Natural Sources and Bioactivities of Polypeptides

14 Pages·2013·0.41 MB·English

International Journal of Modern Biology and Medicine, 2013, 4(3): 176-189
International Journal of Modern Biology and Medicine ISSN: 2165-0136
Journal homepage: www.ModernScientificPress.com/Journals/IJBioMed.aspx Florida, USA
Review
Natural Sources and Bioactivities of Polypeptides
Yu-Jie Zhang 1, Fang Wang 1, Gui-Fang Deng 2, Xiang-Rong Xu 3, Dong-Ping Xu 1, An-Na Li 2,
Sha Li 1, Hua-Bin Li 1,*
1 Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition,
School of Public Health, Sun Yat-Sen University, Guangzhou 510080, China
2 Department of Nutrition, the Affiliated Shenzhen Nanshan Hospital of Guangdong Medical College,
No. 89, Taoyuan Road, Nanshan District, Shenzhen 518052, China
3 CAS Key Laboratory of Marine Biology and Ecology, South China Sea Institute of Oceanology,
Chinese Academy of Sciences, Guangzhou 510301, China
* Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.:
[phone]; Fax: [phone].
Article history: Received 8 October 2013, Received in revised form 11 November 2013, Accepted 13
November 2013, Published 15 November 2013.

Abstract: In recent years, polypeptides have attracted wide attention. They have abundant
natural sources, and can be isolated from plants, nematodes, hydrobionts and mammals.
Polypeptides have many bioactivities, such as regulating blood sugar, immunomodulatory
effects, neuroprotective function, hepatoprotective nature, antioxidant activity, anti-HIV and
antibacterial activity. In this review, we provide an up-to-date coverage of polypeptides with
reference to natural sources and bioactivities.
Keywords: polypeptides; natural source; bioactivity; anticancer; antioxidant.

1. Introduction
In recent years, polypeptides have attracted wide attention. Polypeptides can be readily
extracted from natural sources, such as plants, nematodes, hydrobionts and mammals. Polypeptides
have numerous bioactivities, including regulating blood sugar, immunomodulatory effects,
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Int. J. Modern Biol. Med. 2013, 4(3): 176-189 177

neuroprotective function, hepatoprotective nature, antioxidant activity, anti-HIV and antibacterial
activity (Osaki et al., 1999; Sarkar et al., 2005; Yang et al., 2006; Shen et al, 2008; Ng et al., 2011; Lo
et al., 2013; Zha et al., 2013). Polypeptides would have advantages for drug delivery, tissue
reconstruction, cell seeding and diffusion, and wound care (Banning and Heard, 2002; Yamauchi et al.,
2003; Apel et al., 2008; Gao et al., 2013). Therefore, polypeptides have been widely used in food,
pharmaceutical, cosmetic, and biotechnology industries (Katoh et al., 2004; Tachibana et al., 2005; Xie
et al., 2008; Aluigi et al., 2007; Barba et al., 2008; Lv et al., 2008; Belcarz et al., 2009; Sun et al., 2012;
Lee et al., 2012).
This review provides an up-to-date coverage of polypeptides in regard to natural sources, and
bioactivities, and special attention is paid to the bioactivities.
2. Natural Sources of Polypeptides
Polypeptides can be isolated from plants, nematodes, hydrobionts and mamals. The
well-known natural sources of polypeptides include nematodes, jellfish, horseshoe crab (Tachypleus
tridentatus), Pleuronectes americanus, loach (Misgurnus anguillicaudatus), the Rubiaceae and
Violaceae plant families, the seeds of Luffa cylindrical, Argentinean wine, bovine hair, bovine
neurohypophisis, Achyranthes bidentata, velvet antler from sika deer, Cajanus indicus L., wool and so
on (Osaki et al., 1999; Dong et al., 2002; Froy Oren, 2005; Yang et al., 2006; Zhuang et al., 2010; Ng
et al., 2011; Raquel Apud et al., 2013; Teixeira et al., 2013; Zeng et al., 2013; Zha et al., 2013). In a
word, the natural sources of polypeptides are quite abundant (Table 1).
3. Bioactivities of Polypeptides
3.1. Antioxidant Activity
Recently, several researches have described the antioxidant activity of bioactive polypeptides,
such as jellyfish polypeptides, Pardachirus marmoratus polypeptides and Chlamys farreri
polypeptides (Table 1). Peptides containing hydrophobic amino acids, such as phenylalanine, leucine,
alanine, proline and tryptophan, are believed to have high antioxidant activity. Moreover, acidic
(aspartic acid and glutamic acid) and/or basic amino acids (lysine) play an important role in its ability
to inhibit oxidation as well. Previous research also revealed that peptides containing sulphydryl group
have strong antioxidant activity.
An antioxidant polypeptide was purified and characterized from bovine hair. It was with a
molecular weight of 18.7 KDa in the form of spherical lumps, which was composed of 17 kinds of
amino acids and contained sulphydryl group (Zeng et al., 2013). The polypeptide showed a strong
reducing power and a remarkable antioxidant capability to scavenge free radicals (ABTS, superoxide
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Int. J. Modern Biol. Med. 2013, 4(3): 176-189 178

and hydroxyl radicals). And the polypeptides’ reducing activity increased with increasing
concentration. Moreover, polypeptides also exhibited a significant food protection effect to inhibit the
oxidation of edible oil by controlling the peroxide value. These studies suggested that the antioxidant
polypeptide from bovine hair could be a new potential source for preparing natural antioxidant applied
in oil or oil-rich food. Compared with other natural antioxidant, especially for oil or oil-rich food,
polypeptides have an excellent solubility and a wide range of pH for many food applications.
Polypeptides exhibited effective inhibition against oil oxidation both in peanut oil and lard. Moreover,
the utilization of polypeptides also adds nutritional and functional properties.

Table 1. Resources and bioactivities of polypeptides
Polypeptide Resource Bioactivity Reference
a polypeptide from bovine hair antioxidant Zeng et al., 2013
bovine hair
a polypeptide from Chlamys farreri antioxidant Yang et al., 2006
Chlamys farreri (PCF)
peptides Argentinean wine antioxidant, Raquel Apud et al.,
antihyperglycemic 2013
effects
gelatin polypeptides jellyfish (Rhopilema antioxidant activity Zhuang et al., 2010
esculentum)
antibacterial factors nematodes antibacterial activity Froy Oren, 2005
(ABFs)
tachystatins A, B, and horseshoe crab antibacterial activity Osaki et al., 1999
C (Tachypleus
tridentatus)
a polypeptide from Misgurnus antioxidant, Dong et al., 2002
Misgurnus anguillicaudatus antibacterial activities
anguillicaudatus
(MAPP)
Pa-MAP Pleuronectes antibacterial activity Teixeira et al., 2013
americanus
pardaxin Moses sole fish antibacterial activity Oren et al., 1996
(Pardachirus
marmoratus)
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cyclotides the Rubiaceae, antibacterial, Daly et al., 2004;
Violaceae, and anticancer, anti-HIV Svangard et al., 2004;
Cucurbitaceae plant activities Gerlach et al. 2010
families
polypeptide from velvet antler of Cervus immunomodulation, Zha et al., 2013
velvet antler of sika nippon Temminck anti-HIV activities
deer nVAP32
CI protein Cajanus indicus L. antioxidant, Sarkar et al., 2005
hepatoprotection,
neruoprotective
activities
a polypeptide from Achyranthes bidentata neuroprotection Shen et al., 2008
Achyranthes bidentata
（ABPP）
proline-rich bovine neurohypophisis neuroprotection Gladkevich, 2007
polypeptides
Colostrinin ovine colostrums neuroprotection Gladkevich, 2007
a novel polypeptide Momordica cymbalaria antihyperglycemic Lo et al., 2013
effect
polypeptide-p Momordica charantia antihyperglycemic Wang et al., 2011
effects
M.Cy protein Momordica cymbalaria antidiabetic action Rajasekhar et al., 2010
MC6 Momordica chanrantia antihyperglycemic Liu et al., 2010
effect
LK68 Escherichia coli anticancer Choi et al., 2005
vitri A, varv A and Viola tricolor anticancer Svangard et al., 2004
varv E
Luffin P1 Luffa cylindrica anti-HIV activity Ng et al., 2011
palicourein Palicourea condensata anti-HIV activity Bokesch et al., 2001
cycloviolacin Y5 Viola yedoensi anti-HIV activity Wang et al.,2005

A polypeptide from Chlamys farreri (PCF) possesses strong antioxidant and
photochemo-preventive properties. PCF is an octal peptide (Mr = 879) consists of Pro, Asn, Ser, Thr,
Arg, Hyl, Cys, and Gly. The study has preliminarily demonstrated that PCF could reduce the
intracellular reactive oxygen species (ROS) production and protect UVB-induced HaCaT cells
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apoptosis (Yang et al., 2006). PCF likely exerted its anti-apoptotic effect in HaCaT cells through
decreasing intracellular ROS level and modulating the NF-κB signaling pathway since the activation of
NF-κB signal pathway played an important role in UVB-induced apoptosis (Liu et al., 2009). PCF
could also inhibit the reaction of lipid peroxidation, and PCF presented in the extracellular fluid could
protect murine thymocyte against UV damage and reduce UV-induced apoptosis. The protective
effects of PCF on UVA-induced damage in cultured human skin fibroblasts has also been
demonstrated (Han et al., 2004).
Peptides released from the protein and polypeptide fraction of different Argentinean wine
varietals by Oenococcus oeni were reported to have antioxidant and radical scavenging activities
(Raquel Apud et al., 2013). In addition, MAPP (polypeptides from Misgurnus anguillicaudatus) could
inhibit the autoxidation of pyrogallol in efficiency (Teixeira et al., 2013).
3.2. Antibacterial Activity
Antibacterial factors (ABFs) are secreted polypeptides that have an important role in the innate
immune system of nematodes infections. Part of small (35–50 amino acids) cationic antibacterial
proteins is consisted in the innate immunity of vertebrates and invertebrates which is in response to
bacterial or septic injuries. Arthropods (insects and arachnids) and mollusks have a plethora of
antibacterial polypeptides, among which the defensin family is the most abundant.
The 12 antibacterial factors (ABFs) have been isolated from nematodes, six from the pig
roundworm Ascaris suum (ASABF-a, ASABF-b, ASABF-g, ASABF-d, ASABF-3, ASABF-z) and six
from the soil nematode Caenorhabditis elegans (ABF-1, ABF-2, ABF-3, ABF-4, ABF-5, ABF-6)
(Froy Oren, 2005). ASABF-a and ABF-2 exhibit potent antibacterial activity against Gram-positive
bacteria, weaker activity against some Gram-negative bacteria and even weaker activity against some
yeast species. Similarly, arthropod and mollusk defensins also have antimicrobial activity against a
wide range of Gram-positive and a few Gram-negative bacteria.
Today, many antimicrobial peptides have been found in hydrobionts, such as pardaxins and
tachyplesins found in Moses sole fish and horseshoe crab (Oren et al., 1996; Osaki et al., 1999). Using
Sephadex G-50 gel filtration, DEAE-52 cellulose ion-exchange chromatography, and an improved
polyacrylamide gel electrophoresis together with electroelution, a novel polypeptide with antimicrobial
activity in vitro was isolated and characterized from loach, Misgurnus anguillicaudatus (Dong et al.,
2002). MAPP showed good inhibition of various bacteria including Bacillus subtilis, Escherichia coli,
and Staphylococcus aureus. But no inhibition was found against mold and yeast. The antimicrobial
bioactivity of MAPP was almost completely preserved after being treated by the improved
polyacrylamide gel electrophoresis system. MAPP showed a better inhibition of bacteria, and it is very
different from the known antimicrobial peptides. MAPP did not have any alkaline residue (but contains
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Int. J. Modern Biol. Med. 2013, 4(3): 176-189 181

19 cysteine residues) in the amino acid composition unlike most antimicrobial polypeptides do. In
addition, an alanine-rich peptide, known as Pa-MAP, derived from Pleuronectes americanus showed
antimicrobial activity in vivo (Teixeira et al., 2013).
There are other antimicrobial peptides, such as cyclotides (head-to-tail cyclic polypeptides)
isolated from the Rubiaceae, Violaceae, and Cucurbitaceae plant families. They have a wide range of
bioactivities besides its function in plant defense. Cyclotides are about 30 amino acids in size with a
head-to-tail cyclic backbone and three disulfide bonds arranged in a cysteine knot. The cysteine knot
and the N- and C-termini joined in a peptide bond constitute an extremely stable and rigid structure
that enables them to coexist with various proteases, enabling them perfect host defense function. They
have antibacterial and antifungal activities, inhibit neurotensin binding to cell membranes, and exhibit
uterotonic activity in rat, rabbit, and human uteri. Their antibacterial activities have been reported to be
salt dependent (Gerlach et al. 2010). Studies have also found that the quantity of cyclotides from each
species is very different.
3.3. Immunomodulatory Effects
A native 3.2 kDa polypeptide of velvet antler from sika deer (nVAP32) had
immunomodulatory effects on BALB/c mice immunocytes. It has been suggested that nVAP32
significantly stimulated splenocyte proliferation and enhanced the NK cytotoxicity and CD4+/CD8+
cell subpopulations in vitro (Zha et al., 2013). Moreover, nVAP32 demonstrated a significant capacity
in up- and down-regulating the expression of Th1- and Th2-related cytokines respectively. These
results indicated that nVAP32 might have potential immunomodulatory effect on the immune system
of mice and further investigations on in vivo effects are qualified. nVAP32 might have a similar
immunomodulatory role in both cellular and humoral immunities as well.
3.4. Hepatoprotective Nature
It has been reported that a chymotrypsin inhibitor isolated from the seeds of Momordica
cochinchinensis possessed antioxidant and hepatoprotective activities. In another study, a single
polypeptide having an apparent molecular mass of 43 kD as determined by SDS-PAGE and gel
filtration through sephadex G-75 column was isolated from aqueous extract of the leaves of Cajanus

indicus L. (CI protein), a herb (Sarkar et al., 2006). It has been found when pretreated before
galactosamine administration, it acted as an antioxidant molecule by lowering the lipid peroxidation
and increasing the antioxidant enzyme levels in liver (Manna et al., 2007). These indicated the
hepatoprotective nature of the protein. The protein also possesses preventive role against a number of
toxin induced hepatic damages, showing its curative property. Other studies have found that CI protein
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could modulates doxorubicin induced nephrotoxicty via MAPKs and both mitochondria dependent and
in dependent pathways and might be a beneficial agent in Dox-induced dysfunction (Pal et al., 2012).
3.5. Neuroprotective Function
Polypeptides might have neuroprotective function. Achyranthes bidentata polypeptide is an
active composite constituent, separated from the aqueous extract of Achyranthes bidentata. Some
studies have found ABPP have the neuroprotective function in vitro and in rat middle cerebral artery
occlusion (MCAO) model in attenuating the brain infract area induced by focal ischemia-reperfusion
(Shen et al., 2012). ABPP significantly attenuated, in a concentration-dependent manner, apoptotic cell
damage induced by exposure of cultured hippocampal neurons to N-methyld-aspartate (100 M) for 30
min (Shen et al., 2008). And an active fraction of ABPP could exert protective effects against serum
deprivation induced apoptosis in SH-SY5Y cells. The study also suggested that ABPP could improve
the recovery of sensory, motor and coordination, and cognitive function in MCAO-induced ischemic
rats. This recovery had a good correlation to the less of neuronal injury in brain.
ABPP might target different ischemic cascades, which prevent the NMDA-induced neuronal
apoptosis through inhibition of the excess Ca2+ accumulation, reactive oxygen species production, and
Bax expression (Shen et al., 2010) and exert protective effects against the serum deprivation induced
apoptosis via PI3K/AKT/Gsk3b pathway (Shen et al., 2011). Other single neuroprotective agents, for
example, DP-B99 (a metal ionchelator) directed at one aspect in these cascades. These indicated ABPP
might be a potentially neuroprotective agent. In this regard, ABPP might be effective for ischemic
stroke.
Proline-rich polypeptides also showed neuroprotective activity. Some studies have shown that
proline-rich polypeptides from bovine neurohypophisis possess neuromodulatory and neuroprotective
properties in mice with aluminum neurotoxicosis or neuronal damage caused by venoms and toxins.
Moreover, Proline-rich polypeptides from ovine colostrums, called Colostrinin, have been shown to
produce cognitive improvement in an experimental model and in patients with Alzheimer disease
(Gladkevich, 2007). In addition, CI protein also has neruoprotective activity, which attenuated
Doxorubicin-induced neurotoxicity via NF-kappa B and mitochondria dependent pathways (Pal et al.,
2012).
3.6. Antihyperglycemic Effects
Several polypeptides exhibiting hypoglycemic effects have been identified from Momordica
charantia (MC). For example, polypeptide-p (a 166 amino acid polypeptide) has been reported to have
antihyperglycemic effect in patients with both type І and type II diabetes (Wang et al., 2011). M.Cy
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protein from the MC fruit showed antidiabetic action and didn’t cause hypoglycemia in both normal or
diabetic rats (Rajasekhar et al., 2010). Other anti-hyperglycaemic peptides include MC6, have been
isolated from Momordica Chanrantia (Liu et al., 2010). MC seeds (MCSE) exhibited hypoglycemic
activity mainly via the insulin signal transduction pathway. Moreover, inhibitor against trypsin (TI)
from MC is a protein consisting of 68 amino acid residues with a molecular mass of 7 kDa and a pI of
10.85, and it was newly identified as the hypoglycemic ingredient of MCSE targeting to the insulin
receptor (IR) in a study (Lo et al., 2013). Peptides released from the protein and polypeptide fraction of
different Argentinean wine varietals by Oenococcus oeni were reported to have antihypertensive
activities (Raquel Apud et al., 2013).
3.7. Anticancer
Polypeptides can be used for cancer therapy in many ways, for example, it can be used as
cancer drug delivery and potential cancer therapeutics. Lipoprotein kringle ‘‘LK68’’ is a polypeptide,
which can be produced by overexpressing it as an inclusion body in recombinant Escherichia coli. It is
a modified angiostatin consisting of three kringle structures that might be clinically useful as potential
cancer therapeutics. It might block the formation of new capillary blood vessels of the tumour by
suppressing the proliferation of endothelial cells (Choi et al., 2005).
Cyclotides (from plants) are potential in drug discovery. Three cyclotides named vitri A, varv
A and varv E were isolated from Viola tricolor and they all showed cytotoxicity in a dose-dependent
manner and can be used in cancer therapy (Svangard et al., 2004). And the cytotoxic activity of
cyclotides against several human tumor cell lines, such as lymphoma, leukemia, myeloma, is
influenced by the primary structure as well as by loop size and placement of charged residues.
3.8. Anti-HIV Activity
Cyclotides display a range of interesting bioactivities, including anti-HIV, insecticidal,
cytotoxic, neurotensin antagonistic and hydrophobic activities. More than 100 different cyclotides have
been isolated from two phylogenetically distant plant families, the Rubiaceae and Violaceae, which are
the most important sources of cyclotides. Based on sequence homology, cyclotides are classified into
the bracelet and Mobius subfamilies. The bracelet subfamily has been shown anti-HIV activity.
Otherwise, a member of the Mobius subfamily, kalata B1, also exhibits anti-HIV activity (Daly et al.,
2004). Further more, it was suggested that this activity is critically dependent on an intact circular
backbone.
In a study, five new and three known cyclotides from Viola yedoensi, an important Chinese
herb from the Violaceae family which has been reported to contain potential anti-HIV agents, were
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identified. In the anti-HIV assays, the most active is cycloviolacin Y5, which was eluted last by
RP-HPLC (Wang et al., 2005). And it is one of the most potent of all cyclotides tested so far using in
vitro XTT-based anti-HIV assays, with an EC50 (40 nM) value similar to that of the cyclotides circulin
A and B. In addition, they showed that there is a positive correlation between the hydrophobicity and
the anti-HIV activity of the new cyclotides and this trend tracks with their ability to disrupt membranes,
which was judged from hemolytic assays on human erythrocytes.
In addition, a 37 amino acid cyclic polypeptide (palicourein) has been isolated from the organic
extract of the tropical tree Palicourea condensata, which belongs to the Rubiaceae family. Palicourein
inhibits the in vitro cytopathic effects of HIV-1RF infection of CEM-SS cells with an EC50 value of
0.1 µM and an IC50 value of 1.5 µM (Bokesch et al., 2001).
Besides the cyclotides from the Rubiaceae and Violaceae, polypeptides from other plants also
have anti-HIV activity. For example, Luffin P1, the smallest ribosome-inactivating peptide from the
seeds of Luffa cylindrica was found to have anti-HIV-1 activity in HIV-1 infected C8166 T-cell lines
and be able to bind with HIV Rev Response Element (Ng et al., 2011).
In a study, cytokine-detection ELISA results showed that nVAP32 significantly stimulated the
release of Th1 cytokines (IL-2, IL-12, IFN-γ and TNF-α) while decreased the release of Th2 cytokines
(IL-4, IL-10), and thus the Th1/Th2 arms of the immune system were modulated (Zha et al., 2013).
This finding suggested that Th1 cells are likely the main target cells of nVAP32 displaying biological
activity. If so, nVAP32 would be likely expected to be useful for treating Th2-drived pathological
disorders including AIDS, multiple allergies, viral hepatitis, and cancer.
Besides the bioactivities above, polypeptides have many other uses. For example, they can be
used as drug delivery. Wool polypeptide is a potential material for drug delivery. Both acute oral
toxicity and subacute 30-day oral toxicology studies showed that wool polypeptide had no influence on
body weight, feed consumption, blood chemistry, and hematology at any dose levels (Li et al., 2013).
The polypeptide film was demonstrated to be biodegradable and not to cause any inflammatory or
immunological responses when subcutaneously embedded in mice (Yamauchi et al., 1996). At the
same time, it is necessary to test the toxicity of wool polypeptide in vivo for tissue engineering and
drug delivery.
4. Conclusions and Prospects
Polypeptides have abundant natural sources. They could be isolated from nematodes, jellfish,
Terminalia chebula fruit, turmeric, loach (Misgurnus anguillicaudatus), the Rubiaceae and Violaceae
plant families, the seeds of Luffa cylindrical, Argentinean wine, bovine hair, bovine neurohypophisis,
Achyranthes bidentata, velvet antler from sika deer, Cajanus indicus L. and wool. Polypeptides
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showed a wide range of bioactivities, such as blood sugar regulation, immunoregulation,
neuroprotection, hepatoprotection, antioxidant activity, anti-HIV and antibacterial activity.
Polypeptides from natural sources can be potential functional food and drugs. In the future, more
efforts should be made to search more natural source of polypeptides. In order to explore more
effective products based on polypeptides, more widely pharmacological studies should be carried out
to determine new pharmacodynamic effects.
Acknowledgements
This research was supported by the Hundred-Talents Scheme of Chinese Academy of Sciences,
and the Hundred-Talents Scheme of Sun Yat-Sen University.
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