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Accepted Manuscript

Title: Food peptides: Purification, identification and role in the


metabolism

Author: Naima Arroume Renato Froidevaux Romain Kapel


Benoit Cudennec Rozenn Ravallec Christophe Flahaut
Laurent Bazinet Philippe Jacques Pascal Dhulster

PII: S2214-7993(16)30016-9
DOI: http://dx.doi.org/doi:10.1016/j.cofs.2016.02.005
Reference: COFS 130

To appear in:

Received date: 8-1-2016


Revised date: 11-2-2016
Accepted date: 12-2-2016

Please cite this article as: Arroume, N., Froidevaux, R., Kapel, R., Cudennec,
B., Ravallec, R., Flahaut, C., Bazinet, L., Jacques, P., Dhulster, P.,Food
peptides: Purification, identification and role in the metabolism, COFS (2016),
http://dx.doi.org/10.1016/j.cofs.2016.02.005

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HIGHLIGHTS

Food proteins as source to produce bioactive peptides

1. There is a high biodiversity of bioactive peptides from animal or plant sources

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2. Bioactive peptides play an important role in energy homeostasis

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3. Peptidome identification is needed to understand the bioactivity
4. Controlled bioprocesses are needed for the separation of bioactive peptides

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Page 1 of 15
Food peptides: purification, identification
and role in the metabolism
Naima Arroume1, Rnato Froidevaux1, Romain Kapel1, Benoit Cudennec1, Rozenn
Ravallec1, Christophe Flahaut1, Laurent Bazinet2, Philippe Jacques1,3 and Pascal Dhulster1

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Adresses

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1
Univ. Lille, EA 7394, USC 1281 - ICV- Institut Charles Viollette, F-59000 Lille, France

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2
Institute of Nutrition and Functional Foods (INAF), Department of Food Sciences and
Laboratory of Food Processing and Electromembrane Processes (LTAPEM),Universit Laval,
Qubec (QC), G1V 0A6, Canada.

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3
Terra Research Centre, Microbial Processes and Interactions, Gembloux Agro-Bio Tech,
University of Liege, Passage des Dports, B-5030 Gembloux, Belgium

Abstract an
The search for new active molecules from food protein hydrolysates represents a real
challenge for animal feed, aquaculture, as fertilizer, but also in cosmetics and
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pharmacological fields. The constant discovery of molecules with biological activities
continually brings new insights into the complex mechanisms involved in vivo. However, it
remains difficult to conclude about the structure, amino acid composition, size or the
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physicochemical properties necessary for the activity. This review will highlight the research
carried out to determine the physiological role of these peptides and the development of
new tools for their production and study.
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Introduction
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The multiplicity of peptide sequences generated by the hydrolysis process provides a wide
range of structural and physicochemical properties that can help, using technological
processes such as ultrafiltration membranes, to separate them by family properties and to
draw the necessary conditions to maintain the activity [1]. There are yet no general rules for
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determining the best hydrolysate with the most important activity. Each raw material, each
enzyme and each hydrolysis conditions will give different final peptides. The relationship
between the sequence and activity is still studied and represents a basic research for the
discovery of the complex mechanism of action of these biological activities [2,3,4,5]. A set of
recent reviews described the high biodiversity of bioactive peptides from animal and plant
proteins [6,7*,8**,9*,10]. In this short review, we will focus on the recent evolution of
several research fields related to protein hydrolysis such as the role of bioactive peptides in
energy homeostasis, the importance of peptidomics and the development of controlled
bioprocesses for the separation of bioactive peptides.

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Fig. 1. Summary of tools and type of studies on bioactive peptides
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Dietary proteins as sources of bioactive peptides involved in energy homeostasis


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In economically developed countries, eating behaviors, characterized by an increase in


energy intake which causes an increase in body mass, led to the metabolic syndrome. This
syndrome predisposes to many diseases such as type II diabetes, a deregulation of food
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intake, hypertension, chronic inflammatory bowel disease (IBD) [11] and became one of the
most alarming public health problems of this century. Digestion has for a long time been
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considered as a black box producing unit nutrient compounds such as amino acids involved
in metabolism and indispensable to the physiological function of the body. In recent years,
an abundance of studies have shown the involvement of peptides generated during the
digestion in many physiological functions [12] and especially in energy homeostasis and
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consequently in the "metabolic syndrome" and in its various symptoms.

Regulation of food intake

During a meal, the presence of nutrients in the gastrointestinal tract results in the
production of signals that inform the brain about their qualities and quantities. Among these
signals, peptide hormones secreted by enteroendocrine cells such as cholecystokinins (CCK)
and glucagon-like peptide 1 (GLP-1) were particularly studied and are of great interest for
the development of new drugs and dietary supplements targeting obesity [13]. During
digestion, the products of hydrolysis of food proteins are known to have a high satiating
power, greater than that exercised by carbohydrates or lipids, stimulating the secretion of
gastrointestinal hormones [13]. Thus, recent work has identified peptides able to exert a

Page 3 of 15
strong stimulation on the secretion of hormones involved in the regulation of food intake
[14]. Another promising approach in the research for natural molecules that can be used in
functional foods concerns the identification of peptides exerting agonistic action to that of
CCK and GLP-1 by binding to their cellular receptors distributed in the gastrointestinal tract
and central nervous system. Thus, studies have identified peptides able to bind to these
receptors and to exert in vitro and in vivo agonistic action [15,16,17]. In this way, Pupovac
and Anderson [18] evidenced in rats that peptides arising from digestion contribute to
satiety by independent activation of both opioid and CCK-1 receptors.

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Glucose metabolism

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GLP-1, an intestinal incretin, well known to be involved in the food intake regulation, also
acts on the functionality of pancreatic islets mainly by stimulating insulin secretion [19] and

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slowing the glucagon secretion. An interesting approach is to assume that peptides able to
cross the intestinal barrier will be also able to inhibit the action of the dipeptidyl peptidase

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IV (DPP-IV), a multi-functional enzyme mainly involved in the degradation of GLP -1 and thus
consequently in the regulation of glucose metabolism. The incretin effect is drastically
reduced or lost in type 2 diabetes mellitus (T2DM). Lately, DPP-IV inhibitors have indeed
been considered as innovative molecules for the treatment of T2DM enhancing the GLP-1
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activity and recovering the incretin effect. Therefore, incretin-based therapy using DPP-IV
drug inhibitors (gliptins) is one of the most recent alternative treatments of T2DM as lately
reviewed [20]. Nowadays, several works focus on the strategy to identify natural peptide
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inhibitors of DPP-IV activity as an alternative to synthetic drugs. Such peptides could be
obtained by processing food (protein hydrolysis and microbial fermentation) or by
proteolysis occurring during digestion. Numerous studies had first reported that milk derived
products induced DPP-IV inhibition in vitro [21, 22]. Other studies evidenced DPP-IV
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inhibitory peptides from different protein sources like rice bran hydrolysates [23], fishes or
macro-algae [24, 25]. A recent study demonstrated, in vitro, for the first time that a
cuttlefish hydrolysate submitted to gastrointestinal digestion could extend the incretin
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effect via two mechanisms: the stimulation of intestinal GLP-1 and the inhibition of intestinal
DPP-IV activity [26*]. These results could be linked to those obtained with a porcine skin
gelatin hydrolysate, harboring a DPP-IV inhibition activity in vitro, and improved glucose
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tolerance in diabetic rats in correlation with the increase of insulin and the GLP-1 plasma
levels, the inhibition of plasma DPP-IV activity and the decrease of the plasma glucagon level
[27]. Recently, new prospects demonstrated that the computer-driven screening of bioactive
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peptides and the in silico/in vitro combinatory approaches are attractive tools for the more
rapid discovery of new bioactive peptides [28, 29].

The need to identify peptidomes to understand peptide bioactivities

Long time challenging, the identification of all peptides of a complex mixture has become
easier, rapid and accurate with the emergence of omics techniques [30**]. In the field of
bioactive peptides, peptidomics is by definition the analytical method of choice for the
structural elucidation of peptides and of their post-translational modifications. Peptidomics
is defined as the comprehensive characterization of peptides in a sample [31*]. Practically,
peptidomics is a several steps procedure. First, pre-purification methods are used to
separate peptides from all other molecules (carbohydrates, proteins, lipids, salts). Then a

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combination of peptide fractionation techniques leads to the separation of the different
peptides based on different physico-chemical properties (size-exclusion chromatography
(SEC), liquid chromatography (LC), capillary electrophoresis (CE), gel-free isoelectrofocusing
(GF-IEF)). Finally, Tandem mass spectrometry (matrix assisted laser desorption/ionization-
tandem mass spectrometry (MALDI-MS/MS), electrospray-mass spectrometry (ESI-MS)) and
bioinformatics are used to identify and quantify all peptides in the complex mixture [32, 33,
34**, 35, 36]. Today, the identification of peptides relies on the MS-based fragmentation
methods (collision induced dissociation (CID), electron collision or transfer dissociation (ECD
and ETD, respectively)), the data acquisition speed and the accuracy of the most recent mass

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spectrometers [37*]. Moreover, the MS-data acquire way (data dependent acquisition (DDA)

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or data independent acquisition (DIA); positive or negative mode; ion-mobility), the
repetition of biological and technical experiments, the bioinformatics tools used to match
the experimental MS-data and the protein databases used have a direct impact on the

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exhaustive characterization of peptides [38]. Although the MS-based quantification methods
(label-free, isobaric and isotope labeling) are available and validated [34], the relative

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quantification of bioactive peptides remains rare and therefore the batch-to-batch
reproducibility is too less often reported [39]. Software (owned MS-manufacturer, software
developed by academic laboratories, free-of-charge or costly) of identification and
quantification of peptides are numerous, and all having advantages and drawbacks that
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invite the user to integrate the bioinformatics results in a metascoring system to obtain a
comprehensive view of the peptide heterogeneity of a sample. Even if peptidomics is well
adapted some limitations exist such as ranging from the small peptides (< 5 amino acids)
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that are challenging to identifying by tandem-MS due to the low number of MS fragments
obtained [40]. The hydrophobic and hydrophilic nature of peptides also complexifies their
separation and requires the use of several methods of peptide fractionation. To end with,
databases and bioinformatics tools need to be upgraded to limit the false positive rate that
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is 100 times higher in peptidomics than for proteomics [41].

Controlled separation and purification of bioactive peptides


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Bioactive peptides produced by enzymatic proteolysis are in complex hydrolysates that


contain more than a hundred different peptides. As a consequence, the level of bioactivity of
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hydrolysates containing bioactive peptides is most often low. A classical way to improve this
is to carry out separation processes for enriching the starting mixtures into bioactive
peptides [42*]. Several approaches can be adopted, based on different types of
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chromatography, electrophoresis and membrane separation techniques, in relation with


hydrophobic/hydrophilic, charge, molecular size or affinity properties of peptides. Adoui et
al [43*] have developed a simple and non-expensive method to recover the active peptide
from complex bovine casein hydrolyzate by optimizing the separation conditions through
ionic strength and pH parameters. This method was used to separate antimicrobial peptides
from complex peptic hydrolysate of casein and of RuBisCO [44*]. In this last case, three new
pure antibacterial peptides were obtained in these hydrolysis conditions. Processes have
been also developed and are summarized hereafter. We have chosen to present some
innovations based on surfactant and charge-size combining properties, such as membrane
filtration-electrodialysis or foaming-draining processes.

Membrane-based processes

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Membrane filtration such as ultrafiltration [45] or nanofiltration [46] has been widely used
to do so and a recent review on the subject is available [47, 48, 49].. However, the choice of
membrane, implementation mode and operating condition was rather empirical (non
specific to the peptide of interest and the starting hydrolysate properties). To tackle this
issue, an interesting work proposed to base the choice of membrane molecular weight cut-
off on overall peptide retentions (between 0.4 and 0.7) [50]. These authors also proposed a
calibration method of UF membrane based on size-exclusion chromatography (SEC) analysis
of permeate and retentate that relates peptide retentions to their molecular weights.

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Recently, an original methodology for predicting yield and enrichment of a complex

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hydrolysate in a bioactive peptide has been proposed. This method couples (i) SEC
chromatogram of the hydrolysate and targeted peptide molecular weight to mass balance
equations and membrane calibration [51, 52]. The main problem related to classical

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membrane processes lies on their poor selectivity mainly based on solute hydrodynamic
radius. Interestingly, Bargeman et al. [53, 54] and Lapointe et al. [55] designed a filtration

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module that uses one ultrafiltration membrane and an electrical field as a driving force. The
electrical field strength in the feed solution was maximized in relation to convection in order
to obtain a selective separation of the charged target compounds. However, in these
electromembrane configurations, the selectivity and purity of peptides are limited by
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pressure application and membrane fouling. For these reasons, a technology called
electrodialysis with filtration membrane (EDFM) was developed and carried out successfully
for the production of bioactive peptides (anti-hypertensive, anti-cancer, anti-diabetic or anti-
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microbial) from various protein hydrolysates [45, 47, 56, 57]. EDFM couples size exclusion
capabilities of porous membranes (NF, UF and MF) with the charge selectivity of
electrodialysis (ED) and no pressure is applied in the ED cell. The potential applications of
EDFM were enlarged by carrying-out simultaneously the hydrolysis and the fractionation of
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the generated bioactive peptides [58] and also by stacking filtration membranes of different
molecular weight cut-offs [56].
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Extraction processes

Fractionation processes have already been used for fractionation of bioactive peptides, such
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as antioxidant [59], antihypertensive [60], DPP-IV inhibitory peptides [61], ACE Inhibitory
peptides [62]. Among them, separation processes have been carried out in taking account
hydrophobicity property of peptides. Indeed, researches have been carried out on the
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selective separation of opioid or antimicrobial peptides through ion-pairing assisted


extraction in water/organic solvent biphasic systems. Ion pair formation in an aqueous
phase, thanks to the addition of alkyl sulfonates or Sodium Dodecyl Sulfate agents, allowed
to selectively extracting these bioactive peptides in organic phases consisting of
dichloromethane or octan-1-ol [63]. Such extraction system was intensified using an
ultrafiltration membrane which stabilized the interface and provided a greater exchange
surface [64]. Other authors have worked on the combination of a membrane contactor and
an organic interface consisting of octan-1-ol for the extraction of opioid peptides [65].
Another way to intensify a solvent extraction system is to implement it in centrifugal
partition chromatography (CPC). Recently, a mixed ion mode that uses a charged molecule
to displace equilibrium in the two liquid phases demonstrated very promising results for

Page 6 of 15
purifying the antihypertensive peptide Val-Trp from the alfalfa white proteins hydrolysate
(purification factor around 40 in a single step) [66].

Foaming-Draining processes

Selective separation studies of protein through the exploitation of their surfactant


properties are numerous [67,68] but works on selective extraction of bioactive peptides are
very rare. First study is demonstrated by Dordhain et al. [69*]. They have isolated
antibacterial peptides in a foaming-draining process in exploiting differences in surfactant

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properties of the peptides present in the hydrolysate, related to differences in

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hydrophilicity, hydrophobicity and molecular size. Experimental designs enabled highlighting
the major influent parameters and improving enrichment of the bioactive peptide fraction.

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Development prospects

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Despite the numerous successes of the production and commercialization of hydrolysates
containing one or more bioactive peptides, many industrial obstacles limit the sales of
nutraceutical or functional products. One of the main obstacles is the regulation aspect and
the application for a health claim authorization.
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In addition, the characterization of the biological effect of the dietary peptides needs to be
improved. The development of new in vitro assay is of great importance to mimic the
physiological environment and get closer to the in vivo effect of the bioactive peptides. The
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always growing number of studies on the human gastro intestinal digestion will help to
generate enough knowledge to understand the becoming of the dietary proteins and the
target of the biological active peptides generated during the enzymatic process [70]. This
integrated approach which confronts the biochemistry aspect of the food proteins and the
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physiological aspect of the gut will permit to improve the efficacy of the bioactive peptides
in human and to give added value to food protein hydrolysates.
In this context of better efficacy of the peptides activities and a better knowledge of their
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targets, the substitution of drugs by active peptides able to fight against specific diseases
such as T2D or hypertension will be a safely and economical way to decrease the harmful
side-effects of treatment usually induced by drugs, to potentiate the drug effect and to
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upgrade food processing by-products.


Recently, a number of computational methods have been successfully applied in predicting
the potential of proteins as precursors of novel bioactive sequences. Two main approaches
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are now reported: the former uses in silico enzymatic digestion and the bioactivity
prediction using a combination of sequence biochemical properties and databases of known
bioactive peptides; the latter is based on structure-based molecular modelling approach
coupled to a docking study (if the 3D structure of the target protein is known) to evaluate
the binding affinity between bioactive peptides and their target [71]. In the future, the
mixing of in silico, in vitro and in vivo approaches will constitute without doubt the road to
progress.

In order to extend the industrial growth perspectives, it may be interesting to develop


innovative separating processes of active fractions before the hydrolysis phase.
Furthermore, the active peptide fraction selectivity or even its yield could be improved by
combining separative processes or in association with the hydrolysis reaction.

Page 7 of 15
On the other hand, the valorization issue of natural resources or co-products from food
industry has an interest only if fraction of the co-products is enhanced in terms of its
bioactive properties. Nonetheless, the hydrolysate fraction containing several bioactive
peptides could show a higher effect on animal and human nutrition/health, as the
bioavailability of the peptides into a mixture is enhanced compared to isolated peptides.
Using of hydrolysates in aquaculture allows improving the survival rate of animals and could
be a new method to promote this technology. The antimicrobial properties of fractions or of
purified peptides, revealed through enzyme hydrolysis, constitute another means to
enhance hydrolysates in food safety, animal health and in cosmetology.

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In case of proteins shortage, the use of more exotic, less conventional proteins should be
considered such as the transformation of insects.

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This interesting article develops a simple and non-expansive method to recover the active
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