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

Abstract

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.

Identification, structure-activity relationship andin silicomolecular docking analyses of five novel angiotensin I-converting enzyme (ACE)-inhibitory peptides from stone fish hydrolysates

“…The free energy values obtained for the five peptides (−34.371 to −62.089 kj/mol) were found to be lower compared to the previously reported values of −13.97 to −21.59 kj/mol for peptides purified from Pacific cod skin gelatin-hydrolysates (55) and −31.46 to −39.91 kcal/mol for rape seed protein-generated peptides (51). These observations indicate higher affinity of the peptides identified in the present study for binding with ACE.…”

“…The atomic interactions between the amino acids residues of the peptides and that from the ACE within a distance of 3.5 Å also contributed to the stability of the peptide-ACE complex (50, 51). Right space orientation results in strong bond formation with the peptide in close proximity to ACE.…”

Antihypertensive properties of tilapia (Oreochromis spp.) frame and skin enzymatic protein hydrolysates

“…Angiotensin II is a potent vasoconstrictor, which results in blood pressure increase. Thus, multifunctional peptides with simultaneous inhibition of renin and ACE activities provide a more efficient RAS regulation compared to specific single enzyme inhibitors [19]. …”

Isolation, Purification and Molecular Mechanism of a Peanut Protein-Derived ACE-Inhibitory Peptide

“…From literature, most of researchers have worked only on the ACE inhibitory ability of peptides [20] – [22] . There are only a limited number of studies dealing with the interaction between peptide and ACE [4] , [23] – [25] . Although crystal structure of ACE inhibiting peptide compounds and the active sites on ACE have been identified and uploaded to Protein Data Bank [26] , [27] , trying to find natural antihypertensive agents from different species and investigate their structure-activity relationship still attracts lots of researchers’ interests.…”