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International Dairy Journal 73 (2017) 25e37

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International Dairy Journal


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Review

Dromedary camel milk proteins, a source of peptides having biological


activities e A review
Abderrahmane Mati a, Chahra Senoussi-Ghezali a, Saliha Si Ahmed Zennia a,
Dalila Almi-Sebbane a, Halima El-Hatmi b, c, Jean-Michel Girardet d, e, *
a
Universit
e Mouloud Mammeri, Laboratoire de Biochimie Analytique et Biotechnologies (LABAB), 15000, Tizi Ouzou, Algeria
b
Laboratoire d'Elevage et Faune Sauvage, Institut des R
egions Arides de Medenine, Tunisia
c 
Departement Agro-Alimentaire, Institut Superieur de Biologie Appliqu
ee de Medenine, Universit
e de Gabes, Tunisia
d
Universit
e de Lorraine, UMR-1136 Interactions Arbres/Microorganismes, Facult e des Sciences et Technologies, 54506, Vandœuvre-l
es-Nancy, France
e
INRA, UMR-1136 Interactions Arbres/Microorganismes, Centre INRA Nancy Lorraine, 54280, Champenoux, France

a r t i c l e i n f o a b s t r a c t

Article history: Many useful properties are assigned to camel (Camelus dromedarius) milk, which is traditionally used for
Received 10 September 2016 the treatment of tuberculosis, gastroenteritis, and allergy in many countries. Some amino acid sequences,
Received in revised form which are encrypted in the camel proteins, may play a beneficial role in human health once they are
30 November 2016
released from milk either in vivo during normal digestion or by proteolysis with purified enzymes or
Accepted 1 December 2016
Available online 11 December 2016
during bacterial fermentation. Similar to the bovine milk counterparts, camel milk bioactive peptides
may display a variety of potential activities that were almost always unveiled from in vitro analyses: anti-
microbial, anti-oxidative, anti-hypertensive, anti-inflammatory, and immunomodulatory activities.
Today, there is a growing interest for bioactive peptides generated from camel milk. This paper reviews
available data on the potential biological activities of the camel milk proteins and their peptides liberated
either during milk fermentation with proteolytic bacterial strains or by enzyme hydrolysis with specific
proteases or simulated gastro-intestinal digestion.
© 2016 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2. Camel milk proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2.1. Caseins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2.2. Whey proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2.2.1. a-Lactalbumin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2.2.2. Serum albumin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
2.2.3. Whey acidic protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
2.2.4. Camel whey basic protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
2.2.5. Lactoferrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
2.2.6. Lysozyme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
2.2.7. Lactoperoxidase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
2.2.8. Peptidoglycan recognition protein-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
2.2.9. Lactophorin (GlyCAM-1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
2.2.10. IgGs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
2.3. Milk fat globule membrane proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
3. Bioactive peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.1. Bioactive peptide fractions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

* Corresponding author. Tel.: þ33 383 684 227.


E-mail address: jean-michel.girardet@univ-lorraine.fr (J.-M. Girardet).

http://dx.doi.org/10.1016/j.idairyj.2016.12.001
0958-6946/© 2016 Elsevier Ltd. All rights reserved.
26 A. Mati et al. / International Dairy Journal 73 (2017) 25e37

3.2. Identified bioactive peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33


4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

1. Introduction 2. Camel milk proteins

The one-humped camels (Camelus dromedarius) are well-known Total protein content of dromedarys' milk is 33.5 ± 6.2 g L1
producers of milk. Camel milk is used as a main source of nutrients whole milk and the variability depends on the geographical origin
is consumed fresh or fermented. More than 60% of the dromedary of the animals (Konuspayeva et al., 2009). Caseins account for about
camel population (world population estimated of 23 million) is 80% of the total milk protein content, and whey contains numerous
concentrated in the arid areas of North East African countries like soluble proteins as well as diverse indigenous peptides generated
Somalia, Sudan, Ethiopia and Kenya (Jilo, 2016). by proteases present in camel milk such as chymotrypsin A and
Camel milk is comparable with bovine milk in fat content cathepsin D (Alhaider et al., 2013). The camel milk proteins them-
(38.2 ± 10.8 g L1 whole camel milk; Konuspayeva, Faye, & Loiseau, selves may be bioactive or could serve as precursors for bioactive
2009), but the ratio of unsaturated/saturated acids is more peptides. Table 1 summarises the properties of C. dromedarius milk
favourable in camel milk compared with that of cow; the unsatu- proteins.
rated fatty acids contribute to the overall dietary quality of camel
milk (Konuspayeva, Lemarie, Faye, Loiseau, & Montet, 2008). Camel
milk lacks b-lactoglobulin and is rich in immunoglobulins (Igs; De 2.1. Caseins
Wit, 1998; El-Hatmi, Levieux, & Levieux, 2006). It is three times
richer in vitamin C, which is a strong anti-oxidant, than cow milk Caseins are the most abundant protein fraction, amounting to
(Farah, Rettenmaier, & Attkins, 1992) and contains high concen- between 61.8 and 88.5% of the total protein (Ereifej, Alu'datt,
trations of minerals (calcium, copper, iron, magnesium, phos- AlKhalidy, Alli, & Rababah, 2011). The camel casein components
phorus, potassium, sodium, and zinc; Shamsia, 2009). (CNs) are homologous to the bovine caseins: aS1-CN, aS2-CN, b-CN
Besides the nutritive value of camel milk, it appears that this and k-CN (Table 1; Kappeler, Farah, & Puhan, 1998; Ochirkhuyag,
milk has potential medicinal properties; for a long time, camel milk Chobert, Dalgalarrondo, Choiset, & Haertle , 1997). Recently, the
has been used for medical purposes, such as metabolic and auto- nucleotide sequences of the whole b-CN-encoding gene CSN2
immune disease treatment. Scientific data support the anti-diabetic (Pauciullo, Giambra, Iannuzzi, & Erhardt, 2014) and of the whole k-
(Agrawal et al., 2005a, 2005b, 2007; 2003; Hassan & Bayoumi, CN-encoding gene CSN3 (Pauciullo, Shuiep, Cosenza, Ramunno, &
2010; Kotb-El-Sayed, Al-Shoeibi, Abd El-Ghany, & Atef, 2011), Erhardt, 2013) as well as the complete coding sequence of the
anti-infectious (Almahdy, El-Fakharany, El-Dabaa, Ng, & Redwan, aS1-CN-encoding gene CSN1S1 (Erhardt et al., 2016; Shuiep,
2011; El-Fakharany et al., 2012; Mal, Sena, Jain, & Sahani, 2006; Giambra, El Zubeir, & Erhardt, 2013) have been determined in
Mona, Ragia, Abeer, & Mosa, 2010), anti-cytotoxic (Salwa & Lina, Sudanese dromedary camel. Pauciullo et al. (2013; 2014) found
2010), and immunomodulating (Ebaid, 2014a, 2014b; Ebaid, genetic variants in the regulatory regions of the k-CN and b-CN
Ahmed, Mahmoud, & Ahmed, 2013) effects of camel milk. More- genes, but the k-CN and b-CN components were monomorphic. On
over, this milk can be consumed by persons suffering from allergies the other hand, Shuiep et al. (2013) and Erhardt et al. (2016)
to bovine milk proteins (El-Agamy, Nawar, Shamsia, Awad, & demonstrated genetic variation at protein and DNA level leading
Haenlein, 2009; Rubino et al., 2014) or lactose intolerance to the expression of genetic variants CSN1S1*A (the major allele
(Cardoso, Santos, Cardoso, & Carvalho, 2010). Indeed, the camel with a mean frequency of 0.83), CSN1S1*C, and CSN1S1*D (the
milk lactose is easily metabolised. One explanation would be that amino acid sequence of variant D is not yet available). In another
camel milk produces less casomorphin, which provokes less in- former study, Kappeler et al. (1998) described two genetic variants
testinal motility, and this would cause lactose to be more exposed of aS1-CN (CSN1S1*A and CSN1S1*B, where variant B contains 8
to the action of lactase (Cardoso et al., 2010). It is argued, also, that additional residues in the C-terminal region) by protein and mRNA
camel milk has positive effect on the reduction of autism symptoms sequencing within Somali dromedary camel, but the variant B was
(Shabo & Yagil, 2005). not found in the Sudanese camel. In a recent study, the poly-
The healing properties of camel milk may be linked to some of morphism of the k-CN and aS1-CN genes was also demonstrated for
its components, i.e., lactoferrin, immunoglobulins, lysozyme, lac- North African camels bred in Egypt (Othman, Nowier, & El-Denary,
toperoxidase, vitamin C (Abdel-Salam, Ebaid, Al-Tamimi, & Alhazza, 2016).
2016; Konuspayeva, Serikbayeva, Loiseau, Narmuratova, & Faye, According to Kappeler et al. (1998), the proportion of each
2005) and some bioactive peptides produced during the digestion casein component is: aS1-CN 22, aS2-CN 9.5, b-CN 65, and k-CN 3.5%
of milk in the gastro-intestinal tract (Ebaid et al., 2015). (w/w). The component b-CN is the main camel milk casein followed
The therapeutic potential of camel milk has been the subject of by aS1-CN in contrast to bovine milk, which contains 360 and
numerous review articles, mainly in the last four years (e.g., Dubey, 380 g kg1 total casein of b-CN and aS1-CN, respectively (Davies &
Lal, Mittal, & Kapur, 2016). Peptides derived from camel milk pro- Law, 1980). Only 3.5% of the total casein corresponds to k-CN in
teins and having potential biological activities good for health are camel milk (Kappeler, Farah, & Puhan, 2003) compared with 13% in
the focus of several recent investigations mostly related to in vitro bovine milk (Davies & Law, 1980). Recently, the concentration of
anti-oxidant, anti-hypertensive and anti-microbial activities. Thus, each CN component, except aS2-CN, was determined in camel milk
the purpose of the present article is to sum up the current state of by capillary electrophoresis; it consisted of approximately
the data reported on the potential biological properties of the camel 12.8 g L1 of b-CN, 2.9 g L1 of aS1-CN, and 1.7 g L1 of k-CN (Omar,
milk proteins and of peptides generated by enzyme treatment or Harbourne, & Oruna-Concha, 2016). On the basis of a proportion
during the bacterial fermentation of camel milk. estimated to approximately 10% by Kappeler et al. (1998), the
Table 1
Physico-chemical properties of camel milk proteins, mean concentration (g L1), and amino acid identity with their bovine counterparts.a

Camel protein (accession Residue no. Molecular mass Isoelectric point PTMs Concentration Homologous bovine Amino acid Concentration
no. or NCBI reference no.)b (mature chain)c (mature chain; Da)c (mature chain)c in camel milk protein (accession no.) identity (%)d in bovine milk

aS1-Casein: 2.9(6) aS1-Casein B (P02662) 12.8(6)


Variant A (CAA10077) 207 24,289.24 4.93 6 SerP(3) 41.7
Variant B (O97943) 215 25,307.33 4.89 6 SerP(3) 44.7
Variant C (ADZ98874) 207 24,275.21 4.92 6 SerP(3) 41.7
Variant D (unknown) n.d. n.d. n.d. n.d. n.d.
aS2-Casein (O97944) 178 21,265.90 5.80 9 SerP(3) ca. 1.9(3,6) aS2-Casein A (P02663) 53.3 3.5(11)
(3)
(10% caseins)
b-Casein (CDO50354) 217 24,650.76 5.27 3 SerP(3) 12.8(6) b-Casein A2 (P02666) 66.1 11.7(6)
k-Casein (CCI79378) 162 18,209.79 7.96 1 SerP þ 1.7(6) k-Casein A (P02668) 58.6 4.4(6)
5 Oglyc-Thr(3)

A. Mati et al. / International Dairy Journal 73 (2017) 25e37


a-Lactalbumin (P00710) 123 14,430.36 5.01 No PTMs 2.0(6) a-Lactalbumin B (P00711) 70.4 1.1(6)
GlyCAM-1/lactophorin: >0.9(4) Component PP3/GlyCAM-1/ 0.3(12)
Variant A (P15522) 137 15,442.29 5.20 4 SerP(4) 0.675(4) Lactophorin (P80195) 62.6
Variant B (P15522) 122 13,677.41 5.93 4 SerP(4) 0.225(4) 55.2
Immunoglobulins:
IgAs (light & n.d. 22,500 & 55,500(1) n.d. n.d. 1.54(7) Immunoglobulins: n.d. 0.8(11)
heavy chains) IgAs, IgMs, IgGs1
IgMs (light & n.d. 27,000 & 80,000(1) n.d. (absence of heavy-chain
heavy chains) IgGs2 and IgGs3)
IgGs1 (light & n.d. 30,000 & 50,000(2) n.d.
heavy chains)
Heavy-chain IgGs2 n.d. 46,000(2) n.d.
Heavy-chain IgGs3 n.d. 43,000(2) n.d.
Lactoferrin/lactotransferrin 689 75,250.83 8.63 4 Nglyc-Asn(5) 0.22(8) Lactoferrin/lactotransferrin 75.4 0.17(13)
(Q9TUM0) 1.74(6) (P24627)
Lactoperoxidase 613 69,688.97 8.87 3 predicted n.d. Lactoperoxidase (P80025) 83.8 0.03(14)
(NP_001290481) Nglyc-Asn
Lysozyme C 130 14,851.68 6.33 No PTMs 0.00015(1) Lysozyme C (P04421) 73.0 0.00007(1)
(XP_010984684)
PGRP-1 (Q9GK12) 172 19,143.64 9.02 No PTMs 0.12(9) PGRP-1 (Q8SPP7) 74.2 Not detected
Serum albumin 588 67,092.60 5.61 No PTMs 0.40(6) Serum albumin (P02769) 80.9 0.36(6)
(XP_010981066)
WAP (P09837) 117 12,564.32 4.86 No PTMs 0.16(10) Not found n.d. n.d.
Lactadherin 413 46,041.12 6.41 n.d. n.d. MFGE8 (AAI02355) 84.4 n.d.
(XP_010985034)
a
Abbreviations are: GlyCAM-1, glycosylation dependent cell adhesion molecule-1; MFGE8, milk fat globule-epidermal growth factor-8; NCBI, National Center for Biotechnology Information; n.d., no data; Nglyc-Asn, N-
glycosylated asparagine residue; Oglyc-Thr, O-glycosylated threonine residue; PGRP-1, peptidoglycan recognition protein-1; PP3, proteose peptone 3; PTMs, post-translational modifications; SerP, phophoserine residue; WAP,
whey acidic protein. References, indicated by a superscript number are as follows: (1) El-Agamy et al. (1996); (2) Hamers-Casterman et al. (1993); (3) Kappeler et al. (1998); (4) Kappeler et al. (1999a); (5) Khan et al. (2001); (6)
Omar et al. (2016); (7) Shamsia (2009); (8) Kappeler et al. (1999b); (9) Kappeler et al. (2004); (10) Kappeler (1998); (11) Wal (1998); (12) Sørensen and Petersen (1993); (13) Hagiwara, Kawai, Anri, and Nagahata (2003); (14) De
Wit (1998).
b
Accession number in GenBank or Swiss-Prot database; NCBI reference number for predicted sequences (i.e., camel lactoperoxidase, lysozyme C, serum albumin, & lactadherin).
c
Calculated with the ProtParam program (except for Igs) with cysteine residues in a reduced form, if any (program available at https://www.expasy.org/proteomics).
d
Calculated with the Clustal Omega program (available at http://www.uniprot.org/align/).

27
28 A. Mati et al. / International Dairy Journal 73 (2017) 25e37

concentration of aS2-CN is estimated to approximately 1.9 g L1 & Kelly, 2012). The lack of b-lactoglobulin, one of the major aller-
(Table 1). genic whey proteins in cows' milk, can confer to camel milk a po-
The b-CN sequence alignments performed with the Clustal tential possibility to use it, with some modifications, in infant
Omega program (available at http://www.uniprot.org/align/) reveal formula. Besides, camel milk whey contains other components
that the camel b-CN (GenBank ID: CDO50354) displays 65.7% and such as peptidoglycan recognition protein-1 (PGRP-1; Kappeler,
66.1% amino acid identity with the bovine b-CNs A1 (GenBank ID: Heuberger, Farah, & Puhan, 2004; Sharma et al., 2011), whey
AAA30431) and A2 (Swiss-Prot ID: P02666) respectively, but only acidic protein (WAP; Beg, von Bahr-Lindstro € m, Zaidi, & Jo
€ rnvall,
60.2% identity with the human b-CN (GenBank ID: AAC82978). 1984) and camel whey basic protein (CWBP; Ochirkhuyag et al.,
Similarly to human milk, camel milk contains a high percentage of 1998).
b-CN that could reflect its higher digestibility rate than bovine milk: The beneficial properties of camel milk, among them its anti-
b-CN is more sensitive to pepsin hydrolysis than aS1-CN (El-Agamy microbial activity, can be attributed to the high content of protec-
et al., 2009). Moreover, camel milk results in a lower incidence of tive proteins: Lf, IgGs, lactoperoxidase, lysozyme, PGRP-1, lacto-
allergy, as no immunological cross-reactivity was observed be- phorin, and other enzymes (El-Agamy, Ruppanner, Ismail,
tween camel and cows' milk proteins when sera from children Champagne, & Assaf, 1992; Konuspayeva et al., 2005). These anti-
allergic to cows' milk were tested for the specificity of their IgEs to microbial constituents (except camel lactoperoxidase for which
camel milk proteins (El-Agamy et al., 2009). Regarding phosphor- no data are available) are significantly present in higher concen-
ylation degree, Kappeler et al. (1998) reported that camel aS1-, aS2-, tration in camel milk than in cows' milk and they are more ther-
and b-CNs are multiphosphorylated at serine residues (6, 9, and 3 mostable (El-Agamy et al., 2009). In addition to the anti-microbial
SerP, respectively; Table 1), but to a lesser extent than the bovine activity of camel milk, colostrum has been demonstrated to also
caseins (8, 10, and 5 SerP, respectively). Clustered phosphoseryl have these activities (Benkerroum, Makkaoui, Bennani, & Kamal,
residues (SSSEE, where S is a phosphoseryl residue) are located in 2004).
the N-terminal region of aS1-, aS2- and b-CNs, which bind inorganic
calcium phosphate. The C-terminal region of k-CN is hydrophilic,
monophosphorylated at Ser-141, and poly-O-glycosylated on five 2.2.1. a-Lactalbumin
threonine residues each bound to an N-acetylgalactosamine res- In bovine milk, a-La is the second major whey protein with an
idue (Thr-105, 109, 149, 152, and 153; Kappeler et al., 1998). The average concentration of 1.2e1.5 g L1 but it is the major whey
glycan structures of the camel k-CN are not determined to date. protein in camel milk with a concentration of approximately
Chymosin (calf rennet is composed of 80% chymosin and 20% 2e7 g L1 (El-Hatmi, Girardet, Gaillard, Yahyaoui, & Attia, 2007;
pepsin) hydrolyses bovine milk k-CN at the Phe105eMet106 bond, Kappeler, 1998; Omar et al., 2016). a-La is a calcium metal-
whereas its site of cleavage in the camel species is Phe97eIle98 loprotein, produced in the mammary gland, which participates in
(Kappeler et al., 1998). Moreover, the chymosin sensitive peptide lactose synthesis and facilitates milk production and secretion. The
bond in camel k-CN is more readily hydrolysed with camel chy- protein modulates the carbohydrate binding properties of gal-
mosin than with bovine chymosin (Kappeler et al., 2006; Møller, actosyltransferase in the gland by decreasing the affinity for
Rattray, Sørensen, & Ardo € , 2012) because of a greater flexibility of glucose and N-acetylglucosamine. The a-La protein binds divalent
the camel enzyme structure (Jensen et al., 2013). In comparison cations such as Ca2þ and Zn2þ, and may facilitate in the absorption
with cows', goats', and ewes' milks, camel milk is the least of essential minerals (Permyakov & Berliner, 2000).
favourable for cheese production (Bornaz, Sahli, Attalah, & Attia, Camel a-La is composed of 123 amino acids residues forming a
2009). The origin of rennet (calf or camel), the low k-CN content, globular structure stabilised by four disulphide bridges and the
but also low whole casein concentration (22.8 g L1 versus oxidised form has an average molecular mass of 14,422.18 Da (Si
29.5 g L1 bovine milk), low total calcium concentration (1.10 g L1 Ahmed Zennia et al., 2015). Large differences are found in the
versus 1.25 g L1 for cow's milk), and a large mean diameter of amino acid sequence of camel a-La compared with other species,
casein micelles (380 nm versus 150 nm for bovine casein micelles) including bovine and goat. There is no evidence for glycosylation of
are the principal factors explaining the difficulty of processing camel a-La (Si Ahmed Zennia et al., 2015). Bovine a-La has two or
camel milk into cheese (Bornaz et al., 2009). Different methods possibly three genetic variants (Brew, 2013), while human a-La has
were proposed to improve cheese making, such as addition of two genetic variants (Chowanadisaia et al., 2005). However, for the
calcium chloride and rennet to camel milk (El-Zubeir & Jabreel, camel species, the observation of two isoforms of camel a-La having
2008), mixing camel and cows' milks (Mehaia, 1993), or substitu- isoelectric points of 5.1 and 5.3 (Beg, von Bahr-Lindstro€ m, Zaidi, &
tion of calf rennet by recombinant camel chymosin with high € rnvall, 1985; Conti, Godovac-Zimmerman, Napolitano, & Lib-
Jo
clotting activity for camel milk (Kappeler et al., 2006; Konuspayeva, eratori, 1985; Levieux, Levieux, El-Hatmi, & Rigaudie re, 2005;
Camier, Gaucheron, & Faye, 2014; Kumar, Grover, Sharma, & Batish, Ochirkhuyag et al., 1998) does not correspond to different genetic
2010). The latter is the most promising methodology, as camel re- variants. Indeed, Si Ahmed Zennia et al. (2015) have shown that the
combinant chymosin is used effectively for the production of a-La is partly deamidated in camel milk according to spontaneous
cheese from camel milk (Konuspayeva et al., 2014). nonenzymatic process, that explains the heterogeneity of the camel
a-La. Nonenzymatic deamidation can readily occur under physio-
2.2. Whey proteins logical conditions, i.e., at neutral and near-neutral pH and 37  C, at
Asn45 and Asn16 leading to formation of aspartate (Asp) and, pref-
The dromedary milk whey proteins constitute 20e25% of total erentially, isoaspartate (IsoAsp) residues. According to Aswad,
proteins (Ereifej et al., 2011) and are mainly composed of a-lactal- Paranandi, and Schurter (2000), there is a possible connection be-
bumin (a-La), lactophorin (also called glycosylation-dependent cell tween isoAsp residue formation in pharmaceutical proteins and
adhesion molecule-1 or GlyCAM-1; Groenen, Dijkhof, & Van der autoimmune disease. For Si Ahmed Zennia et al. (2015), it is
Poel, 1995), IgGs, lactoferrin (Lf), and serum albumin (El-Hatmi possible that formation and accumulation of unusual isoAsp in the
et al., 2006; Merin et al., 2001; Ochirkhuyag, Chobert, gut after ingestion of camel milk may cause IgE-mediated allergy to
Dalgalarrondo, Choiset, & Haertle , 1998). camel milk. Indeed, allergy phenomenons attributed to the whey
Both camel and human milks have high contents of a-La and Lf major proteins (i.e., b-lactoglobulin and a-La) have been already
and are devoid of b-lactoglobulin (Hinz, O'Connor, Huppertz, Ross, observed in the case of ingestion of mare's milk (Gall, Kalveram,
A. Mati et al. / International Dairy Journal 73 (2017) 25e37 29

Sick, & Sterry, 1996) in which a-La is readily subject to nonenzy- concentration of approximately 1740 mg L1 camel milk was found
matic deamidation (Girardet et al., 2004). by capillary electrophoresis, a method displaying an excellent res-
olution better than classical polyacrylamide gel electrophoresis
2.2.2. Serum albumin (Omar et al., 2016). In healthy milk, the Lf concentration is signifi-
Serum albumin is a major protein found in blood serum, and cantly correlated to the score of somatic cell counts (SCC) and the
occurs in all body tissues and secretions. It has a principal role in age of lactating camel and this explains the wide range of con-
the transport, metabolism and distribution of ligands (Carter & Ho, centration of Lf found from an animal to another; on the other
1994). Serum albumin represents approximately 8% of camel and hand, the stage of lactation has no effect on the Lf concentration
bovine whey proteins and the camel protein displays an apparent (Al-Majali et al., 2007). Lf is present in camel colostrum at very high
mass of 69.6 kDa by polyacrylamide gel electrophoresis analysis, concentration of 5.1 g L1, a critical concentration needed to protect
compared with 66.2 kDa for the bovine protein (El-Agamy, the neonate (Abd El-Gawad, El-Sayed, Mahfouz, & Abd El-Salam,
Ruppanner, Ismail, Champagne, & Assaf, 1996; Zhang et al., 2005). 1996).
Its concentration in camel milk was recently determined by capil- Camel Lf was found to display the characteristic functions of iron
lary electrophoresis and was approximately 0.46 g L1 (Omar et al., binding and release of Lf (inhibition of lipid peroxidation) as well as
2016). The predicted amino acid sequence of the camel serum al- of iron transport of transferrin (regulation of the hepatic iron),
bumin (NCBI reference sequence: XP_010981066) is highly similar simultaneously (Khan et al., 2001). Indeed, the N-lobe of camel Lf
to the sequence of the bovine serum albumin (Swiss-Prot ID: loses iron at a low pH (2.0e4.0) as in other Lfs. On the other hand,
P02769), as the two proteins display 80.9% amino acid identity the C-lobe of camel Lf loses iron at higher pH (6.0e7.0) like trans-
(calculated with the Clustal Omega program). ferrins, suggesting its functional similarity to that of transferrins
(Khan et al., 2001). Camel Lf has potent anti-bacterial activity and
2.2.3. Whey acidic protein potential immunomodulatory effects suggested from in vitro
WAP was first described by Beg et al. (1984). Camel milk con- lymphocyte proliferation studies (Ismael, Abd El Hafez, Mahmoud,
tains an average concentration of 157 mg L1 (Kappeler, 1998). This Elaraby, & Hassan, 2013).
protein of apparent molecular mass of 14 kDa is rich in cysteine (or A possible mechanism of Lf against micro-organisms that
half-cystine) residues (16 residues), suggesting a tight conforma- require iron is the ability of Lf to chelate this metal, thereby
tion of the molecule due to disulphide bridge formation (Beg, von depriving the micro-organisms of the source of this nutrient.
Bahr-Lindstro€ m, Zaidi, & Jo
€ rnvall, 1986). It has some homology in Another mechanism is the direct interaction of Lf with the path-
its N-terminal region with the phosphorylated region of the aS1- ogen. Positively charged amino acids in Lf can interact with anionic
and b-CNs (Beg et al., 1984). The WAP exhibits distribution pattern compounds on certain bacterial, viral, fungal and parasite surfaces,
of half-cystine residues similar to that found in neurophysins causing cell lysis. The subsequent release of lipopolysaccharides
known to have a carrier function for neurohypophyseal hormones, (LPS) leads to altered permeability and a higher sensitivity to
but the significance of this similarity is still not understood. Ac- lysozyme and other anti-microbial agents (for recent review, see
cording to Beg et al. (1986), the milk WAP may have some carrier Kanwar et al., 2015). The anti-microbial properties of Lf are also
function, possibly in relation to a polypeptide binding. attributed to some of its peptides such as lactoferricin (fragment
17e42) and lactoferranpin (fragment 265e284) that have shown to
2.2.4. Camel whey basic protein possess anti-bacterial, anti-fungal, and anti-parasitic activities
CWBP (20 kDa) has no homologuous counterpart in other spe- stronger than the entire Lf (Bruni et al., 2016). Camel Lf exerts the
cies and displays high isolectric point of 9.3 (Ochirkhuyag et al., highest anti-bacterial activity against Escherichia coli compared
1998). Camel whey contains approximately 1.7 g L1 CWBP (El- with alpaga's (Vicugna pacos), goats', humans', and ewes' Lfs
Hatmi et al., 2006). However, no further information is available (Conesa et al., 2008) and its anti-bacterial activity spectrum is
about this protein to our knowledge. similar to that of the bovine Lf (El-Agamy et al., 1992). However,
camel Lf displays very low free radical scavenging activity and ferric
2.2.5. Lactoferrin reducing anti-oxidant power (El-Hatmi, Jrad, Khorchani, Dary, &
Lf belongs to the transferrin family and plays an important and Girardet, 2014; Habib, Ibrahim, Schneider-Stock, & Hassan, 2013)
multifunctional role in innate and specific host defense against but it is able to inhibit DNA damage and proliferation of colon
infection by micro-organisms. Lf is an important regulator of the cancer cells in vitro (Habib et al., 2013). In addition, camel Lf is able
levels of free iron in the body fluids of mammals. Its ability to bind to inhibit hepatitis C virus entry into human leukocytes in culture
Fe3þ with high affinity (KD z 1020 mol L1) and to retain it to low with more efficiency than human or bovine Lf (Redwan & Tabll,
pH gives the protein bacteriostatic and anti-oxidant properties 2007).
(Baker & Baker, 2004; Wakabayashi, Yamauchi, & Takase, 2006).
Iron-saturated Lf from milk affects intestinal iron absorption in 2.2.6. Lysozyme
infants and is a source of iron. Colostrum and milk Lf may prevent Lysozyme is a bacteriolytic enzyme that cleaves the b-1,4-
microbial growth in the gut and help the suckling young, which is glycosidic bonds of the murein cell wall resulting in lysis. Lyso-
easily infected, to survive the first weeks, until its own immune zyme in milk protects infants from gastro-intestinal invasion by
system becomes developed (Kappeler, Ackermann, Farah, & Puhan, pathogenic bacteria. Milk of healthy camels contains a concentra-
1999b). tion of lysozyme higher than that of cows' milk (0.07 mg L1 bovine
Camel Lf has a molecular mass of 75,250 Da and contains 689 milk; El-Agamy et al., 1996), ranging from 0.15 mg L1 (El-Agamy
amino acid residues. It consists of a single polypeptide chain folded et al., 1996) to 5 mg L1 (Duhaiman, 1988). According to El-
into two homologous N and C-lobes with one ferric iron binding Agamy et al. (1996), the camel lysozyme content varies greatly as
site per lobe (Kappeler et al., 1999b; Konuspayeva et al., 2005). The a function of the lactation stage. With a higher lysis activity than
camel Lf shares 74.9% amino acid sequence identity with bovine Lf the bovine counterpart, the camel lysozyme shows lytic effects on
according to Kappeler et al. (1999b). Comparative surveys of Lf Gram-positive bacteria, such as Micrococcus lysodeikticus (El-
concentration in different milks shows that the content of Lf in Agamy et al., 1996) and Gram-negative bacteria such as E. coli
camel milk (20e2100 mg L1) is 30e100 times higher than in milk (Duhaiman, 1988). The differences in composition and structure
of other species (Al-Majali, Ismail, Al-Hami, & Nour, 2007). A high Lf between the bovine and camel lysozymes may explain the
30 A. Mati et al. / International Dairy Journal 73 (2017) 25e37

difference in activity according to El-Agamy et al. (1992, 1996). The Petersen, 1993), ewe, goat (Lister et al., 1998; Mati, Girardet,
sequence alignment performed with the Clustal Omega program Xenakis, & Linden, 1991; Sørensen, Rasmussen, Møller, &
reveals only 73% amino acid identity between the predicted Petersen, 1997) and llama (Cantisani, Napolitano, Giuffrida, &
sequence of camel lysozyme C (NCBI reference sequence: Conti, 1990). In camel milk, lactophorin, which belongs to the
XP_010984684) and the bovine lysozyme C (Swiss-Prot ID: GlyCAM-1 family (Groenen et al., 1995), was first described by Beg,
P04421). von Bahr-Lindstrom, Zaidi, and Jornvall (1987). Lactophorin is the
second most abundant protein in camel whey after a-La, with a
2.2.7. Lactoperoxidase concentration greater than 900 mg L1 (Kappeler et al., 1999a). In
Lactoperoxidase is a glycoprotein that occurs naturally in contrast to bovine GlyCAM-1, for which mRNA is not subject to
colostrum, milk, and many other human and animal secretions alternative splicing, 75% of the whole camel GlyCAM-1 is expressed
(Conner, Salathe, & Forteza, 2002; Kussendrager & Van Hooijdonk, as a long variant A with 137 residues and a molecular mass of
2000). The molecular mass of non-glycosylated mature camel lac- 15.7 kDa, and 25% as a splicing variant (variant B) of 13.8 kDa for
toperoxidase is 69.7 kDa (69.5 kDa for bovine lactoperoxidase). which 15 amino acid residues are missing in the N-terminal region
Sequence alignments performed with the Clustal Omega program (Girardet et al., 2000; Kappeler et al., 1999a).
show that camel lactoperoxidase (NCBI reference sequence: Several functions have been attributed to bovine lactophorin
NP_001290481) shares 83.8% amino acid sequence identity with (Girardet & Linden, 1996), including emulsification (Shimizu,
bovine lactoperoxidase (Swiss-Prot ID: P80025) and 84.5% identity Yamauchi, & Saito, 1989), in vitro inhibition of lipase activity
with human lactoperoxidase (P22079). This protein contributes to (Girardet, Linden, Loye, Courthaudon, & Lorient, 1993), mitogenesis
the non-immune host defense system, exerting bacteriostatic and activity measured with MARK 3 hybridoma culture (Mati et al.,
bactericidal activity, mainly on Gram-negative bacteria (Touch, 1993), bifidobacterial growth-promoting activity (Etienne,
Hayakawa, Yamada, & Kaneko, 2004). For anti-microbial function, Girardet, & Linden, 1994). In addition, the bovine lactophorin pos-
lactoperoxidase needs the presence of hydrogen peroxide and sesses five phosphoserine residues (against four for the camel
thiocyanate, which have been called together ‘lactoperoxidase lactophorin) distributed throughout an area of 17 residues (region
system'. At present, this system is considered to be an important 29e46) and able to bind calcium ion (Bernos, Girardet, Humbert, &
part of the natural host defense system in mammals (Boots & Floris, Linden, 1997). It is thought that lactophorin may control the solu-
2006). The anti-bacterial action of the lactoperoxidase system is bility of calcium phosphate that is not bound to the casein micelle
due to the effect of reaction products of thiocyanate oxidation, (Sørensen & Petersen, 1993). Lactophorin may prevent mastitis
OSCN and HOSCN, which are able to oxidise free thiolate groups of type infections from occurring in lactating animals or could play a
various proteins that are important for the viability of pathogens, role in inhibiting the replication of pathogens in the respiratory and
thus inactivating crucial enzyme and protein systems (Sermon gastro-intestinal tracts of the suckling young (Girardet & Linden,
et al., 2005). Camel lactoperoxidase shows significant anti- 1996).
bacterial effects against Pseudomonas aeruginosa (Mehrin et al.,
2011), and is bacteriostatic against the Gram-positive bacteria 2.2.10. IgGs
Lactococcus lactis subsp. cremoris and Staphylococcus aureus, and Camel IgGs are not limited to one major subclass IgGs1, but
bactericidal against the Gram-negative bacteria E. coli and Salmo- include two other subclasses IgGs2 and IgGs3, which are devoided
nella typhimurium (El-Agamy et al., 1992). of light chains and have heavy chains of 46 and 43 kDa, respectively
(Azwai, Carter, & Woldehiwet, 1996; Hamers-Casterman et al.,
2.2.8. Peptidoglycan recognition protein-1 1993). The camel heavy-chain antibodies interfere with several
PGRP-1is a soluble, conserved pattern-recognition protein of biological processes and may make good candidates for human
vertebrates and invertebrates that binds to bacterial peptidoglycan therapy, as they act as true competitive inhibitors by penetrating
(Liu, Gelius, Liu, Steiner, & Dziarski, 2000). The protein was first into the active sites of some enzymes such as human immunode-
described in pigs (Fornhem, Peterson, & Alving, 1996) and later ficiency virus type 1 (HIV-1) reverse transcriptase, protease, and
isolated from camel milk (Kappeler et al., 2004). The camel PGRP-1 integrase that are crucial to the HIV-1 life cycle (Daley-Bauer et al.,
sequence has 172 amino acid residues, a molecular mass of 19.1 kDa 2010; Holt, Herring, Jespers, Woolven, & Tomlinson, 2003;
and displays 74.2 and 72.4% amino acid identities with bovine Lauwereys et al., 1998; Martin, Volpari, Steinkuhler, & Dimas, 1997).
PRGP-1 (Swiss-Prot ID: Q8SPP7) and human PGRP (GenBank ID:
AAC31822), respectively (performed with the Clustal Omega pro- 2.3. Milk fat globule membrane proteins
gram). Camel PGRP-1 forms a tetramer with two functional sites: a
peptidoglycan binding site and a second site involved in the bind- Recently, C. dromedarius and Lama glama milk fat globule
ing of non-peptidoglycan molecules (Sharma et al., 2011). Not membrane (MFGM) proteins have been identified that are involved
found in bovine milk, PGRP-1 is present in camel milk with a mean in many biological functions (Saadaoui et al., 2014, 2013; Yang et al.,
concentration of 120 mg L1 (Kappeler et al., 2004). PGRP-1 can 2015). Among 322 functional groups identified, the MFGM proteins
bind to peptidoglycan structures in the cell wall and inhibit the are predominately involved in protein transport, lipid biosynthesis,
growth of pathogens. This protein is multifunctional because it can and actin cytoskeleton organisation (Saadaoui et al., 2013; Yang
bind to lipopolysaccharide from Gram-negative bacteria and to et al., 2015). A total of 520 proteins have been identified in the
lipoteichoic acid from Gram-positive bacteria and, consequently, MFGM fractions of cow, yak, buffalo, goat, camel, horse, and human
inhibit expression of inducible pro-inflammatory cytokines (Yang et al., 2015); fatty acid synthase, xanthine oxidase, butyr-
(Sharma et al., 2011). ophilin, and lactadherin are the major proteins of the MFGM. Yang
et al. (2015) revealed by an isobaric tag for relative and absolute
2.2.9. Lactophorin (GlyCAM-1) quantification (iTRAQ) proteomic approach, differences in relative
Formerly, GlyCAM-1, identified in bovine milk, was called quantities of the MFGM proteins between the ruminant group
component-3 of proteose peptone (PP3). It is a minor phospho(- (cow, yak, buffalo, and goat) and the non-ruminant group (camel,
glyco)protein characterised in the milk of various species, for horse, and human). For instance, lactadherin was the predominant
instance, camel (Girardet, Saulnier, Gaillard, Ramet, & Humbert, MFGM protein in camel milk, whereas butyrophilin and GlyCAM-1
2000; Kappeler, Farah, & Puhan, 1999a), cow (Sørensen & were rather the most abundant proteins in MFGM of cows' and
A. Mati et al. / International Dairy Journal 73 (2017) 25e37 31

goats' milk, respectively (Yang et al., 2015). Lactadherin, also known (ABTS) or 2-diphenyl-1-picrylhydrazyl radical (DPPH) in the pres-
as MFG-EGF factor 8 (MFGE8), is a glycoprotein which function is ence of peptide(s), determination of ferric reducing anti-oxidant
not completely clear; however, it is linked to cell damage and power (FRAP) of peptide(s), measurement of ACE activity towards
apoptosis (Hettinga et al., 2011). Lactadherin plays an important hippuryl-L-histidyl-L-leucine (HHL) or N-[3-(2-furyl)acryloyl]-L-
role in the maintenance of intestinal epithelial homeostasis and the phenylalanyl-glycyl-glycine (FAGPP) in the presence of peptide(s).
promotion of mucosal healing. It may be an important milk protein, In general, the in vitro experiments show that the peptide mixtures
therefore, for protecting the intestinal tract of the newborn enzymatically generated either from caseins or whey proteins are
(Hettinga et al., 2011). more efficient anti-oxidant and ACE-inhibitory components than
the proteins. This is particularly observed when the potential
3. Bioactive peptides bioactive peptides are produced by simulated gastro-intestinal
digestion (Jrad et al., 2014a, 2014b; Tagliazucchi, Shamsia, &
3.1. Bioactive peptide fractions Conte, 2016). In the same way, the anti-bacterial activity is
enhanced by enzyme treatment (e.g., papain) and the resulting
During the last decade, increasing attention is being focused on peptide hydrolysate exhibits significantly higher anti-bacterial ac-
the identification of the bioactive peptides derived from cows' milk tivity than the native camel proteins (Abdel-Hamid, Goda, De
proteins; this is discussed in numerous review articles (e.g., Gobba, Jenssen, & Osman, 2016).
Brandelli, Daroit, & Corre^a, 2015). Limited studies have been carried Anti-oxidant activity determined with the ABTS, DPPH and FRAP
out on bioactive peptides from milks of other lactating animals, assays increases with the time of enzyme hydrolysis, i.e., with the
such as buffalo, camel, goat, mare, sheep and yak, for instance (Abd degree of hydrolysis (Kumar, Kumar Chatli, Singh, Mehta, & Kumar,
El-Salam & El-Shibiny, 2013). Potential bioactive peptides are 2016a). The most efficient peptides in term of free radical scav-
encrypted in proteins as inactive sequences and may be released by enging, and also of ACE inhibition, display molecular sizes less than
proteolysis. Regarding camel milk, investigations mainly focus on 3 kDa (El-Hatmi et al., 2016; Rahimi et al., 2016; Salami et al., 2011;
caseins as the source of potential bioactive peptides, and to a lesser Tagliazucchi et al., 2016), but Moslehishad et al. (2013a) found that
extent whey proteins. Peptide fractions are prepared from camel the peptide fraction with 5e10 kDa prepared from camel milk
milk proteins according to three ways: fermentation of milk with fermented with Lactobacillus rhamnosus had the highest free
various proteolytic bacterial strains (Table 2), enzyme hydrolysis of radical scavenging activity. However, Kumar, Kumar Chatli, Singh,
milk proteins either with purified specific proteases or with a Mehta, and Kumar (2016b) showed that whole camel casein hy-
mixture of pepsin and pancreatin simulating the gastro-intestinal drolysate obtained by action of proteases, such as chymotrypsin,
digestion (Table 3). alcalase, or papain, exhibited better anti-oxidant and anti-microbial
Until now, the data available on the bioactive peptides from activities than its ultrafiltred fractions with 1e5 and 5e10 kDa.
camel milk mainly focus on the anti-oxidant, angiotensin-con- According to these authors, this may be due either to synergistic
verting enzyme (ACE) inhibition, and anti-bacterial activities effects of peptides of different molecular masses or to the higher
against Gram-positive and Gram-negative food-borne pathogenic concentration of peptides in the whole hydrolysate as compared
strains. However, very few peptides with a potential or effective with fractions. It is noteworthy that the good anti-oxidant prop-
bioactivity have been identified to date (Table 4). erties of the whole hydrolysate may also reflect the anti-oxidant
In vitro experiments rather than in vivo investigations are car- power of N-termini that are more abundant than in the ultra-
ried out almost always to unveil camel milk peptides with potential filtred fractions.
biological activity. The usual in vitro tests are based on assay of 2,20 - On the other hand, the peptide hydrolysates from camel milk
azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) radical cation appear to be more efficient free radical scavengers (ABTS and DPPH

Table 2
In vitro biological activities of peptide fractions obtained from camel milk fermented by various bacteria.a

In vitro biological activity In vitro test Fermentative bacteria Origin of bacteria Substrate used Products tested References
for fermentation

ACE inhibition HHL Lactobacillus Traditionally fermented Reconstituted Whey fractions Shuangquan
helveticus 130B4 camel milk (Inner skim milk (1 peptide identified) et al. (2008)
Mongolia, China) (10%, w/w)
Free radical scavenging ABTS Lactobacillus rhamnosus Persian Type Culture Whole milk Peptide fractions Moslehishad
PTCC1637 Collection (Teheran, Iran) et al. (2013a)
Free radical scavenging DPPH Pediococcus pentosaceus Native laboratory isolate Whole milk Water-methanol Balakrishnan and
from cheese (India) soluble fraction Agrawal (2014)
Free radical scavenging ABTS Streptococcus American Type Culture Skim milk Peptide fractions El-Hatmi
thermophilus Collection (Manassas, (347 peptides et al. (2016)
LMD-9 ATCC BAA-491 VA, USA) identified)
Free radical scavenging ABTS, DPPH Lactobacillus kefiri Chal (traditionally Whole milk Whey fractions Soleymanzadeh
Lb. paraplantarum fermented camel milk; et al. (2016)
Lb. paracasei Golestan Province, Iran)
Lb. plantarum
Lb. gasseri
Enterococcus faecium
Weissella cibara
Leuconostoc lactis
Bacterial growth E. coli St. thermophilus American Type Culture Whole milk Whey fraction Lafta, Jarallah, and
inhibition Ps. Aeruginosa Lb. delbrukii subsp. Collection (Manassas, Darwash (2014)
S. aureus bulgaricus VA, USA)
a
Abbreviations are: ABTS, 2,20 -azino-bis(3-ethylbenzothiazoline-6-sulphonic acid); ACE, angiotensin-converting enzyme; DPPH, 2-diphenyl-1-picrylhydrazyl; HHL, hip-
puryl-L-histidyl-L-leucine.
32 A. Mati et al. / International Dairy Journal 73 (2017) 25e37

Table 3
In vitro and in vivo biological activities of peptide fractions obtained by enzyme treatment of camel milk or colostrum proteins.a

Enzyme Protein source of peptides Biological activity Test References

Pepsin þ pancreatin Colostrum (181 peptides Free radical scavenging ABTS Jrad et al. (2014a)
identified) and milk ACE inhibition HHL
proteins Bacterial growth inhibition E. coli & L. innocua
Pepsin þ pancreatin Whole casein Free radical scavenging ABTS Jrad et al. (2014b)
Pepsin þ pancreatin Whole casein Bacterial growth inhibition E coli, Ps. aeruginosa, Jrad et al. (2015)
L. innocua, B. cereus, & S. aureus
Gastro-intestinal juices Milk proteins (at least 71 ACE inhibition FAPGG Tagliazucchi et al. (2016)
supplemented with aminoacids & peptides
papain & pancreatin identified)
Trypsin Whole casein Anti-oxidant DPPH & lipid peroxidation inhibition Al-Saleh, Metwalli, Ismail,
and Alhaj (2014)
Trypsin Whey proteins Speed-up of wound healing SOD & CAT activity; GSH & MDA levels Ebaid et al. (2015)
in diabetic rats: TNF-a & NF-kB levels;
Anti-oxidant TNF-a & MIF mRNA expression
Anti-inflammatory &
immunostimulant
Trypsin Whole casein Vasorelaxant & In vivo experimental design Kanso et al. (2016)
anti-hypertensive with spontaneously hypertensive rats
Trypsin Whey proteins Free radical scavenging ABTS Salami et al. (2010)
Chymotrypsin Bacterial growth inhibition E. coli
Thermolysin
Proteinase K
Trypsin Whole casein & Free radical scavenging ABTS Salami et al. (2011)
Chymotrypsin b-CN ACE inhibition FAGPP
Pepsin
Pepsin þ trypsin/
chymotrysin
Proteinase K Whole casein Free radical scavenging ABTS Rahimi et al. (2016)
ACE inhibition FAGPP
Chymotrypsin Whole casein Anti-oxidant ABTS,DPPH, & FRAP Kumar et al. (2016a)
Alcalase
Papain
Chymotrypsin Whole casein Anti-oxidant ABTS, DPPH, & FRAP Kumar et al. (2016b)
Alcalase Bacterial growth inhibition E. coli, B. cereus, S. aureus, & L. monocytogenes
Papain
Papain Whey proteins Bacterial growth inhibition E. coli, S. typhimurium, B. cereus, & S. aureus Abdel-Hamid et al. (2016)
a 0
All the tests are in vitro except for the study of Kanso et al. (2016) that was performed in vivo. Abbreviations are: ABTS, 2,2 -azino-bis(3-ethylbenzothiazoline-6-sulphonic
acid); ACE, angiotensin-converting enzyme; CAT, catalase; DPPH, 2-diphenyl-1-picrylhydrazyl; FAPGG, N-[3-(2-furyl)acryloyl]-L-phenylalanyl-glycyl-glycine; FRAP, ferric
reducing anti-oxidant power; GSH, glutathione; HHL, hippuryl-L-histidyl-L-leucine; MDA, malondialdehyde; MIF, macrophage migration inhibitory factor; NF-kB, nuclear
factor kB; SOD, superoxide dismutase; TNF-a, tumour necrosis factor a.

Table 4
Identified camel milk peptides with potential biological activities.a

Potential bioactive peptide Sequence or mass In vitro biological activity References

k-CN (99e107) AIPPKKNQD ACE inhibition (HHL assay): IC50 ¼ 19.9 mM Shuangquan et al. (2008)
Peptides purified after papain 414.05 and 452.06 Da Anti-bacterial activity against E. coli, Abdel-Hamid et al. (2016)
treatment of whey proteins S. typhimurium, S. aureus, & B. cereus
b-CN (170e184) KVLPVPQQMVPYPRQ Anti-oxidant (ABTS, DPPH, hydroxyl, Homayouni-Tabrizi et al. (2016)
aS1-CN (138e149) NEDNHPGALGEPV & superoxide assays, lipid peroxidation
inhibition, & SOD mRNA expression)
b-CN (205e207) LHP ACE inhibition (FAPGG assay): Tagliazucchi et al. (2016)
b-CN (50e51)/aS2-CN (145e146) IY IC50 ¼ 1.6 mM
aS1-CN (113e114)/aS2-CN (28e29)/k-CN AI IC50 ¼ 2.1 mM
(99e100)/k-CN (113e114) IC50 ¼ 3.4 mM
k-CN (99e102) IPP IC50 ¼ 5.0 mM
b-CN (60e61)/aS2-CN (161e162)/PGRP-1 (82e83) VY IC50 ¼ 7.1 mM
aS1-CN (134e135)/GlyCAM-1(9e10)/PGRP-1(160e161) LY IC50 ¼ 18.0 mM
b-CN (51e52)/aS2-CN (39e40)/aS2-CN (151e152) TF IC50 ¼ 18.0 mM
a
Only the most efficient peptides with IC50 less than 100 mmol L1 are listed. Abbreviations are: ABTS, 2,20 -azino-bis(3-ethylbenzothiazoline-6-sulphonic acid); ACE,
angiotensin-converting enzyme; DPPH, 2-diphenyl-1-picrylhydrazyl; FAPGG, N-[3-(2-furyl)acryloyl]-L-phenylalanyl-glycyl-glycine; HHL, hippuryl-L-histidyl-L-leucine; IC50:
concentration required to inhibit 50% of the enzymatic activity; SOD, superoxide dismutase.

assays) and bacterial growth inhibitors than bovine hydrolysates Camel whey proteins are more susceptible to pepsin and com-
(Moslehishad et al., 2013a; Salami et al., 2010; Soleymanzadeh, bined trypsin/chymotrypsin digestion in comparison with that of
Mirdamadi, & Kianirad, 2016). However, Balakrishnan and bovine whey proteins (Abderrahmane, Mezmaze, Chekroun, Saidi,
Agrawal (2014) reported that peptides from goats' milk fer- & Kheroua, 2015), whereas Salami et al. (2008) found that trypsin
mented with Pediococcus pentosaceus have greater anti-oxidant and chymotrypsin hydrolysis of camel whey proteins is lower than
activity (DPPH assay) than the camel peptides. that of bovine whey proteins. In addition, they have observed that
A. Mati et al. / International Dairy Journal 73 (2017) 25e37 33

caseins are more rapidly hydrolysed than whey proteins by to have in vivo effective biological properties was identified in
chymotrypsin for both bovine and camel species. camel milk proteins. However, the first camel peptide that exhibits
Differences in amino acid sequences between milk homologous a biological activity in vitro was identified by Shuangquan, Tsuda,
proteins of the mammal species studied produce different biolog- and Taku (2008), and corresponded to a k-CN fragment of nine
ical effects. Indeed, the camel caseins display low amino acid residues, which was moreover stable to digestive enzymes
identity with the bovine caseins (Table 1; Kappeler et al., 1998). (Table 3). This peptide of 9 residues was generated during the
They are more susceptible to proteolysis during milk fermentation fermentation of camel milk with Lactobacillus helveticus and
than their bovine counterparts, probably because more sites are exhibited an ACE-inhibition activity (Table 3). On the other hand,
available for enzymatic hydrolysis. This may explain why the po- two other peptides displaying anti-oxidant capacity have been
tential bioactive peptides generated are different from that ob- recently identified (Homayouni-Tabrizi, Shabestarin, Asoodeh, &
tained from bovine caseins (El-Hatmi et al., 2016). Soltani, 2016). They correspond to camel b-CN and aS1-CN frag-
Mo €ller, Scholz-Ahrens, Roos, and Schrezenmeir (2008) reported ments of 15 and 13 residues, respectively (Table 3).
that, in comparison with simulated gastro-intestinal digestion, the Peptides generated in fermented milk may also be precursors for
proteolytic system of the bacteria strains use different cleavage smaller bioactive peptides released in the intestinal tract by
sites to degradate the bovine milk proteins during fermentation digestive enzymes (El-Hatmi et al., 2016; Mo € ller et al., 2008).
and release therefore different peptides. In the case of camel milk, Numerous potential precursors of bioactive peptides have been
El-Hatmi et al. (2016) observed that peptide fractions prepared identified from camel milk and may be a source of a variety of
after fermentation with Streptococcus thermophilus exhibit a higher predictive bioactive peptides having potential anti-inflammatory,
free radical scavenging activity than peptide fractions obtained by anti-hypertensive, anti-oxidant, mineral binding (for casein-
simulated gastro-intestinal digestion (Jrad et al., 2014a). In good ophosphopeptides containing the SSSEE phosphate cluster),
agreement, Moslehishad et al. (2013a) showed that the free radical immunomodulatory, cytomodulatory, or anti-diabetic properties
scavenging power of peptides generated by the proteolytic system (Ebaid et al., 2015; El-Hatmi et al., 2016; Jrad et al., 2014a; Taglia-
of L. rhamnosus was stronger than that of peptides produced by zucchi et al., 2016). For instance, precursors of casomorphin-like
gastric (pepsin) or pancreatic (trypsin and chymotrypsin) enzymes peptides are generated from camel k-CN during milk fermenta-
(Salami et al., 2011), probably due to the generation of breakdown tion with Str. thermophilus (El-Hatmi et al., 2016). The encrypted
products different in their amino acid composition. These experi- sequences YPSYGIN and YFPIQFVQSR are tightly homologous to
mental results highlight the crucial importance of the fermentation those of the opioid antagonists, casoxins A and C, respectively
for the dairy processing to develop functional foods for health. In (YPSYGLN and YIPIQYVLSR; Chiba, Tani, & Yoshikawa, 1989).
addition, the fermented dairy product must possess high sensory Erhardt et al. (2016) have listed 83 predictive bioactive di- and
quality, as it was highlighted for camel milk fermented with tripeptides according to the BIOPEP database (http://www.uwm.
different species of Lactobacillus (Moslehishad, Mirdamadi, Ehsani, edu.pl/biochemia/index.php/pl/biopep) from in silico digestion of
Ezzatpanah, & Moosavi-Movahedi, 2013b). the camel aS1-CN.
It is therefore necessary to characterise the proteolytic system of In the case of the whey proteins, no bioactive peptides have yet
the lactic acid bacteria used in fermentation process and this is the been identified. The anti-oxidant ability of camel a-La after enzyme
purpose of a number of studies, especially with regard to the hydrolysis has not been investigated to date, although the native
fermentation of bovine milk (e.g., Sadat-Mekmene et al., 2011). protein exhibits a high free radical scavenging power (El-Hatmi
Recently, El-Hatmi et al. (2016) identified the cleavage sites of et al., 2014; Salami et al., 2009). Anti-microbial peptides gener-
camel milk proteins (aS1-CN, aS2-CN, b-CN, k-CN, GlyCAM-1, and ated by the proteolytic system of Str. thermophilus on camel milk
PGRP-1) by the proteolytic system of Str. thermophilus LMD-9 strain GlyCAM-1 and PGRP-1 have been suggested (El-Hatmi et al., 2016).
grown in camel milk. Thus, among the 347 peptides identified, Indeed, the bovine GlyCAM-1 (lactophorin) releases lactophoricin,
some potential bioactive peptides were suggested based on ho- a peptide with anti-microbial properties that correspond to the C-
mology with known bioactive bovine peptides. terminal domain, which is folded into a long amphipathic a-helix
(Campagna, Mathot, Fleury, Girardet, & Gaillard, 2004). The C-ter-
3.2. Identified bioactive peptides minal region of the camel GlyCAM-1 may be also folded into an
amphipathic a-helix involving approximately 35 amino acid resi-
To exert their biological activity in vivo, the peptides have to be dues (Girardet & Linden, 1996). Such amphipatic a-helices confer
resistant toward hydrolysis by peptidases of the brush border and anti-microbial properties to peptides, as they allow them to interact
able to be absorbed through the gastro-intestinal barrier. This is directly with microbial membranes, which they can rapidly per-
particularly the case for the di- and tripeptides that possess their meabilise (Tossi, Sandri, & Giangaspero, 2000). No corresponding
own transport system PepT1 (Ganapathy & Miyauchi, 2005). peptide was found in the camel fermented milk (El-Hatmi et al.,
Recently, Tagliazucchi et al. (2016) identified several ACE-inhibitory 2016), but lactophoricin might be released by pancreatic enzymes
peptides from camel milk proteins degraded by simulated gastro- such as trypsin during the post-prandial phase (i.e., after camel
intestinal digestion; five dipeptides and two tripeptides exhibited milk ingestion) and act in the gut as protective peptide. Indeed,
remarkable activity (Table 4). Pedersen et al. (2012) showed that bovine lactophoricin with anti-
It is noteworthy that the tripeptide IPP is generated by the bacterial properties was produced by trypsin action. PGRP-1 pro-
simulated digestion of camel milk. The bovine lactotripeptide IPP is tein is capable of inactivating pathogens by binding to peptido-
well-known for its anti-hypertensive and atherosclerosis preven- glycan in the bacterial cell wall and may generate peptides with
tion activities (Boelsma & Kloek, 2009; Nakamura et al., 2013). An anti-microbial properties. However, El-Hatmi et al. (2016) found
IPP amount of about 2.56 mg L1 was released from k-CN in the that this protein was less susceptible to the action of the proteolytic
digested camel milk, a quantity suitable to observe a significant system of Str. thermophilus and generated few peptides, all corre-
hypotensive effect in vivo. Indeed, Tagliazucchi et al. (2016) re- sponding to the C-terminal domain forming a tail oriented into the
ported that several clinical studies on hypertensive subjects aqueous phase. However, this tail is not involved in the binding to
showed that the administration of daily doses of IPP in the range of the bacterial toxicants (Sharma et al., 2011).
2e6 mg was associated with a decrease of the blood pressure be- Recently, two anti-bacterial peptides were isolated after papain
tween 1.5 and 10 mm Hg. This is the first time that a peptide known treatment of camel whey proteins. However, only their molecular
34 A. Mati et al. / International Dairy Journal 73 (2017) 25e37

masses were determined but not the precise amino acid sequence signaling e Towards understanding the insulin-like properties of camel milk.
Frontiers in Endocrinology, 7, 4.
(Table 4; Abdel-Hamid et al., 2016).
Agrawal, R. P., Beniwal, R., Sharma, S., Kochar, D. K., Tuteja, F. C., Ghorui, S. K., et al.
Finally, it is noteworthy that raw milk already contains (2005a). Effect of raw camel milk in type 1 diabetic patients: 1 year randomised
numerous indigenous peptides, and the major peptides present in study. Journal of Camel Practice and Research, 12, 27e31.
camel milk have been identified by Alhaider et al. (2013), some of Agrawal, R. P., Budania, S., Sharma, P., Gupta, R., Kochar, D. K., Panwar, R. B., et al.
(2007). Zero prevalence of diabetes in camel milk consuming Raica community
them being possible bioactive candidates. Recently, Abdulrahman of north-west Rajasthan, India. Diabetes Research and Clinical Practice, 76,
et al. (2016) found a peptide in camel milk with molecular mass 290e296.
lower than 10 kDa that demonstrated an activating effect on human Agrawal, R. P., Jain, S., Shah, S., Chopra, A., & Agrawal, V. (2011). Effect of camel milk
on glycemic control and insulin requirement in patients with type 1 diabetes:
insulin receptor (hIR) expressed in human embryonic kidney 293 2-years randomized controlled trial. European Journal of Clinical Nutrition, 65,
(HEK293) cells in culture (human insulin has a mass of 5807 Da). 1048e1052.
This insulin-like peptide may confer to camel milk a substantial Agrawal, R. P., Sahani, M. S., Tuteja, F. C., Ghouri, S. K., Sena, D. S., Gupta, R., et al.
(2005b). Hypoglycemic activity of camel milk in chemically pancreatectomized
hypoglycemic activity (Agrawal, Jain, Shah, Chopra, & Agrawal, rats e An experimental study. International Journal of Diabetes in Developing
2011). Countries, 25, 75e79.
Agrawal, R. P., Swami, S. C., Beniwal, R., Kochar, D. K., Sahani, M. S., Tuteja, F. C., et al.
(2003). Effect of camel milk on glycemic control, risk factors and diabetes
4. Conclusions quality of life in type-1 diabetes: A randomised prospective controlled study.
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