Antihypertensive and Angiotensin-I-Converting Enzyme (ACE)-Inhibitory Peptides from Fish as Potential Cardioprotective Compounds

Abstract

The term metabolic/cardiometabolic/insulin resistance syndrome could generally be defined as the co-occurrence of several risk factors inclusive of systemic arterial hypertension. Not only that organizations, such as the world health organization (WHO) have identified high blood pressure as one of the main risk factors of the cardiometabolic syndrome, but there is also a link between the occurrence of insulin resistance/impaired glucose tolerance and hypertension that would consequently lead to type-2 diabetes (T2D). Hypertension is medicated by various classes of synthetic drugs; however, severe or mild adverse effects have been repeatedly reported. To avoid and reduce these adverse effects, natural alternatives, such as bioactive peptides derived from different sources have drawn the attention of researchers. Among all types of biologically active peptides inclusive of marine-derived ones, this paper's focus would solely be on fish and fishery by-processes' extracted peptides and products. Isolation and fractionation processes of these products alongside their structural, compositional and digestion stability characteristics have likewise been briefly discussed to better address the structure-activity relationship, expanding the reader's knowledge on research and discovery trend of fish antihypertensive biopeptides. Furthermore, drug-likeness of selected biopeptides was predicted by Lipinski's rules to differentiate a drug-like biopeptide from nondrug-like one.

Keywords: ACE-inhibitory peptide; antihypertensive; cardiometabolic-syndrome; fish; high blood pressure; hydrolysate; hypertension.

Figure 1

Human renin-angiotensin system pathway map. AGT: Angiotensinogen, ACE2: Angiotensin I converting enzyme 2, AngA: Angiotensin A, AP-A: Glutamyl aminopeptidase, AP-N: Alanyl aminopeptidase (membrane), AT1R: Angiotensin II receptor type 1, AT2R: Angiotensin II receptor type 2, CMA1: Chymase 1, CPA3: Carboxypeptidase A3, CTSA: Cathepsin A, CTSG: Cathepsin G, IRAP: Leucyl and cystinyl aminopeptidase, MAS1: MAS1 proto-oncogene, G protein-coupled receptor, MME: Membrane metalloendopeptidase, MRGPRD: MAS related GPR family member D, NLN: Neurolysin, PRCP: Prolylcarboxypeptidase, PREP: Prolyl endopeptidase, PRR: ATPase H+ transporting accessory protein 2, REN: Renin, THOP1: Thimet oligopeptidase. Figure 1 has been adapted and modified from KEGG Pathway Maps.

Figure 2

3D plots of the frontier molecular orbital of three food-extracted anti-ACE (angiotensin-I-converting enzyme) biopeptides. Per docking results Tyr-Leu-Val-Pro-His occupied an active groove surrounded by Ala352, Glu411, Tyr523, and His387 (His387, His512, Ser355, Val518, Trp357, Ser517, Pro519, Pro391, His410, and Arg522 having van der Waals contacts with the penta-peptide YLAPH), Tyr-Leu-Val-Arg occupied an active groove surrounded by His353, Ala356, His383, and His387 (Asn70, Val518, Trp357, Arg522, Val351, Phe512, and Ser355 having van der Waals contacts with the tetra-peptide, YLVR), Leu-Ile-Val-Thr occupied an active groove surrounded by Ala356, His353, His383, His387, His513, Tyr523 (Ser355, Glu411, Tyr520, Gln281, Phe457, Lys511, Phe527, Lys454, Val379, and Val380 having van der Waals contacts with the tetra-peptide, LIVT). Adapted and modified from Fang et al. [32].

Figure 3

Sequence and secondary structure of chain A human ACE (PDB code: 1O8A). Active sites, according to Attique et al. are; His317, Ala318, Ser319, His347, Glu348, His351, Glu375, Phe421, Lys475, Phe476, His477, Val482, Tyr484, Tyr487.