)接技術(shù)研究了不同溫度下托拉塞米(Torasemide,TOR)與胃蛋白酶(Pepsin)和胰蛋白酶(Trypsin)間的相互作用。所有熒光數(shù)據(jù)均進(jìn)行了內(nèi)濾光校正以獲得更準(zhǔn)確的結(jié)合參數(shù)。結(jié)果表明,TOR-Pepsin和TOR-Trypsin體系的猝滅常數(shù)(KSV)均與溫度呈負(fù)相關(guān),說明TOR與Pepsin及Trypsin之間的作用機(jī)制均為靜態(tài)熒光猝滅。利用紫外-可見吸收光譜、同步熒光光譜、3D熒光光譜和圓二色光譜法考查了TOR對(duì)Trypsin和Pepsin構(gòu)象的影響。結(jié)果發(fā)現(xiàn)胃蛋白酶或胰蛋白酶中酪氨酸殘基的極性改變較色氨基更明顯,TOR可改變色氨酸殘基的微環(huán)境并降低Trypsin和Pepsin中β-折疊結(jié)構(gòu),進(jìn)而可能影響其生理功能。分子對(duì)接結(jié)果表明,TOR與Pepsin的結(jié)合位點(diǎn)位于由Asp-32和Asp-215組成的活性中心周圍,從而抑制Pepsin活性。而TOR通過疏水作用力結(jié)合在Trypsin的口袋型底物結(jié)合位點(diǎn)(S1口袋),促進(jìn)底物進(jìn)入酶活性中心,最終表現(xiàn)為Trypsin活性升高。該研究探討了TOR與胃蛋白酶和胰蛋白酶的結(jié)合作用和毒性機(jī)制,為TOR的安全使用提供重要依據(jù)。
[Abstract]:Tora Semie (TOR), a pyridine sulfonylurea loop diuretic, is widely and effectively used in the treatment of hypertension, heart failure, chronic renal failure and liver disease. However, the interaction between TOR and pepsin (trypsin and pepsin) molecules is rarely reported. Under simulated physiological conditions, the interaction of Tora Semi (Torasemide,TOR) with pepsin (Pepsin) and trypsin (Trypsin) at different temperatures was studied by fluorescence spectra, UV-Vis absorption spectra, circular dichroism and molecular docking techniques. All fluorescence data were corrected by internal filter to obtain more accurate binding parameters. The results show that the quenching constant (KSV) of TOR-Pepsin and TOR-Trypsin system is negatively correlated with temperature, indicating that the mechanism of interaction between TOR and Pepsin and Trypsin is both static fluorescence quenching. The effects of TOR on the conformation of Trypsin and Pepsin were investigated by UV-Vis absorption spectra, synchronous fluorescence spectra, 3D fluorescence spectra and circular dichroism spectroscopy. The results showed that the polarity of tyrosine residues in pepsin or trypsin was more obvious than that in chromoamino group. TOR could change the microenvironment of tryptophan residues and decrease the 尾 -fold structure in Trypsin and Pepsin, which might affect its physiological function. The molecular docking results showed that the binding sites of TOR and Pepsin were located around the active sites composed of Asp-32 and Asp-215, which inhibited the activity of Pepsin. However, TOR binds to the pocket substrate binding site (S1 pocket) of Trypsin by hydrophobic force, which promotes the substrate to enter the enzyme active center, and finally shows the increase of Trypsin activity. In this study, the binding and toxic mechanism of TOR with pepsin and trypsin were discussed, which provided important basis for safe use of TOR.
【作者單位】： 中央民族大學(xué)生命與環(huán)境科學(xué)學(xué)院;中央民族大學(xué)北京市食品環(huán)境與健康工程技術(shù)研究中心;
【基金】：The National Natural Science Foundation of China(21177163) 111 Project B08044 First-Class University First Class Academic Program of Minzu University of China(YLDX01013) Special Guidance Fund of Building World First-Class Universities(Disciplines)and Characteristic Development of Minzu Unviersity of China(2016) Coordinate Development of FirstClass and First-Class University Discipline Construction Funds(10301-0150200604) The Academic Team Construction Project of Minzu University of China(2015MDTD25C&13C) The Fundamental Research Funds for the Central Universities”(10301-01404031,2015) First-Class Universities and First-Class Discipline Construction Transitional Funds under Special Funding(2016.ph.D),2015MDTD08C
【分類號(hào)】：R446.1
本文編號(hào)：2283914
[Abstract]:Tora Semie (TOR), a pyridine sulfonylurea loop diuretic, is widely and effectively used in the treatment of hypertension, heart failure, chronic renal failure and liver disease. However, the interaction between TOR and pepsin (trypsin and pepsin) molecules is rarely reported. Under simulated physiological conditions, the interaction of Tora Semi (Torasemide,TOR) with pepsin (Pepsin) and trypsin (Trypsin) at different temperatures was studied by fluorescence spectra, UV-Vis absorption spectra, circular dichroism and molecular docking techniques. All fluorescence data were corrected by internal filter to obtain more accurate binding parameters. The results show that the quenching constant (KSV) of TOR-Pepsin and TOR-Trypsin system is negatively correlated with temperature, indicating that the mechanism of interaction between TOR and Pepsin and Trypsin is both static fluorescence quenching. The effects of TOR on the conformation of Trypsin and Pepsin were investigated by UV-Vis absorption spectra, synchronous fluorescence spectra, 3D fluorescence spectra and circular dichroism spectroscopy. The results showed that the polarity of tyrosine residues in pepsin or trypsin was more obvious than that in chromoamino group. TOR could change the microenvironment of tryptophan residues and decrease the 尾 -fold structure in Trypsin and Pepsin, which might affect its physiological function. The molecular docking results showed that the binding sites of TOR and Pepsin were located around the active sites composed of Asp-32 and Asp-215, which inhibited the activity of Pepsin. However, TOR binds to the pocket substrate binding site (S1 pocket) of Trypsin by hydrophobic force, which promotes the substrate to enter the enzyme active center, and finally shows the increase of Trypsin activity. In this study, the binding and toxic mechanism of TOR with pepsin and trypsin were discussed, which provided important basis for safe use of TOR.
【作者單位】： 中央民族大學(xué)生命與環(huán)境科學(xué)學(xué)院;中央民族大學(xué)北京市食品環(huán)境與健康工程技術(shù)研究中心;
【基金】：The National Natural Science Foundation of China(21177163) 111 Project B08044 First-Class University First Class Academic Program of Minzu University of China(YLDX01013) Special Guidance Fund of Building World First-Class Universities(Disciplines)and Characteristic Development of Minzu Unviersity of China(2016) Coordinate Development of FirstClass and First-Class University Discipline Construction Funds(10301-0150200604) The Academic Team Construction Project of Minzu University of China(2015MDTD25C&13C) The Fundamental Research Funds for the Central Universities”(10301-01404031,2015) First-Class Universities and First-Class Discipline Construction Transitional Funds under Special Funding(2016.ph.D),2015MDTD08C
【分類號(hào)】：R446.1
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