Food Biochemistry and Food Processing (2 edition)

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36 Biological Activities and Production of Marine-Derived Peptides 687

Rennin-angiotensin system (RAS)

Angiotensinogen

Angiotensin I

Angiotensin II

Kallikrein-kinin system

Kininogen

Bradykinin

Inactive fragments

Vasoconstriction

Increased peripheral

vascular resistance

Aldosterone secretion

Increased blood pressure

Increased Na+and

water retention

Vasodilatation

Decreased blood pressure

Decreased peripheral

vascular resistance

Increased

ACE prostaglandin synthesis

Renin Kallikrein

Figure 36.1.Role of angiotensin converting enzyme (ACE) in blood pressure regulation.

BIOLOGICAL ACTIVITIES OF

MARINE-DERIVED PEPTIDES

ACE Inhibitory Peptides

ACE inhibition has become an important target in the devel-

opment of drugs to control high blood pressure, which is a

significant health problem worldwide. ACE (EC 3.4.15.1) is a

zinc-metallopeptidase that needs zinc and chloride ions for its

activity (Erdos and Skidgel 1987). It is widely distributed in

mammalian tissues, predominantly as a membrane-bound ec-

toenzyme in vascular endothelial cells and also in several cell

types including absorptive epithelial, neuroepithelial, and male

germinal cells (Steve et al. 1988, Sibony et al. 1993). In the

renin-angiotensin system (RAS), ACE plays a crucial role in

the regulation of blood pressure as well as cardiovascular func-

tion (Li et al. 2004). Within the enzyme cascade of the RAS

(Fig. 36.1), ACE converts the inactive angiotensin I by cleaving

dipeptide from theC-terminus into the potent vasoconstricting

angiotensin II. This potent vasoconstrictor is also involved in

the release of a sodium-retaining steroid, aldosterone, from the

adrenal cortex, which has a tendency to increase blood pressure.

ACE is a multifunctional enzyme that also catalyses the degrada-

tion of bradykinin, a blood pressure lowering nonapeptide in the

kallikrein-kinin system (Erdos and Skidgel 1987, Johnston and

Franz 1992). Moreover, ACE has been shown to degrade neu-

ropeptides including enkephalins, neurotensin, and substance P,

which may interact with the cardiovascular system (Wyvratt and

Patchett 1985).

A large number of highly potent and specific ACE inhibitors

have been developed as orally active drugs that are used in ther-

apy to reduce morbidity and mortality of patients with hyperten-

sion. However, these synthetic drugs, such as captopril, enalapril,

alacepril, and lisinopril, which are used extensively, are believed

to have certain side effects, such as cough, taste disturbances,

and skin rashes angioedema and many other dysfunctions of hu-

man organs (Atkinson and Robertson 1979). Therefore, a search

for ACE inhibitors from foods and natural sources has become

a major area of research.

Marine-derived ACE inhibitory peptides have been discov-

ered in enzymatic hydrolysates of different marine animals

(Table 36.1). These peptides are generally short chain, often

carrying polar amino acid residues like proline, lysine, or argi-

nine atC-terminal residue (Meisel 1997). Cheung and Chush-

man (1971) suggested that tryptophan, tyrosine, proline, or

phenylalanine at theC-terminal and branched-chain aliphatic

amino acids at theN-terminal are suitable for peptides to act

as competitive inhibitors by binding with ACE. Furthermore,

structure–activity relationships among variety of peptide in-

hibitors of ACE indicate that binding to ACE is strongly influ-

enced by theC-terminal tripeptide sequence of the substrate, and

it is suggested that peptides, which contain hydrophobic amino

acids at these positions, are potent inhibitors (Qian et al. 2007).

It has been demonstrated that some marine-derived ACE-

inhibitory peptides exhibit higher or comparable in vivo anti-

hypertensive activity to captopril (Fujita and Yoshikawa 1999,

Lee et al. 2010). By intravenous administration, Fujita and

Yoshikawa (1999) reported a reduction in blood pressure by

30 mm Hg in spontaneously hypertensive rats (SHR) by giving

Leu–Lys–Pro–Asp–Met, a peptide derived from thermolysis-

digest of dried bonito at a dose of 100μg/kg. A greater reduction

by 50 mm Hg was observed when Leu–Lys–Pro, the hydrolyzed

product of Leu–Lys–Pro–Asp–Met by ACE, was given at a dose

of 30μg/kg. Furthermore, a study conducted over an 8-week

period in humans involving 30 subjects with hypertension pro-

duced an interesting result that blood pressure was reduced by

60–66% in individuals fed a thermolysis-digest of dried bonito.

In another study (Kawasaki et al. 2002), sardine protein hy-

drolysate incorporated at a dosage of 0.5 g into a vegetable drink

was shown in a randomized double-blind placebo-controlled

study on 63 subjects over 13 weeks to lower systolic blood