Evaluating molecular mechanism of hypotensive peptides interactions with renin and angiotensin converting enzyme.
Evaluating molecular mechanism of hypotensive peptides interactions with renin and angiotensin converting enzyme.
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评估降血压肽与肾素和血管紧张素转换酶相互作用的分子机制
DOI：
10.1371/journal.pone.0091051
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Ju XR
中科院分区：
文献类型：
--
作者：
He R;Aluko RE;Ju XR
我们之前的研究表明，三种油菜籽蛋白衍生肽（TF、LY 和 RALP）可抑制血管紧张素转换酶（ACE）和肾素的体外活性。自发性高血压大鼠口服这些肽可导致收缩压降低。在目前的工作中，我们研究了这些肽的 ACE 和肾素抑制活性的潜在分子机制。酶抑制动力学显示对肾素和 ACE 活性的竞争性、非竞争性和混合型肽依赖性抑制。固有荧光强度数据表明，与TF相比，LY和RALP对ACE分子的结合作用更强。 LY 和 RALP 分别对 ACE 和肾素活性具有最高的抑制作用。圆二色性数据表明，抑制机制涉及 ACE 和肾素蛋白构象的 α 螺旋和 β 折叠部分的广泛肽依赖性减少。分子对接研究证实，RALP 较高的肾素抑制活性可能是由于与酶的活性位点残基形成了多个氢键（H 键）。油菜籽肽主要通过与酶活性位点或非活性位点结合并形成广泛的氢键来抑制肾素和 ACE 活性，从而扭曲催化所需的正常构型。这项工作提供的数据可以促进高效抗高血压天然肽或肽模拟物的开发。
Our previous study showed that three rapeseed protein-derived peptides (TF, LY and RALP) inhibited the in vitro activities of angiotensin converting enzyme (ACE) and renin. Oral administration of these peptides to spontaneously hypertensive rats led to reductions in systolic blood pressure. In the present work, we examined the potential molecular mechanisms responsible for the ACE- and renin-inhibitory activities of these peptides. Enzyme inhibition kinetics showed competitive, non-competitive and mixed-type peptide-dependent inhibition of renin and ACE activities. Intrinsic fluorescence intensity data showed that LY and RALP have stronger binding effects on ACE molecule compared to that of TF. LY and RALP showed the highest inhibition of ACE and renin activities, respectively. Circular dichroism data showed that the inhibitory mechanism involved extensive peptide-dependent reductions in α-helix and β-sheet fractions of ACE and renin protein conformations. Molecular docking studies confirmed that the higher renin-inhibitory activity of RALP may be due to formation of several hydrogen bonds (H-bonds) with the enzyme’s active site residues. The rapeseed peptides inhibited renin and ACE activities mostly through binding to enzyme active site or non-active sites and forming extensive H-bonds that distorted the normal configuration required for catalysis. Data presented from this work could enhance development of highly potent antihypertensive natural peptides or peptidomimetics.
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