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Review

Bioactive peptides in milk

Nashat Dahiyat

The university of Jordan, Food Science and technology, Amman, Jordan

Abstract

The role of proteins as physiologically active components in the diet is being increasingly

acknowledged. Many of the proteins that occur naturally in raw food materials exert their physiological action

either directly or upon enzymatic hydrolysis in vitro or in vivo. In recent years it has been recognized that

dietary proteins provide a rich source of biologically active peptides. Such peptides are inactive within the

sequence of the parent protein and can be released in three ways: (a) through hydrolysis by digestive

enzymes, (b) through hydrolysis by proteolytic microorganisms and (c) through the action of proteolytic enzymes

derived from microorganisms or plants.

© 2013 Ltd. All rights reserved.

Keywords: Milk proteins; Bioactive peptides;; Functionality; Health effects

Contents

5. Bioactive peptides in whey proteins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . … . 7

6.3Effects on the nutrition system. . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . 8

E-mail address: nashatdhiat@yahoo.com / ndhayyat@aseza.jo (N. Dahiyat)

6.2 Effects on the immune system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .... . . . . ..... 8

2.2. Microbial fermentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . .. .. . . 5

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.2. Production of bioactive peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .... . .. .. 4

3. A fermented milk high in bioactive peptides has a blood pressure –lowering effect . . . .. . .. .. . . . . 6

6.1 Effects on the nervous system. . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........ . . . 7

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . ........ . . ... . 10

6.Physiological effects of bioactive peptides from milk. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . ...... . . . .7

2.1. Enzymatic hydrolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . .4

1. Introduction . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... ... .. ... .. .. . .......... 3

..4. Caseins as source of bioactive peptides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . 6

8.Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...... . . . .... 9

7.Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . ... ....... . . .. . .8

1. Introduction

The role of proteins as physiologically active components in the diet is being

increasingly acknowledged. Many of the proteins that occur naturally in raw food

materials exert their physiological action either directly or upon enzymatic hydrolysis

in vitro or in vivo. In recent years it has been recognized that dietary proteins provide

a rich source of biologically active peptides. Such peptides are inactive within the

sequence of the parent protein and can be released in three ways: (a) through

hydrolysis by digestive enzymes, (b) through hydrolysis by proteolytic

microorganisms and (c) through the action of proteolytic enzymes derived from

microorganisms or plants.

Bioactive peptides have been defined as specific protein fragments that have a

positive impact on body functions or conditions and may ultimately influence health

(Kitts & Weiler, 2003). Upon oral administration, bioactive peptides, may affect the

major body systems namely, the cardiovascular, digestive, immune and nervous

systems (Fig. 1)—depending on their amino acid sequence. For this reason, the

potential of distinct dietary peptide sequences to promote human health by reducing

the risk of chronic diseases or boosting natural immune protection has aroused a lot of

scientific interest over the past few years. These beneficial health effects may be

attributed to numerous known peptide sequences exhibiting, e.g., antimicrobial,

antioxidative, antithrombotic, antihypertensive and immunomodulatory activities.

(FitzGerald & Meisel, 2003).

2. Production of bioactive peptides

biologically active peptides can be produced from precursor milk proteins in

the following ways: (a) enzymatic hydrolysis by digestive enzymes, (b) fermentation

of milk with proteolytic starter cultures, (c) proteolysis by enzymes derived from

microorganisms or plants. In many studies, combination of (a) and (b) or (a) and (c),

has proven effective in generation of short functional peptides (Korhonen & Pihlanto,

2003b). Examples of bioactive peptides produced by the above treatments are given

below.

2.1 Enzymatic hydrolysis

The most common way to produce bioactive peptides is through enzymatic

hydrolysis of whole protein molecules. Many of the known bioactive peptides have

been produced using gastrointestinal enzymes, usually pepsin and trypsin.

Angiotensin-converting enzyme (ACE)-inhibitory peptides and calcium-binding

phosphopeptides (CPPs), for example, are most commonly produced by trypsin

(FitzGerald et al, 2004).

Other digestive enzymes and different enzyme combinations of proteinases

including alcalase, chymotrypsin, pancreatin, pepsin and thermolysin as well as

enzymes from bacterial and fungal sources—have also been utilized to generate

bioactive peptides from various proteins (Kilara & Panyam, 2003).

2.2 Microbial fermentation

Many industrially utilized dairy starter cultures are highly proteolytic.

Bioactive peptides can, thus, be generated by the starter and non-starter bacteria used

in the manufacture of fermented dairy products. The proteolytic system of lactic acid

bacteria (LAB), e.g. Lactococcus lactis, Lactobacillus helveticus and Lb. delbrueckii

ssp. bulgaricus, is already well characterized. This system consists of a cell wall-

bound proteinase and a number of distinct intracellular peptidases, including

endopeptidases, aminopeptidases, tripeptidases and dipeptidases (Christensen

et al, 1999).

Table 1. Examples of bioactive peptides released from milk proteins by various

microorganisms and microbial enzymes

Micro-organisms used

Precursor

proteina

Peptide sequence

Bioactivity

Lactobacillus helveticus,

Saccharomyces cerevisiae

b-cn, k-cn

Val-Pro-Pro, Ile-Pro-Pro

ACE inhibitory,

antihypertensive

Lb. delbrueckii subsp.

bulgaricus IFO13953

k-cn

Ala-Arg-His-Pro-His-Pro-His-Leu-Ser-

Phe-

Met

Antioxidative

Lb. delbrueckii subsp.

bulgaricus

b-cn

Ser-Lys-Val-Tyr-Pro-Phe-Pro-Gly Pro-

Ile

ACE inhibitory

Lb. helveticus ICM 1004

cellfree

extract

Skim milk

hydrolysate

Val-Pro-Pro, Ile-Pro-Pro

ACE inhibitory

aAbbreviations: cn ¼ casein, ACE ¼ angiotensin I-converting enzyme.

2.2.1 A fermented milk high in bioactive peptides has a blood pressure–lowering effect in hypertensive subjects

Hypertension is a risk factor for cardiovascular diseases, including coronary

heart disease, peripheral arterial disease, and stroke. The renin-angiotensin system is

an important regulator of blood pressure. Therefore, drugs that inhibit the renin-

angiotensin system, either by inhibiting angiotensin-converting enzyme (ACE; EC

3.4.15.1) or by blocking angiotensin (AT1) receptors, are widely used in the treatment

of hypertension. ACE inhibitors have a dual effect on the renin-angiotensin system:

they inhibit the production of the vasoconstrictor angiotensin II and they inhibit the

degradation of the vasodilator bradykinin. In addition, ACE inhibitors have other

beneficial effects in hypertensive patients, for example, in those with cardiac or renal

insufficiency or diabetes. Through fermentation, peptides that have an ACE-

inhibiting and thus a blood pressure–lowering effect can be derived from milk

proteins.

3. Caseins as source of bioactive peptides

Casein is the main proteinaceous component of milk, where it accounts for

ca. 80% of the total protein inventory. Until recently, the main physiological role of

casein in the milk system was widely accepted to be a source of amino acids required

by growth of the neonate. However, the dominant physiological feature of the

casein micelle system has more recently been proven to be the prevention of

pathological calcification of the mammary gland (Holt, 1997). While no specific

physiological property has been proposed for the whole casein system (or its

individual fractions, for that matter), various peptides hidden (or inactive) in the

amino-acid sequence have been the subject of increasingly intense studies. Much

work regarding those peptides, which are known to possess bioactivities, is currently

underway regarding their release via selective enzymatic hydrolysis.

4. Bioactive peptides in whey proteins

Two tetrapeptides in the primary structure of whey proteins have potential

opioid activities: Tyr-Gly-Leu-Phe (residues 50-53) from human and bovine α-

lactalbumin and Tyr-Leu-Leu-Phe (residues 102-105) from bovine β- lactoglobulin.

The corresponding amides - named α and β lactorphin, respectively - were

chemically synthesized and their opioid activity was established.

5. Physiological effects of bioactive peptides from milk

5.1 Effects on the nervous system

It is a common belief that falling asleep is easier after drinking a

glass of milk in the evening, and that babies are soothed after breast or bottle

feeding. Recent studies have provided evidence that peptides exist in dairy

products which play an active role in the nervous system; known as opioid peptides,

they can have agonistic or antagonistic activities

5.2 Effects on the immune system The systems involved in the human body’s defense

against invaders are rather complex; diet is known to play an important role therein.

Research concerning the role of functional peptides in this field is quite recent,

but it already seems very promising. The two main activities are the

immunomodulatory one (i.e. stimulation of the immune system) (Table 4) and the

antimicrobial one (i.e. inhibition of pathogenic bacteria).

5.3 Effects on the nutrition system Some peptides are able to sequester calcium and other minerals,

hence acting as biocarriers—they are called phosphopeptides glycomacropeptide

(GMP) may also exhibit a number of nutritional features.

6. conclusion

Bioactive peptides are ubiquitous biomolecules widely abundant and easily

obtainable from food proteins. There is no limit therefore to the number of peptides

that can be obtained from a single food protein.

Each of these peptides may present unique structure and biofunctionalities that can

be exploited in the pharmaceutical industry. As research continues to uncover

technologies and means to overcome challenges to the use of peptide therapeutics,

the prospects of

food-derived bioactive peptides will likely fuel in the pharmaceutical industry an

exodus from small molecules and biologics to bioactive peptides.

7. Discussion

The potential health benefits of milk protein-derived peptides have been a

subject of growing commercial interest in the context of health-promoting functional

foods. So far, antihypertensive, mineral-binding and anticariogenic peptides have

been most studied for their physiological effects. A few commercial developments

have been launched on the market and this trend is likely to continue alongside with

increasing knowledge about the functionalities of the peptides. The optimal

exploitation of bioactive peptides for human nutrition and health possesses

an exciting scientific and technological challenge, while at the same time offering

potential for commercially successful applications. Bioactive peptides can be

incorporated in the form of ingredients in functional and novel foods, dietary

supplements and even pharmaceuticals with the purpose of delivering specific health

benefits.

8. References

functionality, (945 – 960)

Seppo.L, Jauhiainen.T, Poussa,T, Korpela.R. A fermented milk high in bioactive

peptides has a blood pressure–lowering effect in hypertensive subjects.

Meisel.H, Frister.H, Sehlimme.E (1989). Biologically active peptides in milk

proteins. (267-278).

Sofia V. Silva, F. Caseins as source of bioactive peptides

Pihlanto. A, Korhonen. H . (2011) . Review Bioactive peptides: Production and

Biotechnology

Agyei.D. (2012). Pharmaceutical applications of bioactive peptides. OA