Bioactive compounds in wine _ recent advances and perspe.pdf

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BIOCHEMISTRY RESEARCH TRENDS

BIOACTIVE

COMPOUNDS

IN WINE

RECENT ADVANCESAND PERSPECTIVES

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BIOACTIVE COMPOUNDS

IN WINE

RECENT ADVANCESAND PERSPECTIVES

PEDRO ADRIN AREDES-FERNNDEZMARA JOS RODRIGUEZ-VAQUERO

GISSELLE RAQUEL APUDAND

MARA GILDA STIVALAEDITORS

New York


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Copyright 2016 by Nova Science Publishers, Inc.

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NOTICE TO THE READERThe Publisher has taken reasonable care in the preparation of this book, but makes no expressed orimplied warranty of any kind and assumes no responsibility for any errors or omissions. No liability isassumed for incidental or consequential damages in connection with or arising out of informationcontained in this book. The Publisher shall not be liable for any special, consequential, or exemplarydamages resulting, in whole or in part, from the readers use of, or reliance upon, this material. Anyparts of this book based on government reports are so indicated and copyright is claimed for those parts

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Library of Congress Control Number: 2015948678

Published by Nova Science Publishers, Inc. New York

ISBN:(eBook)


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CONTENTS

Preface vii

Chapter 1 Bioactive Peptides in Wine: Recent Advancesand Perspectives 1

Pedro A. Aredes-Fernndez, Gisselle R. Apud,

Mara G. Stivala and Mara J. Rodrguez-Vaquero

Chapter 2 Wine Polyphenols: Biological Activities and Reusefrom Winery Waste 35

Mara J. Rodrguez-Vaquero,

Sofa M. Sosa-Marmol, Mara G. Stivala,

Gisselle R. Apud and Pedro A. Aredes-Fernndez

Chapter 3 Factors Affecting Biogenic Amines Occurrence inWine: An Overview of Analytical Methods 61

Silvana C. Ledesma, Mara G. Stivalaand Pedro A. Aredes-Fernndez

Chapter 4 Impact of Fungal Diseases in Grapes and Wine:General Aspects and Recent Advances 91

Gisselle R. Apud, Pedro A. Aredes-Fernndez

and Diego A. Sampietro

Editors Contact Information 111

Index 113


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PREFACE

Wine has been part of human culture for about 6000 years. From ancienttimes, wine was used to treat fever as well as different diseases; howveer, its

benefitial effects related to human health are associated mainly with theprevention of cardiovascular diseases, principally due to the high content ofbioactive compounds. Presently, there is consensus among the scientificcommunity that moderate wine consumption produces potentially beneficialeffects on the human body mainly due to its preventive properties on the

cardiovascular system. These beneficial effects are related to the presence ofdifferent components with an antioxidant-promoting capacity against reactiveoxygen species produced naturally in the body, as well as antihypertensiveeffects, lipid profile regulation and anti-inflammatory effects. The relationship

between wine consumption and cardiovascular disease prevention emerged in1989 with the French paradox, which is based on countries like France wheremany fatty foods are consumed, but the incidence of death from cardiovasculardisease was lower than in others countries like in Northern Europe. This is due

to the fact that wine is correlated with low incidence of cardiovascular disease,indicating a protective effect of wine. In this sense, it is established thatmoderate daily wine consumption (150 mL for women and 300 mL in men)

produces benefits on cardiovascular diseases due to the action of bioactivecompounds such as polyphenols. Recently, also has been shown that in the

prevention of hypertension have an important role the presence of bioactivepeptides generated by the metabolism of the microflora naturally present in thefermentation process. On this subject, is a current and interest topic the

isolation and selection of wine microflora that possess advantageoustechnological properties for vinification process, guaranteeing the wine qualityand sometimes incorporates an added value to final product. At present, thestudy of the use of products and by-products generated in wine processes,


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P. A. Aredes Fernndez, M. J. Rodriguez Vaquero, G. R. Apud et al.viii

which can be used in the pharmaceutical, food and cosmetic industries is aninteresting topic. The development of new processing technologies, acco-mpanied by the evolution of scientific knowledge on bioactive comp-oundsand the increasing consumer concern over for his health, has carried a growingand sustained interest in wine components with beneficial biological activities.However, some wine bioactive compounds generated under certain conditionscan modify the organoleptic properties and quality of wines. Biogenicaminesnitrogen compounds generated mainly by the metabolism ofmicroorganisms associated to winemaking processcan exert negative effectson consumers health. Another compound produced by contaminant filam-entous fungi are mycotoxins, Ochratoxin A being the most relevant mycotoxinin wine produced by Aspergillus carbonarius and Aspergillus niger thatcontaminates grapes. This compound has nephrotoxic, hepatotoxic, terato-genic, genotoxic and immunotoxic properties on several animal species, andcauses kidney and liver tumors in mice and rats.

This book attempts to transfer scientific results and the most comp-rehensive and updated knowledge on bioactive compounds in general

particularly in wineand updates on the most recent advances in the field.With this book, oenologists will be able to update their knowledge from a

deeper understanding of the importance of bioactive compounds in wine.Moreover, researchers in oenology can expand their knowledge and conducttheir experiments in areas of growing interest.


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In: Bioactive Compounds in Wine ISBN: 978-1-63482-765-2Editors: P. A. Aredes Fernndez et al. 2016 Nova Science Publishers, Inc.

Chapter 1

BIOACTIVE PEPTIDES IN WINE:RECENT ADVANCES AND PERSPECTIVES

Pedro A. Aredes-Fernndez*, Gissel le R. Apud,

Mara G. Sti vala and Mara J. Rodrguez-VaqueroFacultad de Bioqumica, Qumica y Farmacia,

Universidad Nacional de Tucumn, Tucumn, Argentina

ABSTRACT

In recent years, a growing number of scientists have publishedevidence, that many peptides from fermented beverages exhibit specificbiological activities. In view of the current trend to study the role of the

diet in the prevention and treatment of diseases, efforts are being put intothe production of foods with beneficial effects on human health.Although most of the scientific literature links the benefits of wineconsumption on human health to the presence of phenolic compounds,other compounds present in wine like peptides could also play asignificant role in the beneficial effects of wine on health, particularly inthe prevention of cardiovascular diseases. The purpose of this chapter isto review the current literature regarding bioactive peptides in general andrecent findings regarding bioactive peptides in wine. Special attention is

paid to information in recent research papers with respect to the structure-activity relationships of angiotensin-converting enzyme (ACE) inhibitorypeptides, absorption and bioavailability in the human body, mechanisms

*Corresponding Author address: Email: [email protected]


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Pedro A. Aredes-Fernndez, Gisselle R. Apud, Mara G. Stivala et al.2

of action and the role of the vinification process in the occurrence ofbioactive peptides in wine.

Keywords: bioactive peptides, wine, antihypertensive activity, antioxidantactivity

INTRODUCTION

Our diet plays a crucial role in enhancing good health. Some foods containbioactive components that are beneficial to health and are able to reduce the

risks of chronic diseases. These foods are known as functional foods (Teck-Chai et al. 2013). The growing interest in disease prevention and health

promotion has led to the use of these functional foods because they may exertpositive health effects when present in a normal diet (Ruttarattanamongkol2012). A wider definition of functional foods has been proposed by Diplock etal. (1999), who described them as foods that beneficially affect one or moretarget functions in the body in a way that is relevant to an improved state ofhealth and well-being, in addition to their adequate nutritional effects.

According to Sir et al. (2008), certain types of functional food like bioactivepeptides, are considered foods naturally containing increased content ofnutrients or components. Several authors have revealed scientific evidencethat food peptides exhibit specific biological activities on health aside fromtheir nutritional value (Hartmann and Meisel 2007; Tripathi and Vashishtha2006; Yalcin 2006; Mller et al. 2008).

Bioactive peptides are considered functional components that have beenidentified in different fermented foods and beverages. They have been defined

as specific protein fragments that have a positive impact on body functions orconditions and may ultimately influence health (Kitts and Weiler 2003). Theycan be produced through enzymatic hydrolysis of proteins presents in severalfoods or through fermentation by proteolytic microorganisms (Korhonen andPihlanto 2006). Milk and dairy products are the most thoroughly studiedfoodstuffs, and it has been found that they are a rich source of bioactive

peptides (Pihlanto 2011; Choi et al. 2012; Mandal et al. 2014). However, inthe past decade, bioactive peptides have been identified in other foods such as

meat (Baltiet al. 2014), fish (Senevirathne and Kim, 2012), eggs (Majumderet al. 2015), soybean (Singh et al. 2014), wheat (Cian et al. 2015), corn(Zhuang et al. 2013) and wine (Takayanagui and Yokotsuka 1999; Pozo-Bayn 2007; Alcaide-Hidalgo 2008).


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Bioactive Peptides in Wine 3

Some food proteins can directly produce physiological effects in theirintact form. However, most peptides become bioactive after, hydrolysis or

breakdown during microbial fermentation. These peptides are often morebioactive than the parent protein (Moughan and Rutherfurd-Markwick 2013).Therefore, bioactive peptides can be generated by the starter and non-startermicroorganisms associated with fermented products. Lactic acid bacteria(LAB), ubiquitous microorganisms involved in numerous fermentation

processes, exhibit proteolytic activity on proteins from natural environmentsand they contribute to the release of bioactive peptides from dietary proteins(Saavedra et al. 2013). The proteolytic system of many LAB speciesassociated with dairy products like Lactococcus lactis, Lactobacillushelveticus and Lb. delbrueckii ssp. bulgaricus, has already been thoroughlycharacterized. The proteolytic system in these LABs consists of a cell wall-

bound proteinase and a number of distinct intracellular peptidases, includingendopeptidases, aminopeptidases, tripeptidases and dipeptidases (Christensenet al. 1999).

1.W

INEB

IOACTIVEP

EPTIDES

The composition of the peptide fraction in wine is continuously affectedduring the vinification process. Some wine peptides are derived from grapes

and then transferred to the must. The concentration of peptides generallyreduces during alcoholic fermentation. However, during the final stages of thisfermentation a maximum release of peptides takes place because of yeastdeath and lysis (Usseglio-Tomasset and Bosia 1990). The presence of endo

and exocellular proteases has been observed during winemaking conditions(Feuillat et al. 1980; Alexandre et al. 2001). The increase in wine peptidescould be the result of their release from the yeast cells or the action of endoand exoproteases on proteins derived from yeast or grape juice (Moreno-Arribas and Polo 2005). This phenomenon has been evidenced in wine modelsemploying autolyzed yeasts (Martinez-Rodriguez et al. 2001; Aredes-Fernndez et al. 2011).

During the vinification process, many LABs associated with wine are ableto carry out malolactic fermentation and peptides are released through their

proteolytic system. The exoproteases of certain LAB species involved in thevinification process have been described (Faras et al. 1996, 2000; Folio et al.2008) and their activity against wine and grape proteins has been documented


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(Manca de Nadra et al. 2005; Aredes-Fernndez et al. 2004). Similarly, it hasbeen found that LABs associated with malolactic fermentation are able torelease bioactive peptides from yeast and wine proteins (Aredes-Fernndez etal. 2011; Apud et al. 2013a, b).

2.FUNCTIONALITY OF BIOACTIVE PEPTIDES

Bioactive peptides are known to have antimicrobial, antioxidative,antithrombotic, antihypertensive, anticarcinogenic, satiety regulating andimmunomodulatory activities and they may affect cardiovascular, immune,nervous and digestive systems (Di Bernardini 2011; Mars et al. 2012).Moreover, many known bioactive peptides are multifunctional and can presenttwo or more health promoting activities (Di Bernardini et al. 2011).

Bioactive peptides derived from milk proteins are known to exert diverseeffects, including opioid, mineral-binding, immunomodulatory, antimicrobial,antioxidant, antithrombotic, hypocholesterolemic and antihypertensive active-ities (Pihlanto 2011). They could also play an important role in the preventionand treatment of metabolic syndrome and its complications through severalmechanisms: satiety response, regulation of insulin levels and blood pressure,scavenging of free radicals and alteration of the lipid profile (Ricci-Cabello etal. 2012). Pedersen et al. (2000) demonstrated that consumption of whey

proteins that contain bioactive peptides (mainly glycomacropeptide) leads toappetite suppression by stimulation of the release of cholecystokinin, whichmay promote satiety in rats. Several bioactive peptides isolated and purifiedfrom soymilk, have been characterized by their angiotensin I-convertingenzyme inhibitory (ACE-I) activity (Vallabha and Tiku, 2013), as well ashypocholesterolemic (Kobayashi et al. 2012), antioxidant (Park et al. 2010),anti-obesity (Ascencio et al. 2004), immunomodulatory (Kong et al. 2008) andanticancer (Hsieh et al. 2010) activities. Hydrolysis of whey proteins can alsogenerate bioactive peptides with many physiological effects such asantioxidant, antimicrobial, antihypertensive, antidiabetic, immunomodulatory,anticancer, opioid and hypocholesterolemic activities (Brandelli et al. 2015).Fermented marine food (Harnedy and FitzGerald 2012) and fermented meat

products (Lafarga and Hanes 2014) are found to be rich sources of bioactivepeptides. Bioactive peptides derived from marine food have numerousbeneficial effects on health such as antioxidant, antihypertensive, antidiabeticand anti-obesity activities (Ko and Jeon 2013).
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Antioxidant and antihypertensive properties are the most important andrecognized biological activities of peptides.

2.1. Antioxidant Peptides

Oxidation is a vital process that provides the necessary energy for survivalto all organisms. Reactive oxygen species (ROS) are products generated byoxygen metabolism and have a single unpaired electron in their outer orbit that

becomes highly reactive. They are produced in all aerobic organisms that carryout cellular metabolisms. ROS comprise free radical and non-free radicaloxygen-containing molecules such as hydrogen peroxide (H2O2), ozone (O3),superoxide (O2

.-), singlet oxygen (1O2), hydroxyl radical (OH.), nitric oxide

(NO.), nitrogen dioxide (NO2.), peroxyl (ROO.) and lipid peroxyl (LOO.),

hypochlorous acid, nitrous acid (HNO2), peroxynitrite, dinitrogen trioxide andlipid peroxide (Genestra 2007; Di Bernardini et al. 2011). Under normalconditions, these products perform beneficial functions in the human body.They act as intermediaries in phagocytosis, apoptosis, detoxification reactions,executioners of precancerous cells and infections, etc. They also regulate many

metabolic and cellular processes including proliferation, migration, geneexpression, immunity and wound healing (Salganik 2001). In the human body,an endogenous antioxidant system neutralizes reactive molecules and avoidshigh ROS levels. This system includes enzymes such as catalase or superoxidedismutase, non-enzymatic compounds like vitamin C as well as a number ofantioxidant peptides such as carnosine and anserine (Xiong 2010). However,when the production of these reactive molecules exceeds the capacity of theantioxidant defense mechanism of the organism, oxidative stress occurs. This

imbalance between ROS generation and antioxidant defense mechanismsproduces oxidative damage of biological macromolecules like proteins, lipidsand nucleic acids (Majzunova et al. 2013).

An antioxidant is a substance that, when present at a low concentrationcompared with that of an oxidizable substrate, inhibits oxidation of thesubstrate (Halliwell et al. 2007).

Peptides generated after digestion of certain proteins are reported to haveantioxidant properties and can be incorporated into food products to provide

antioxidant benefits.anldere Aloluandner (2011) studied the antioxidanteffect of peptides released after microbial proteolysis from yogurt proteins.They found that the total antioxidant activity of yogurt was low, but afterfractionation of peptides by HPLC one of the fractions showed high
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antioxidant activity. Chen et al. (2012) confirmed antioxidant activity ofpeptides released after enzymatic hydrolysis of walnut proteins.

2.2. Antihypertensive Peptides

Hypertension is a major risk factor for the development of cardiovasculardiseases, a key cause of global morbidity and mortality (Danaei et al. 2013).

The blood pressure in the human body is regulated by many factors andthe most important one is the balance between the renin-angiotensin system(RAS) and kallikrein-kinin system (KKS). Angiotensin-converting enzyme(ACE), a carboxyl-terminal dipeptidyl exopeptidase responsible for vasoco-nstriction, plays a crucial role in the regulation of the blood pressure as well ascardiovascular functions (Li et al. 2007). ACE is a key enzyme of the RAS. Inthis system, renin stimulates angiotensinogen to release a non-active peptide,angiotensin I (decapeptide), which ACE catalyzes into angiotensin II(octapeptide). The latter peptide performs a powerful vasoconstrictive actionand stimulates the secretion of aldosterone, favoring the retention of sodiumand water resulting in an increase in arterial blood pressure. In the KKS

system, ACE inactivates the bradykinin, a vasodilator, causing high bloodpressure. If ACE activity is inhibited by ACE-inhibiting compounds,biosynthesis of angiotensin II is reduced and bradykinin is activated.Consequently, the blood pressure goes down (Zhao and Li 2009; Majumder etal. 2015).

Several synthetic ACE inhibitors such as captopril, enalapril, lisinopril,and ramipril are effective in the treatment of hypertension in humans (Ondettiet al. 1977). However, they also cause adverse side effects. Thus, the

development of safe and natural ACE inhibitors has gained attention in thetreatment of hypertension (Suzuki et al. 2006; Li et al. 2013).

Bioactive peptides released from food proteins have been widely used forthe treatment of hypertension, mostly based on their ability to inhibit ACE inthe physiological blood pressure-regulating RAS pathway (Udenigwe andMohan, 2014). Peptide fractions have been reported to decrease the blood

pressure in spontaneously hypertensive rats and in mild hypertensive humanvolunteers (Pihlanto and Korhonen 2015).

Several scientific studies have demonstrated antihypertensive activity ofmilk-protein derived peptides (FitzGerald et al. 2004; Lpez-Fandio et al.2006; Contreras et al. 2009; Pihlanto et al. 2010). Recently, Kumar (2013)showed that bioactive peptides from yak milk possess good antihypertensive
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activity and Tomatsu et al. (2013) confirmed ACE-I activity of eight novelpeptides purified from soymilk using reversed-phase chromatography.

Figure 1. Diagram representing the blood pressure regulation mechanism by renin-angiotensin and kallikrein-kinin systems.

With respect to wine peptides, Perrot et al. (2003) observed that the low

molecular weight fraction of Champagne wine exhibited antihypertensiveactivity in hypertensive rats whereas it did not affect normotensive rats.Alcaide-Hidalgo et al. (2007) found that peptides released during acceleratedautolysis of Saccharomyces cerevisiaein a wine model showed ACE-I activityin addition to oxygen radical scavenging capacity. Aredes-Fernndez et al.(2011) reported that sequential inoculation of the proteolytic X2L strain ofOenococcus oeni in a synthetic wine medium increased the peptide nitrogenconcentration after accelerated yeast autolysis and improved antihypertensiveand antioxidant activities. Apud et al. (2013a) detected antihypertensive,antioxidant and radical scavenging activities of peptides released from the

protein and polypeptide fraction of different Argentine wine varietals after


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proteolytic activity of O. oeni m1. The authors showed that these activitieswere higher when the peptide nitrogen source was derived from red wines.

Several authors have found that antihypertensive peptides with ACE-Iactivity in fermented foods also present radical scavenging activity, suggestingmultifunctional activity of these compounds (Hernndez-Ledesma et al. 2005;Aredes-Fernndez et al. 2011; Apud et al. 2013a).

3.STRUCTURE-ACTIVITY RELATIONSHIPOF BIOACTIVE PEPTIDES

Bioactive peptides generally contain short chains of approximately 320amino acids linked in specific sequence and derived from proteins with amolecular mass less than 6 kDa (Mller et al. 2008; Shahidi and Zhong, 2008;Di Bernardini et al. 2011).

The primary structure and amino acid composition of bioactive peptidesare closely related to their activity. The presence of aromatic or alkaline aminoacids in the N-terminus of peptides with ACE inhibitory (ACE-I) activity can

improve its activity. In addition, peptides containing leucine, isoleucine andvaline in the N-terminus exhibited good antihypertensive characteristics.However, the presence of N-terminal proline diminished ACE-I activity(Aleman et al. 2011; Pan et al. 2012). With respect to the C-terminus, Wu etal. (2006) found that ACE-I activity was greatly affected by the three-dimensional chemical properties and hydrophobicity of the C-terminaltripeptide sequence. Jia et al. (2009) showed that the amino acids tyrosine,

proline, tryptophan, phenylalanine and leucine were more probable in peptides

with ACE-I activity. This means that the larger volume and the greaterhydrophobicity of these amino acids contribute to the antihypertensive effectincreasing ACE-I activity.

Alcaide-Hidalgo et al. (2007) demonstrated that a fraction from a yeastautolysate obtained through liquid chromatography with high content ofhydrophobic peptides, exhibited high ACE-I activity. Some authors havereported that the presence of hydrophilic amino acid residues in the peptidesequence could negatively affect the inhibitory activity by blocking the entry

of the peptide to the active site of ACE (Li et al. 2004). On the other hand,ACE-I activity did not improve with the increasing percentage of hydrophobicamino acids in the peptide structure (Pripp et al. 2006; Otte et al. 2007).Furthermore, it has been found that the presence of positively charged amino


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acids like lysine and arginine in the C-terminus of peptides can promote ACE-I activity (Ferreira et al. 2007). ACE is a zinc-dependent peptidase that

presents two homologous domains, the N-domain and the C-domain, each ofwhich contains an active site (Soubrier et al. 1988). The C-domain of ACE hasa short consensus sequence and zinc-binding motif, HEXXH, and it hasdemonstrated to play a dominant role in the blood pressure control (He et al.2014). Two histidine amino acids act as zinc ligands and the glutamate asgeneral base (Gomis-Rth, 2003). When the active site of the ACE C-domainis occupied by inhibitory peptides that bind to specific amino acid residues, theACE activity is lost (He et al. 2014).

Presence of certain amino acids such as cysteine, methionine and histidinethat possess antioxidative activity is related to antioxidant activity in peptides.It has been demonstrated that the activity of a single antioxidant amino acid ismuch lower than the activity evidenced in a peptide containing that amino acid(Zhu et al. 2012). In general, peptides with hydrophobic amino acids likehistidine, proline, cysteine, tyrosine, tryptophan, phenylalanine and methioninedisplay strong antioxidant activity whether they are present in the side chain orC-terminus and/or N-terminus. The antioxidant activity is related to the delayin the lipid peroxidation chain reaction by combining with oxygen or by

inhibition of hydrogen release (Cheng et al. 2009).

4.MODE AND MECHANISM OF INHIBITION OF ACEINHIBITORY PEPTIDES

Compared to synthetic drugs, bioactive peptides derived from food are

safe, effective and economical ACE inhibitors to prevent and treathypertension (Chen et al. 2007). The inhibition mode of ACE inhibitorypeptides can be explained by a hypothetic model proposed by Ondetti andCushman (1982). ACE has two active sites and each of them has three sub-sites, S1, S1 and S2, that interact with C-terminal tripeptide amino acidresidues of substrates or inhibitors (Cushman and Ondetti, 1991). The zinc ionis located between S1 and S1 of the active site and participates in thehydrolytic cleavage of the peptide bond. A hydrogen bond donating group

between sub-sites S1 and S2 is able to bind to the last peptide bond of thesubstrate or the inhibitor molecule. The active site also possesses a positivelycharged group that establishes ionic interactions with the negatively chargedcarboxyl group of the C-terminal amino acid of the substrate or the inhibitor.


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Several studies of the inhibition mode of peptides with ACE-I activityhave demonstrated that they can act as competitive, noncompetitive anduncompetitive inhibitors. Competitive inhibitors have a structure similar tothat of the substrate of the enzyme and when they bind to the active site, they

block it. They can also bind to the inhibitor-binding site that is distant from theactive site, resulting in a modification of the enzyme conformation andconsequently the substrate cannot bind to the active site (Hong et al. 2008).This model was first proposed by Ondetti and Cushman (1982), whodemonstrated that the substitution of the carboxyl group by sulfhydryl group inan ACE inhibitor produced a marked competitive inhibition, because itenabled a strong ionic bond to the positively charged recognition site of ACE.An example of such behavior is captopril.

In the noncompetitive inhibition system, both the inhibitor and thesubstrate can bind to the enzyme at the same time. When this occurs, theenzyme-substrate-inhibitor complex cannot form a product but can only beconverted back to the enzyme-substrate complex or the enzyme-inhibitorcomplex (Si et al. 2009). However the noncompetitive inhibition mechanismof ACE inhibitory peptides is not clear yet. When ACE is in the unboundform, hypuril histidil leucine (HHL), an artificial substrate analogue to the

natural substrate of ACE, Angiotensin I, can enter the active site and is thenconverted into hypuric acid (HA) (Ni et al. 2012). These authors found that the

presence of the inhibitory peptide TPTQQS does not block the active site ofACE.

Consequently, TPTQQS does not compete with the substrate for the activesite, indicating that this peptide is a non-competitive ACE inhibitor. Eventhough HHL would bind to the active site, it would be impossible to convert itinto HA, because of a change in the conformation of the active site of the

enzyme.In the case of uncompetitive inhibition, the inhibitor is able to bind to the

substrate-enzyme complex but not to the free enzyme and because of thisinhibition, a decrease in the maximum enzyme activity occurs. Peptides suchas IW, FY and AW have been reported to act as uncompetitive ACE inhibitors(Sato et al. 2002). Nevertheless, like the noncompetitive mechanism, theinhibition mechanism of this system is not clear either.


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5.ABSORPTION AND BIOAVAILABILITY OF ACEINHIBITORY PEPTIDES

The physiological effects of bioactive peptides have been determined bytheir ability to reach the target sites, which may involve absorption through theintestinal epithelium to get to peripheral organs (Vermeirssen et al. 2004). Ingeneral, digestion of proteins and peptides begins in the stomach through theaction of pepsine at a low pH. Then the polypeptides are hydrolyzed by

pancreatic enzymes like trypsin, -chymotrypsin, elastase and carboxy-peptidases A and B. Absorption of peptides in the gastrointestinal tract takes

mainly place in the small intestine (approximately 90%) and in the colon(Garcia-Redondo et al. 2010). Bioactive peptides can resist the digestive actionof acids and digestive enzymes. Korhonen and Pihlanto (2006) foundantihypertensive bioactivity of peptides after oral ingestion when absorbed inan intact form. Some studies have also demonstrated that several peptides withACE-I activity were resistant to the digestive proteases after experimentssimulating gastrointestinal digestion (Choi et al. 2001; Ohsawa et al. 2008;Ren et al. 2011). Other peptides were hydrolyzed into shorter but active forms

after simulation of gastrointestinal digestion (Shiozaki et al. 2010). Mizuno etal. (2004) proved that antihypertensive peptides containing C-terminal prolinewere resistant to proteolytic enzymes. Finally, tripeptides containing the C-terminus proline-proline have been reported to be resistant to proline-specific

peptidases (FitzGerald and Meisel, 2000).The action of brush-border peptidases, recognition by intestinal peptide

transporters and the subsequent susceptibility to plasma peptidases determinethe physiological effect of bioactive peptides (Vermeirssen et al. 2004). The

mechanisms of intestinal absorption are mainly classified into three categoriesaccording to Wada and Lnnerdala (2014): (1) the proton-dependent peptidetransporter, PepT1, present in intestinal epithelial cells that actively transportsdi- and tripeptides. Peptides transported into the cell are generally hydrolyzedinto amino acids by cytoplasmic peptidases, but certain peptides may resisthydrolysis,allowing absorption of particular bioactive di- and tripeptides viathis mechanism; (2) transcytosis through an intracellular vesicular transportsystem. The vesicles are present in intestinal epithelial cells and enable the

traslocation of certain oligopeptides. However peptides are likely to behydrolyzed by cytoplasmic peptidases in this pathway; (3) paracellulartransport.This transport mechanism, which seems to be the more importantthan transcytosis, is based on the passive diffusion of peptides between cells


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and it does not possess specific transporters. Permeability between cells duringparacellular transport is regulated by tight junctions comprised of two proteins,occludins occludin and cingulin that form small pores in the junction, enablingtransport of larger oligopeptides and di- and tripeptides by passive diffusion.This paracellular pathway is non-digestive and it is considered to play animportant role in the absorption of bioactive peptides in an intact form. It isknown that di- and tripeptides may be transported through the intestinalmucous membrane, although there is some evidence that larger peptides mayalso be absorbed in the small intestine.

The half-life of peptides in plasma is generally very short. Two tripeptidesknown for their antihypertensive bioactivity, IPP and VPP, have been detectedin human plasma at picomolar concentrations after oral administration. Thiswould mean that paracellular transport plays a crucial role in VPP transport(Shimizu and Son 2007), since transport mediated by the PepT1 carrier leadsto a rapid hydrolysis of the peptide (Regazzo 2010). Once absorption of

peptides occurs, high peptidase concentrations in the blood cause fasthydrolysis of peptides in plasma. After intravenous administration of thetripeptide IVY to spontaneously hypertensive rats, this molecule wasmetabolized by plasma peptidases to form a subsequent ACE inhibitor, VY

with has a lower in vivoantihypertensive effect (Matsui et al. 2002). Sanchez-Rivera et al. (2014) recently published results obtained with peptidescontaining four or more amino acids from dietary sources with antihyp-ertensive activity. Based on pharmacokinetic parameters, the authors suggest aconsiderable uptake of the antihypertensive pentapetide HLPLP in tissues afteroral or systemic administration in spontaneously hypertensive rats. This

peptide was characterized by its resistance to in vitrogastrointestinal digestionand brush border peptidases (Quirs et al. 2008). After oral administration to

spontaneously hypertensive rats, the HLPLP peptide was rapidly absorbed andbiotransformed into the smaller and active LPLP and HLPL fragments, whichwere distributed throughout the body by circulation (Snchez-Rivera et al.2014).

6.ROLE OF FERMENTATIVE PROCESS AND OCCURRENCE

OF BIOACTIVE PEPTIDES IN WINEModerate consumption of red wine has been associated with reduced risk

of developing cardiovascular heart disease. This property is partly attributed to


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peptides with biological characteristics, mainly antihypertensive and anti-oxidant activities. Some wine peptides originate from the must, but most ofthem appear during the different stages of wine production either after yeastautolysis or after proteolytic activity of lactic acid bacteria on wine proteins(Covas et al. 2010).

The first study regarding bioactive peptides in wine was carried out byTakayanagi and Yokotsuka (1999), who determined for the first time ACEinhibitory (ACE-I) activity both in red and white wines. The authors alsodemonstrated that red wines had higher ACE-I activity that white wines. Theyhypothesized that peptides from the pulp of the grapes constitute the majorityof ACE inhibitory substances found in wine. This hypothesis is based on thefact that ACE-I activity in the wines assayed declined during the fermentative

process. Considering that many phenolic compounds with ACE-I activitycould be extracted from the skin and seeds, the authors supposed that phenoliccompounds have a negligible incidence in the ACE-I activity. In studies

performed with normotensive and spontaneously hypertensive rats, Perrot etal. (2003) found that the extract of the low molecular weight fraction fromChampagne wine exerted an antihypertensive effect on the hypertensive rats

but not on normotensive ones. The authors postulated that in view of the

complex composition of the extracted wine fraction it is unlikely that thedecrease in blood pressure can be attributed to the presence of a singlecompound. In fact, since wine is rich in phenolic compounds and peptides,

both groups could comprise individual components with antihypertensiveactivity (Sarr et al. 2006). Similarly, Pozo-Bayn et al. (2007) reported that redwines showed higher ACE-I activity than white wines, confirming the results

by Takayanagi and Yokotsuka (1999). Furthermore, Pozo-Bayn et al. (2007)postulated that phenolic compounds could have important participation in

wine ACE-I activity, although the authors only determined this activity in alow peptide wine fraction and a total peptide wine fraction.

Wine is the product of complex interactions between yeasts and bacteria ingrape must (Costantini et al. 2009) and multiple metabolic reactions occurduring the fermentative process. Yeasts of the genus Saccharomyces, mainlyS. cerevisiae, develop during the alcoholic fermentation, and under anaerobicconditions, they transform sugars present in the juice, mainly glucose andfructose, intoethanol andcarbon.During this process the medium is depleted

of assimilable nitrogenous compounds because the yeasts use these nutrients toobtain energy and increase their population (Ribrau-Gayon et al. 2000). Atthe end of the fermentation process, yeast autolysis can occur, resulting in therelease of intracellular compounds, thus increasing the concentration of
http://en.wikipedia.org/wiki/Sugarhttp://en.wikipedia.org/wiki/Ethanolhttp://en.wikipedia.org/wiki/Carbon_dioxidehttp://en.wikipedia.org/wiki/Carbon_dioxidehttp://en.wikipedia.org/wiki/Ethanolhttp://en.wikipedia.org/wiki/Sugar


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nitrogen compounds. After the fermentation process, special wines likesparkling wine are exposed to an aging process in the presence of yeast cells.Yeast autolysis occurs during this period, resulting in the release ofintracellular compounds that modify the organoleptic characteristics of thewine (Charpentier et al. 2005; Nunez et al. 2005). The principal constituentsreleased after yeast lysis are peptides and to a lesser extent amino acids and

proteins (Alexandre and Guilloux- Benatier, 2006). Similarly, Alcaide-Hidalgoet al. (2007) demonstrated that under accelerated autolysis conditions in asynthetic wine, a commercial S. cerevisiaestrain increased the release of highmolecular weight nitrogen compounds, mainly proteins, during the first stageof autolysis. These high molecular weight nitrogen compounds are wereenzymatically hydrolyzed producing peptides and amino acids. This meansthat peptides are the main autolysates, thus demonstrating their importance inaged wines. The authors showed that under accelerated autolysis, peptidesreleased from yeast exhibited both ACE-I and antioxidant activities. Theyconcluded that these activities could be exclusively attributed to yeast

peptides, and highest activity was observed in a hydrophobic peptide isolatedfraction. Aredes-Fernndez et al. (2011) also demonstrated the release ofnitrogen compounds during accelerated autolysis of S. cerevisiae mc2 in a

synthetic wine medium. Yeast autolysis was confirmed by viable cell countsand determination of dry weight before and after yeast autolysis. Underaccelerated autolysis conditions,yeast viability decreased dramatically after 24hours, observing a reduction of 38% in dry weight. As a result, an increase inthe concentration of proteins, peptides and amino acids of 7.92, 3.66 and 5.97mg N/L respectively, was detected (Aredes-Fernndez et al. 2011).

The nutrients released after yeast lysis become available for growth ofOenococcus oeni, a lactic acid bacterium responsible for carrying out the

enzymatic conversion of L-malic acid to L-lactic acid in a process known asmalolactic fermentation (MLF) during the second stage of winemaking. MLFis a significant process in wine making that affects operation efficiency and

product quality and safety. This fermentation produces stabilization, areduction in acidity and production of desirable wine aroma and flavorcompounds. O. oeni is the main bacterium responsible for this fermentation

process because of its ability to survive the harsh wine conditions (highalcohol content, low pH, and low nutrient content) and production of desirable

sensory compounds (Bartowsky 2014).During the first days of the alcoholic fermentation, the population of

O. oeni is limited to levels of about 104 CFU/mL. As the fermentationadvances, these values decrease to 102 CFU/mL owing to its sensitivity to


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ethanol and the low pH of the medium. After the alcoholic fermentation, thecells start multiplying and they can reach the necessary population of 106108CFU/mL to start the MLF (Fleet et al. 1984), even though wine is anunsuitable substrate for the growth of lactic acid bacteria. In general, wine is a

poor medium for bacterial growth because it has few available nutrients(Guilloux- Benatier et al. 1985). Because lactic acid bacteria have complexnutritional requirements, the release of peptides and amino acids plays animportant role in maintaining O. oeni growth in natural media. O. oeni hascomplex free amino acid requirements to sustain growth, because it is unableto synthesize certain amino acids (Saguir and Manca de Nadra 2007). Toovercome this inconvenience, it has developed complex enzyme systems,

producing small peptides and releasing free amino acids from larger peptidesinto the immediate environment. Manca de Nadra et al. (1997, 1999) reported

proteolytic activity of O. oeniX2Lon the macromolecular nitrogen fraction ofwhite and red wines, which favored peptide release. The authors also foundthat the release of O. oeniproteases into the extracellular medium increasedunder starvation conditions (Manca de Nadra et al. 2005). Faras and Manca de

Nadra (2000) partially purified and characterized an exoprotease from O. oeni.In addition, Remize et al. (2005) confirmed the presence of extracellular

protease activity in O. oeni IOB84-13 during the growth phase in a poor-nitrogen medium. Moreover, Folio et al. (2008) demonstrated the presence ofextracellular proteins from O. oeni ATCC BAA-1163. One of them, EprA,was isolated and the enzyme was able to hydrolyse several proteins.

O. oeni is able to use small peptides of up to eight amino acid residues(Aredes-Fernndez et al. 2004; Ritt et al. 2008). Aredes-Fernndez et al.(2004) exhaustively studied peptide utilization in O. oeni X2L, assaying theindividual and joint effect of different dipeptides as amino acids sources on the

growth of O. oeni X2L in a synthetic medium supplemented with L-malic acid.They demonstrated that substitution of essential amino acids by dipeptidesresulted in a significant increase in the growth parameters of themicroorganism.

A previous report by No et al. (2008) evidenced that the increase in theACE-I activity takes place after alcoholic fermentation. The authors alsoreported that the ACE inhibitors could be peptides. Aredes-Fernndez et al.(2011) showed that after sequential inoculation of O. oeniin synthetic simil-

wine medium bacterial proteolytic activity caused a decrease in theconcentration of proteins released after yeast autolysis. A concomitant increasein peptide release also produced a significant increase in ACE-I activity


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(36.5%) and antioxidant activity (430.67 mol FeSO4/L and 3.47% for FRAPand DPPH scavenging, respectively).

Apud et al. (2013a) demonstrated that culturing O. oenim1 in a syntheticsimil-wine medium supplemented with the protein and polypeptide fractionwith a molecular weight higher than 12 KDa (obtained after dialysis with acellulose membrane) from four varietals of Argentine wines from Cafayate,(Cabernet Sauvignon, Malbec, Tannat and Torronts) allowed the release of

biologically active peptides. The authors also observed simultaneous proteinconsumption. These results confirm that the release of bioactive peptides is aresult of bacterial proteolytic activity.

Figure. 2. Proteolytic activity in synthetic simil-wine medium (SW) (open square) andSW added with protein-polypeptide fraction of Cabernet Sauvignon (filled square);Malbec (open circle); Tannat (filled circle) and Torronts (triangle) during 96 hincubation.

Figure 2 shows the change in proteolytic activity of O. oeni m1 insynthetic simil-wine medium (SW) supplemented with the high molecular

weight nitrogen fraction (HMN) obtained from different wine varietals. Insynthetic simil-wine medium (control medium), low proteolytic activity (0.396mmol/L) of O. oeni was detected after 24 h of incubation. In SWsupplemented with Cabernet Sauvignon and Torronts HMN, maximum

0.0

0.5

1.0

1.5

2.0

2.5

0 24 48 72 96

ProteolyticA

ctivity[mmol/L]

Time [h]


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proteolytic activity was detected after 24 h of incubation with values of 1.372and 1.054 mmol/L, respectively. In SW supplemented with HMH fromMalbec and Tannat wines, proteolytic activity significantly increased after 48h, reaching values of 0.992 and 1.536 mmol/L, respectively.

The highest increase in peptides in synthetic simil-wine mediumsupplemented with Cabernet Sauvignon, Malbec, Tannat and Torronts HMNoccurred after 48 h incubation time with a release of 1.067, 0.397, 0.916 and0.705 mg N/L of peptide nitrogen, respectively. Simultaneously with the

peptide release in synthetic simil-wine medium supplemented with HMN ofCabernet Sauvignon, Malbec and Tannat wines, maximum ACE-I activity wasdetected after 24 h of incubation showing an increase of 63.8, 36.4, and 70.0%respectively. Nevertheless synthetic simil-wine medium supplemented withTorronts HMN showed ACE-I activity that was lower than that in the redwine varietals, presenting a maximum activity after 24 h incubation (18%).With respect to antioxidant activities, evaluation of ferric reducing antioxidant

power (FRAP) and free radical scavenging ability (DPPH) showed that duringincubation of O. oeni in the presence of HMN of Cabernet Sauvignon andTannat wines, the highest increase in these activities was detected after 24 hincubation. A synthetic simil-wine medium with O. oeni but without

supplement, did not exhibit significant changes in the two biological activities.Figure 3 shows the relationship between the changes in peptide nitrogen and

biological activities in the presence of O. oeni m1 in SW added with eachHMN fraction obtained from the four different wine varietals. These resultsare in agreement with those published by Apud et al. (2013b) who reportedthat inoculation of O. oeni m1 in SW supplemented with HMN of CabernetSauvignon and Syrah wines from Colalao del Valle, Tucumn, Argentina

produced a release of 1.247 and 1.373 mg N/L of peptide nitrogen,

respectively, after 48 h of incubation. The released peptides from CabernetSauvignon and Syrah wines allowed an increase in the FRAP capacity, DPPHactivity and ACE-I activity.

Unpublished results presented at the XIV Congreso Latinoamericano deViticultura y Enologa showed a change in ACE-I activity after proteolyticactivity of O. oeni X2L on the HMN from Cabernet Sauvignon wine fromTucuman, Argentina. The HMN was obtained after precipitation withtrichloroacetic acid in acetone at -20C. O. oeni X2L was inoculated in a

synthetic simil-wine medium supplemented with the protein fractionpreviously obtained. The major increase in proteolityc activity was detectedafter 96 h of incubation reaching a value of 0.300 mmol/L. At this time asignificant consumption of 215.93 mg N/L in protein nitrogen was observed


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with a release of 77.73 mg N/L of peptide nitrogen (Table 1). Results obtainedin synthetic simil-wine medium without supplement of HMN, showed that O.oeni did not grow and proteolytic activity was not detected. The peptidesreleased as a consequence of proteolytic activity in the presence of HMN fromCabernet Sauvignon wine, increased ACE-I activity reaching the maximumvalue at 96 h of incubation (17.73%).

Table 1. Changes in O. oeniX2L proteolytic activity and nitrogencompounds in synthetic simil-wine medium supplemented with HMN

from Cabernet Sauvignon wine

Incubationtime[h]

Proteolyticactivity

[mmol/L]

Proteinconcentration

[mg N/L]

Peptideconcentration

[mg N/L]

Amino acidconcentration

[mg N/L]

0 0.000.02 289.2420.0 1.660.09 28.931.35

48 0.110.01 246.0521.52 7.030.20 26.732.23

96 0.300.04 73.315.60 79.395.97 27.121.78

Values are the means of three independent determinations carried out in duplicate.

Recently, Su et al. (2015) studied the antioxidant properties of intact cellsand cell-free extracts of different strains of O. oeni isolated from wine. Theauthors suggest their possible use as probiotics, taking into account theiradaptation to the hostile wine environment, which mimics the acidicconditions of the digestive tract.They demonstrated that the two fractions of19 strains assayed presented different antioxidant activities. However theauthors did not establish the type of compounds involved in these activities.

7.FRACTIONATION AND ISOLATION OFBIOACTIVE PEPTIDES

Peptides have many different physicochemical properties such as size,charge, adsorption characteristics and solubility, making their fractionationand isolation difficult. Successive fractionation steps are necessary for

peptides studies in order to eliminate high molecular weight compounds asmuch as possible.


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Figure 3.Changes in peptide release (lines) and biological activities (bars): FRAP: Ferric reducing antioxidant power (black bars);DPPH scavenging: 2,2- diphenyl-1-picrylhydrazyl radical scavenging capacity (white bars) and ACE-I: angiotensin I-converting enzymeinhibitory activity (gray bars) during 96 h incubation in synthetic wine (SW) and SW added with HMN from four different winesvarietals: ca: Cabernet Sauvignon; ma: Malbec; tn: Tannat and to: Torronts.


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Proteins are removed from samples by precipitation with differentprecipitants like 7% Trichloroacetic acid (TCA) (Yokotsuka et al. 1975) or95% ethanol (Moreno-Arribas et al. 1996, 1998a; Martnez-Rodrguez et al.2002).

Ultrafiltration (UF) is especially useful to remove proteins duringfractionation of peptides. This size-exclusion pressure-driven separation

process uses membranes with a certain pore size that will retain particles or letthem through according to their size. This process retains proteins but notsmall peptides or carbohydrates (Berk 2013). Desportes et al. (2000) andPozo-Bayn et al. (2007) used this technique in the firt stage of isolation ofwine peptides.

A more recent technology, electrodialysis with ultrafiltration membranes(EDUF), has been developed to fractionate peptides from complex mixtures

based on their electrical charge, size, or molecular weight. It is essentially abatch process which one or more filtration membranes stacked inside aconventional electrodialysis cell. This technique allows separation ofmolecules according to their charge and molecular size in an electric field.EDUF has been successfully used to separate bioactive peptides from variousfood protein hydrolysates (Suwal et al. 2014). Lately, Roblet et al. (2014)

isolated soybean peptides using electrodialysis with an ultrafiltrationmembrane. Doyen et al. (2011, 2012) successfully fractionated antimicrobialand anticancer peptides from a snow crab using EDUF.

After precipitation or ultracentrifugation of proteins, traditionalchromatographic methods are generally used to separate peptide mixtures

because of their high selectivity. The most commonly used chromatographicmethods for separation and purification of peptides is gel filtration or size-exclusion chromatography (SEC), ion-exchange chromatography (IEC),

affinity chromatography (AC) and hydrophobic interaction chromatography(HIC). Of these methods, SEC is the technique of choice to separate wine

peptides (Desportes et al. 2000, Pozo-Bayn et al. 2007). SEC allowsseparation of peptides according to their molecular size. The pore size isdetermined by the molecular weight range of the peptides in the sample.

High Performance Liquid Chromatography (HPLC) is a widely usedtechnique to separate, identify, and purify bioactive peptides. Reverse-phaseHPLC (RP-HPLC), which uses hydrophobic interactions as the main

separation principle, is considered the most powerful method to purifypeptides. It is characterized by the use of a stationary phase and an aqueousmobile phase containing an organic solvent, such as acetonitrile or an alcohol.


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Mandal et al. (2014) recently fractionated and purified twenty-four peptidesfrom human milk using RP-HPLC.

Peptides are difficult to isolate from wine because they are together withnon-peptidic compounds in a complex mixture (Desportes et al. 2000). This isthe reason that not many studies have been carried out to separate thesecompounds from wine.

Desportes et al. (2000) separated peptides from wine using ultrafiltrationfollowed by gel-filtration chromatography with Sephadex columns and thefractions obtained were subjected to RP-HPLC in order to isolate small

peptides. Pozo-Bayn et al. (2007) isolated peptides with antihypertensiveactivity from red and white wines using ultrafiltration and SEC with aSephadex LH-20 column. Alcaide-Hidalgo et al. (2008) fractionated peptidesof from red wines using SEC and HPLC with Sephadex LH-20 and Cosmosil140 C18-OPN columns respectively.

Peptides are generally detected at an absorbance between 200 and 220 nm,but many compounds present in wine could interfere in the ultravioletdetection of peptides when low wavelengths are used. Therefore, it is better toapply sensitive and selective detection methods. A solution is to synthesize

peptide derivatives because these are detectable at higher and more specific

wavelengths. Peptides that contain fluorescent amino acids, like tyrosine andtryptophan, may be detected using fluorescence. Peptides without this propertycan be derivativatized using special fluorescent agents, a technique that hasshown to be very useful (Moreno-Arribas et al. 1998a).

Determination of the amino acid sequence can be carried out using massspectrometry or Edman degradation sequencing. Edman degradation is achemical method based on the cleavage of one amino acid at a time from the

N-terminus of the peptide chain. This terminal amino acid is then separated

and identified. The cleavage reaction is repeated until the complete peptidesequence is known.

A complication is that this method requires highly purified samples. Thistechnique can be carried out manually or automatically using specialautomated peptide sequencers (Gouda et al. 2006; Kuba et al. 2009; Rho et al.2009).

Mass spectrometry (MS) and tandem mass spectrometry (MS/MS) arepowerful techniques widely employed for the characterization of bioactive

peptides. With MS, an unknown peptide undergoes fragmentation and thefragments (ions) are subsequently registered in a peptide mass spectrum. WithMS/MS these ions are called precursor ions and they break into two partsgenerating one fragment containing the N-terminus of the original peptide


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sequence and a complementary fragment containing the C-terminus. Then,computational methods deduce the peptide sequence from its spectrum.MS/MS and MS spectra are similar to one another, with the difference that inthe former technique, the peaks correspond to fragment ions of a peptide andin the later one, the peaks correspond to complete peptide ions (Steen andMann 2004; Menschaert et al. 2010; Costa et al. 2013).

Junfeng et al. (2009) determined the amino acid sequence of a peptidederived from fermented soybean food with ACE-I activity applying Edmandegradation. Boutrou et al. (2013) identified milk-protein bioactive peptideswith opioid and antihypertensive activity using tandem mass spectrometry.

8.PERSPECTIVES

The most challenging task in the study of bioactive peptides from wine isidentification of peptides with biological activity produced after microbialmetabolism during the vinification process and evaluation of their in vitroandin vivoactivity. Current studies should focus on the isolation and selection ofwine microflora with advantageous technological vinification properties thatguarantee the wine quality and may even add additional value to the final

product. More studies on this topic are necessary to ensure that orally ingestedbioactive peptides present in wine pass through the digestive tract and aresubsequently absorbed through the intestinal epithelium. Finally, the beneficialeffect of these peptides on the target organs or tissues should be assessed.Another current topic of interest is the supplement of bioactive peptides astherapeutic agents in food and beverages. They are used as natural ingredientsin functional and novel foods, dietary supplements and even pharmaceuticalswith the purpose of delivering specific health benefits. In this way, it isnecessary to investigate strategies for increasing the resistance of digestiveenzymes and cellular permeability of bioactive peptides.

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