Studies on the molecular recognition between bioactive peptides and angiotensin‐converting enzyme

Abstract

High blood pressure or hypertension is a condition affecting many individuals and represents a controllable risk factor for cardiovascular diseases such as coronary heart disease and stroke. A non-pharmacological approach to manage these includes the application of food components with antihypertensive activity. Milk protein-derived peptides have been exploited as natural hypotensive agents, namely the peptides Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP), already commercialized in functional foods as a potential alternative to synthetic drugs. These bioactive peptides inhibit in vitro and in vivo the Angiotensin I-converting enzyme (ACE), a protein with an important role in blood pressure regulation. In this work, we attempted to elucidate the possible mode of interaction between the peptides and ACE, including mechanisms of binding to the cofactor Zn2+, and further contrast this with the known mode of inhibition exerted by synthetic drugs (Captopril, Enalaprilat and Lisinopril). The bioactive peptide Ala-Leu-Pro-Met-His-Ile-Arg (ALPMHIR), also known to inhibit the enzyme ACE but with a lower efficiency than VPP and IPP, was utilized in the docking studies for comparison. It was observed that the best docking poses obtained for VPP and IPP were located at the ACE catalytic site with very high resemblance to the drugs mode of interaction, including the coordination with Zn2+. As for ALPMHIR, the best docking poses were located in the narrow ACE channel outside the catalytic site, representing higher affinity energies and fewer resemblances with the interaction established by drugs.

Angiotensin I-converting enzyme (ACE) inhibitory peptides derived from arachin by simulated gastric digestion

“…The modeling study with NAQRP shows that the peptide orients in such a way that the carbonyl oxygen of the peptide bond between Ala and Gln co-ordinates the catalytic Zn (II) to complete the tetrahedral geometry. This differs from that reported for tripeptide-tACE complexes, wherein the carbonyl oxygen between the P1 and P1 0 co-ordinates Zn (II) (Pina & Roque, 2009). The tripeptide QRP-tACE complex studied by this modeling simulation (Fig.…”

“…The predicted binding affinity (Table 1) of the peptide suggests that it is a more potent inhibitor than NAQRP. Further, the best pose of the QRP docked at tACE shows it is buried in the active site channel as reported for other tripeptides (Pina & Roque, 2009). The carbonyl oxygen of the peptide bond between Q and R is positioned at a distance of 3.2 Å to coordinate the active site Zn (II) atom.…”

Milk intelligence: Mining milk for bioactive substances associated with human health

“…Moreover, bioavailability studies by Foltz et al (2007) demonstrated that the tri-peptide, Ile-Pro-Pro, selectively escapes from intestinal degradation and reaches the circulation undegraded. It was also demonstrated that Val-Pro-Pro and Ile-Pro-Pro have the potential to inhibit ACE in a very similar fashion to the current synthetic ACE inhibitors Captopril, Enalaprilat and Lisinopril, by hydrogen-bonding with similar residues in the ACE catalytic site (Pina & Roque, 2008). Interestingly, antihypertensive peptides have now been produced using recombinant DNA technologies, whereby recombinant fusion proteins have been expressed in Escherichia coli, which are then purified and cleaved by proteinase from a selected strain of L. helveticus (Losacco, Gallerani, Gobbetti, Minervini, & De Leo, 2007).…”

In silico analysis and antihypertensive effect of ACE-inhibitory peptides from smooth-hound viscera protein hydrolysate: Enzyme-peptide interaction study using molecular docking simulation

“…Roque [55] have reported that ACE contained three active pockets, S1, S2 and S1'. S1 included Ala354, Glu384 and Tyr523 residues, S2 included Gln281, His353, Lys511, His513 and Tyr520 residues, while S1' contained Glu162 residue.…”