Abstract
In order to rapidly and efficiently excavate antihypertensive ingredients in Todarodes pacificus, its myosin heavy chain was hydrolyzed in silico and the angiotensin-converting enzyme (ACE) inhibitory peptides were predicted using integrated bioinformatics tools. The results showed the degree of hydrolysis (DH) theoretically achieved 56.8% when digested with papain, ficin, and prolyl endopeptidase (PREP), producing 126 ACE inhibitory peptides. By predicting the toxicity, allergenicity, gastrointestinal stability, and intestinal epithelial permeability, 30 peptides were finally screened, of which 21 had been reported and 9 were new. Moreover, the newly discovered peptides were synthesized to evaluate their in vitro ACE inhibition, showing Ile-Ile-Tyr and Asn-Pro-Pro-Lys had strong effects with a pIC50 of 4.58 and 4.41, respectively. Further, their interaction mechanisms and bonding configurations with ACE were explored by molecular simulation. The preferred conformation of Ile-Ile-Tyr and Asn-Pro-Pro-Lys located in ACE were successfully predicted using the appropriate docking parameters. The molecular dynamics (MD) result indicated that they bound tightly to the active site of ACE by means of coordination with Zn(II) and hydrogen bonding and hydrophobic interaction with the residues in the pockets of S1 and S2, resulting in stable complexes. In summary, this work proposed a strategy for screening and identifying antihypertensive peptides from Todarodes pacificus.
Highlights
The angiotensin-converting enzyme (ACE) is a metal carboxypeptidase involved in the renin-angiotensin system, which controls blood pressure and electrolyte homeostasis, and renal function and myocardial remodeling [1]
Two proteases derived from plants were used to hydrolyze the myosin heavy chain of Todarodes pacificus to produce ACE inhibitory peptides
They showed a wider specificity in comparison with other enzymes such as trypsin or pepsin, cleaving peptide bonds from multiple regions and frequently acting as both exo- and endopeptidase [24]. Another enzyme prolyl endopeptidase (PREP) was selected for a supplementary hydrolysis after the action of plant proteases, which cleaved peptide bonds at the C-terminal side of Pro residues [25]. This hydrolysis specificity played a key role in the release of potent ACE inhibitory peptides, because a common feature of many potent ACE inhibitory sequences was the presence of Pro residues at one or more positions of the C-terminal region [26]
Summary
The angiotensin-converting enzyme (ACE) is a metal carboxypeptidase involved in the renin-angiotensin system, which controls blood pressure and electrolyte homeostasis, and renal function and myocardial remodeling [1]. A population-based cohort study has revealed a relationship between the long-term use of ACE inhibitors and an increased risk of lung cancer [5]. Their side effects have focused researchers’ interest on the search for alternative non-toxic and naturally generated peptides for controlling blood pressure
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