7 research outputs found

    Evaluating Molecular Mechanism of Hypotensive Peptides Interactions with Renin and Angiotensin Converting Enzyme

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    <div><p>Our previous study showed that three rapeseed protein-derived peptides (TF, LY and RALP) inhibited the <i>in vitro</i> 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.</p></div

    Lineweaver-Burk plots of the inhibition of ACE and renin by peptides.

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    <p>(A) TF, (B) LY, and (C) RALP are at varying concentrations of ACE substrate (0.0625–0.5 mM), and V is rate of reaction (ΔA345 nm/min); (D) TF, (E) LY and (F) RALP are at varying concentrations of renin substrate (1.25–10 µM), and V is rate of reaction (FIU/min).</p

    Kinetics constants of angiotensin converting enzyme-catalyzed reaction at different peptide concentrations.

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    <p><i>K<sub>m</sub></i> or <i>K</i>′<i><sub>m</sub></i> is Michaelis-Menten constant in the absence (control) or presence of a peptide; <i>V<sub>max</sub></i> or <i>V</i>′<i><sub>max</sub></i> is maximum reaction velocities in the absence (control) or presence of a peptide; <i>K<sub>i</sub></i> is the enzyme-inhibitor dissociation constant.</p

    ACE (PDB: 1O86) and renin (PDB: 2V0Z) residues having at least one atom at a distance of 3.5 Ã… around the docked peptide.

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    <p>The residues around crystallized lisinopril and Aliskiren in the ACE and renin structures are also shown.</p

    Molecular docking of the peptides at ACE and renin active sites.

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    <p>Results of peptide-ACE interactions are showed in A (TF), B (LY), C (RALP), and that of peptide-renin interactions are D (TF), E (LY), F (RALP). Enzyme hydrophobic residues are represented in red, positively charged residues are represented in blue, negatively charged residues and hydrogen bonds are represented in green, and other residues are represented automatically. (Image obtained with Accelrys DS Visualizer software).</p

    Kinetics constants of renin-catalyzed reaction at different peptide concentrations.

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    <p><i>K<sub>m</sub></i> or <i>K</i>′<i><sub>m</sub></i> is Michaelis-Menten constant in the absence (control) or presence of a peptide; <i>V<sub>max</sub></i> or <i>V</i>′<i><sub>max</sub></i> is maximum reaction velocities in the absence (control) or presence of a peptide; <i>K<sub>i</sub></i> is the enzyme-inhibitor dissociation constant.</p

    Emission spectra of ACE and renin proteins in the presence of peptides.

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    <p>Results of peptide-ACE interactions are showed in A (TF), B (LY), C (RALP), and that of peptide-renin interactions are D (TF), E (LY), F (RALP). In all cases λ<sub>ex</sub> = 280 nm.</p
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