Study on the domain selective inhibition of angiotensin‐converting enzyme (ACE) by food‐derived tyrosine‐containing dipeptides

Abstract

In this article, the selective inhibition of several tyrosine‐containing dipeptides on N and C domain of ACE (angiotensin‐converting enzyme) was studied, and the interaction mode of ACE and inhibitors was simulated by molecular docking. MTT assay was used to detect the effect of dipeptide on human umbilical vein endothelial cells (HUVEC). The results showed that the food‐derived dipeptides AY (Ala‐Tyr), LY (Leu‐Tyr), and IY (Ile‐Tyr) containing tyrosine at the C‐terminal were favorable structures for selective inhibition of ACE C‐domain. These dipeptides showed competitive and mixed inhibition patterns, while the dipeptides EY (Glu‐Tyr), RY (Arg‐Tyr), FY (Phe‐Tyr), and SY (Ser‐Tyr) showed noncompetitive inhibition. Food‐derived dipeptides containing tyrosine have no cytotoxicity on HUVEC cells, which provides a basis for the application of food‐derived tyrosine dipeptides as antihypertensive peptides. This study provides a theoretical basis for exploring the selective inhibition mechanism of ACE inhibitory peptides containing tyrosine residue. Practical applications Angiotensin‐converting enzyme (ACE) is a two‐domain dipeptidyl carboxypeptidase, which is a key enzyme to regulate blood pressure. ACE has two active sites, C‐ and N‐domain, which have high catalytic activity. Although the amino acid sequences of the two active sites have 60% similarity, there are some differences in structure and function. The action mechanism of ACE domain should be clarified, and the structure‐activity relationship between inhibitors and ACE domain has not been systematically studied. The aim of this study was to identify the selective inhibitory effect of food‐derived tyrosine dipeptides on the domain of ACE. This provides a new idea for finding new antihypertensive drugs with less side effects.

Abalone Viscera Fermented with Aspergillus oryzae 001 Prevents Pressure Elevation by Inhibiting Angiotensin Converting Enzyme

“…V max was concentration-dependent while K m was relatively constant suggesting that ACE inhibition by L- m -tyrosine is a non-competitive inhibition. Similar to the present study, several tyrosine-containing dipeptides noncompetitively inhibited ACE [ 44 ]. In previous reports, ACE inhibitors obtained by hydrolysis of marine products, such as squid and tuna noncompetitively inhibited ACE [ 52 , 53 ].…”

“…ACE inhibitors of natural origin were present in carp scales, salmon processing by-products, and aosa-derived substances [ 41 , 42 , 43 ]. Previous studies have reported tyrosine-containing dipeptides [ 39 , 44 , 45 ] and tripeptides over [ 46 , 47 ] ACE inhibitory peptides. Inhibitory dipeptides with a tyrosine residue at the C-terminus are effective [ 48 , 49 ].…”

“…In previous studies, ACE-inhibitory activity and the mode of inhibition of peptides containing tyrosine were measured [ 44 , 51 ], but the mode of inhibition of tyrosine alone or L- m -tyrosine was not determined. This study is the first to investigate the ACE-inhibitory activity of L- m -tyrosine.…”

A Novel UPLC-MS/MS Method Identifies Organ-Specific Dipeptide Profiles

“…For example, treatment with carnosine or anserine prevented alterations of renal function in diabetic (db/db) mice [29][30][31]. Additionally, for proline-containing dipeptides the biological activities seem to be not only based on the free amino acid alone [1]; for Tyr-containing dipeptides [32] an inhibitory effect on ACE activity has been demonstrated, and Tyr-Asp improves plant tolerance to oxidative stress by directly interfering with glucose metabolism [33]. Gly-containing dipeptides can provide osmoregulation in preimplantation embryos [34].…”

Machine annealing‐guided navigation of antihypertensive food peptide selectivity between human ACE N‐ and C‐domains in structurally interacting diversity space

“…Over the past decades, a variety of small peptides derived from food sources such as milk, egg, fish, and rice have been found to exhibit potential antihypertensive activity by inhibiting ACE 21,22 . In particular, the food‐derived tyrosine/tryptophan‐containing dipeptides have recently been found as the C‐domain selective inhibitors of ACE 23,24 . These selective peptide inhibitors possess low toxicity and high biocompatibility, and thus serve as the good antihypertensive peptide (AHP) candidates of functional medicines to lower blood pressure and reduce the mortal risk in patients with HTN syndromes.…”