Appl Microbiol Biotechnol (2012) 93:7182

DOI 10.1007/s00253-011-3666-8

MINI-REVIEW

Algal fucoidan: structural and size-dependent bioactivities

and their perspectives
V. K. Morya & Jungeun Kim & Eun-Ki Kim

Received: 21 July 2011 / Revised: 3 October 2011 / Accepted: 22 October 2011 / Published online: 17 November 2011
# Springer-Verlag 2011

Abstract Fucoidan is a complex-sulfated polysaccharide

distributed in various marine organisms, and the brown algae
are reported as the major producer. The fucoidan is important
for their high bioactive properties, like antibacterial, anticoagulant, antiviral, anti-tumor, etc., and many more to be
explored. There is a strong archival support for the bioactivity
and promising properties of this molecule, which creates a
hope for this molecule as future drug against thrombosis and
some kind of cancers. Reports other than the above bioactive
properties have also been a matter of interest for the design of
signal or enzyme-arrested new class of drugs. In the past three
decades, the research on isolation, molecular characterization,
and screening of biological applications has significantly
increased. One major issue associated with this molecule is the
higher size and seasonal variation in their chemical composition; to resolve the issue and maintain its bioactivity, a
prioritized and literal hydrolysis process is required to be
developed. Here, in this mini-review, we have tried to
summarize the algal fucoidan research and the bioactivities
influenced by their molecular size.
Keywords Fucoidan . Brown algae . Antioxidant .
Anticoagulant . Antiviral . Anti-tumoral

Introduction
Diversity creates a variety of biomolecule, and these
molecules are responsible for this diversity, either directly
V. K. Morya : J. Kim : E.-K. Kim (*)
National Research Lab of Bioactive Materials, Dept. Biological
Engineering, Inha University,
Incheon, South Korea 402-751
e-mail: ekkim@inha.ac.kr

or indirectly. The secondary metabolites have been used as

a biologically active agent in different purposes like
pharmaceuticals, cosmetics, nutraceuticals, pesticide, antibiotic, etc. (Kim et al. 2007, 2010a, b). Various carbohydrates are being regarded by researchers as hypnotic
because of their diversity and respective bioactivities. The
saccharides are naturally assembled from monosaccharides
having different types of linkages, at varying positions in
the carbohydrate ring, forming straight chain or branched
polymers. Further modifications such as alkylation, phosphorylation, and sulfation provide an additional structural
complexity and peculiar activities to the already diverse
compounds. The high degree of variability among biologically relevant sulfated carbohydrates is attributed to a
number of factors. There is inconsistency among sulfated
monosaccharides (i.e., glucose (Glc), galactose (Gal), the
corresponding N-acetyl (NAc) amines GlcNAc, GalNAc,
and mannose among others), the total number of sulfate
moieties, and the hydroxyl(s) to which the sulfate group(s)
are linked (i.e., 2-O, 3-O, 4-O, and 6-O sulfates);
furthermore, the varied structure of the underlying oligosaccharide moiety. An important consequence of this
structural diversity is that each unique structure has the
potential to be recognized by an individual receptor,
making sulfated oligosaccharides ideal for carrying information in complex biological systems.
Among sulfated polysaccharide, fucoidan is extensively
explored for its medicinal properties in the past two decades
and being isolated from various species of brown seaweed.
Fucoidan can exist essentially in two distinct forms of
glycosaminoglycans: F-fucoidan which is more than 95%
of the fucoidans in seaweeds andcomposed of sulfated
esters of l-fucose and U-fucoidan which is approximately
20% glucuronic acid. Depending on the source of algae, the
sulfated polysaccharide does not only mainly consist of L-

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fucose units but can also contain other sugars such as

galactose, mannose, xylose, or uronic acid and sometimes
proteins (Pomin et al. 2005; Venugopal 2009). Sulfated
fucan is the characteristic feature of the fucoidans. These
compounds in total comprise less than 10% in composition
(Li and Xu 2007; Pomin et al. 2005).
Fucoidan occupied about more than eight hundred citation
in PUBMED since 1918 after the first isolation, by Kylin. The
research boom in the field of fucoidan is a story of last two
decades, about 485 papers between 2000 and 2010 while 310
papers during 19902000. The figures show that the
passionate inclination of scientific community in this field is
rapid and recent. The hope with this group of polysaccharide
attracts researchers because of their numerous bioactive
properties. The new arena for green technology with a
molecule is about to come with promising fucoidans.
Various reports show that this polymer has numerous
bioactive properties like antibacterial, anticoagulant, antiviral,
and anti-tumor, etc., and many more to be explored. In recent
years, the interest in fucoidan from different sources, its
structure and its possible biological applications has increased.
For the past three decades, the bioactivities of fucoidans have
been extensively studied due to their various biological
activities, including anti-tumor, antivirus, immunomodulatory, anticoagulant, anti-inflammatory, antioxidant, antithrombotic, anticomplementary properties, activity against
hepatopathy, blood lipids reducing, anti-allergic, uropathy,
anti-adhesive, antineoplastic, renal pathy, gastric protective
effects, and therapeutic potential in surgery and hypoxic
ischemic brain injury, (Cumashi et al. 2007; Tanaka et al.
2011; Li et al. 2008). Our lab is focused on applicability of
fucoidan in cosmetics as depigmenting agent (Jin et al. 2006;
Kim et al. 2010a, b, 2011a, b). Development of non-arbutinbased skin whitening cosmetics without any side effect is a
challenge for the researcher (Jin et al. 2005; Lam et al. 2008;
Babitha et al. 2009; Lam et al. 2011). We successfully
explored the depimentation effect of fucoidan, in vitro. We
are trying to modify the molecule chemically and biologically to enhance the depigmenting properties of the fucoidan
(Jin et al. 2005, 2006; Kim et al. 2011a).
In contrast to other sulfated polysaccharides, the fucoidans are prevalently distributed among marine organisms
like brown algae and echinoderms. The demand of this
polysaccharide will increase with the increase of exploration of bioactivities. Therefore, it is required to explore
more organisms for isolation of fucoidan. The aim of this
review is to discuss the algal fucoidan and the bioactivities
influenced by their molecular weight.
Source
Among various sources of fucoidan, brown algae, sea
urchin, and sea cucumber were well explored for isolation

Appl Microbiol Biotechnol (2012) 93:7182

and evaluation of bioactivity (Holtkamp et al. 2009). In the

past two decades, different brown algae were analyzed for
their content of fucoidans including Adenocystis utricularis
(Ponce et al. 2003), Analipus japonicus (Bilan et al. 2007),
Ascophyllum nodosum (Medcalf and Larsen 1977), Chorda
filum (Bakunina et al. 2002; Chizhov et al. 1999),
Cladosiphon okamuranus (Sakai et al. 2003b), Cystoseira
indica (Mandal et al. 2007), Dictyota menstrualis
(Albuquerque et al. 2004), Fucus distichus (Bilan et al.
2005), Fucus evanescens (Bakunina et al. 2002), Fucus
serratus (Bilan et al. 2006), Fucus vesiculosus (Wu et al.
2004), Hizikia fusiforme (Li et al. 2006), Kjellmaniella
crassifolia (Bilan et al. 2006), Laminaria cichorioides
(Anastyuk et al. 2010), Laminaria japonica (Huang et al.
2010), Lessonia vadosa (Chanda and Matsuhiro 2008),
Lobophora variegate (Medeiros et al. 2008), Padina
gymnospora (Silva et al. 2005), Pelvetia canaliculata
(Descamps et al. 2006a), Saccharina latissima (Bilan et
al. 2010), Sargassum stenophyllum (Duarte et al. 2001),
Stichopus japonicas (Zhang et al. 2010), Stoechospermum
marginatum (Adhikari et al. 2006), and Undaria pinnatifida
(Chen et al. 2009). The bioactivity of fucoidan depends on
nature and extent for sulphation, which must be taken care
during extraction. Because of harshness of extraction method,
the sulphation pattern may be destroyed and the bioactivity
can thus be lost (Qiu et al. 2006). In most of the reported
research, extraction and characterization were evaluated up
to bioactivity screening while until date fucoidan only from
F. vesiculosus (Bladder wrack) are available commercially,
which embark to explore the other possibilities. The
extraction method of the supplier is adapted to the method
of Black (1954). The problem of this fucoidan is that it is
very crude and differs in color and constitution between
different batches. The bioactivity of this molecule is vast and
promising for development of new class of drug or
nutraceuticals. Therefore, there is a strong need for a
comprehensive study on its size dependent bioactivity and
precise generation of specific size low molecular weighted
fucoidan. Therefore, this molecule needs more attention for
developing better methodology for extraction and functionaries. About 1,800 species of brown algae are known
worldwide and most of them are from relatively colder
marine habitat. Very few numbers of species from the
Laminariales and Fucales are being utilized commercially
for biomass and other uses. The world production of
seaweeds was some 8 m ton in 2003. The seaweeds are
used in the production of food, feed, chemicals, cosmetics
and pharmaceutical products. Seaweeds are mainly produced
for these end uses in Asian countries such as China, the
Philippines, North and South Korea, Japan, and Indonesia
(Reith et al. 2005). The total market of the brown algae is
estimated to be approximately about $100 million. In spite of
the persistent increase in interest regarding brown algae as

Appl Microbiol Biotechnol (2012) 93:7182

sources of fucoidans, basic knowledge of mechanisms and

metabolic regulation of this group of polysaccharides is in a
juvenile period. Some studies have mentioned the species,
age of sample, thallus composition and season and method
of extraction as the probable reason of diversity of fucoidan
structure (Skriptsova et al. 2010; Usov et al. 2005). Maximal
content was found in sporophyll, which was several times
higher than any other part of the thallus. Moreover,
publications establishing a correlation between fucoidan
content and seasonality generally report that the highest
amount of the polysaccharide is obtained during the
reproductive stage (Skriptsova et al. 2010). Reproduction,
however, can be a long process involving several stages.
Within this period, the physical and morphological state of
the alga varies and physiological and biochemical processes
undoubtedly accompany such changes (Aguilar-Rosas et al.
2004). This figure may augment in the coming years because
of the wonder molecule which may revolutionize the marine
biotechnology, to meet the needs of the market. In this
review, we have tried to compile various aspects of this
wonder molecule, which may further be explored.
Structure
Since 1913, after the discovery of fucoidan by Kylin, the
structures of fucoidans from different brown seaweeds have
been investigated and deduced. The results were promising as
well as paradoxical, in terms of composition. The diversity
among distribution is not only its interesting feature but also
its divergence of structure. Fucoidans from various species of
brown seaweed has been investigated and still in progress.
One of the most studied fucoidans isolated from F.
vesiculosus, has simple chemical compositions, mainly being
composed of fucose and sulfate. However, the chemical
compositions of most fucoidans are complex. Besides fucose
and sulfate, they also contain other monosaccharides
(mannose, galactose, glucose, xylose, etc.) and uronic acids,
even acetyl groups and protein. Furthermore, the structures
of fucoidans from different brown algae vary from species to
species. Despite all that, some fucoidans structures or their
structural backbones have been elucidated.
Fucoidan prepared from F. vesiculosus is commercially
available at present. It is composed of 44.1% fucose, 26.3%
sulfate, and 31.1% ash, with a little amount of a aminoglucose (Nishino et al. 1994). Later, it was discovered that
the 1,2--fucose is the main component unit and most of the
sulfate groups were located at C-4 position of the fucose
units (Anno et al. 1970). The suggested structural models of
fucoidan of F. vesiculosus based on GC/MS data of
methylation reveal that the core region of fucoidan was
primarily a polymer of -(13) linked fucose with sulfate
groups substituted at the C-4 position on some of the fucose
residues. Within the chain at every two to three residues, the

73

fucose is attached to form branched point. The structural

variability was observed by different workers because of the
difference of preparation method and their methylation
methods for analysis (Patankar et al. 1993).
The 40-year-old structural model fucoidan was finally
revised in 1993 by Patankar, based on GC/MS analysis. In the
last two decades, research have isolated and characterized
fucoidan from various sources like F. evanescens, F. distichus,
F. serratus L., S. marginatum, P. gymnospora, etc., and
resolved the structures (Bilan et al. 2006; Adhikari et al.
2006). The fucoidan from other than F. vesiculosus was
found to be complex chemical, instead of homopolymeric
they show heteropolymer of fucose, galactose, mannose,
glucose, xylose, and glucuronic acid (Jingjing et al. 2009;
Skriptsova et al. 2010). The fucoidan from Ecklonia kurome
and C. filum is structurally 13-linked fucopyranose with
branched structure. Fucoidan isolated from C. filum shows
highly branched poly--(13)-fucopyranoside backbone
(Chizhov et al. 1999). While 13-linked fucopyranose is
dominant in nature, 12- or 14-linked fucopyranose was
also reported from some brown algae, with some unusual
branching. The structure of fucoidan from A. nodosum was
[3)--L-Fuc(2SO3-)-(14)--L-Fuc(2,3diSO3-)-(1]n with
highly branched core region with primarily -(13)-fucosyl
residues and a few -(14)-linkages, while sulfate groups
were at positions 2 and/or 4 (Chevolot et al. 2001; Marais
and Joseleau 2001). The structural properties of fucoidan
from different algal sources are summarized in Table 1.
It has been discussed that the fucoidans are a heterogeneous assemblage with regard to their monosaccharide
composition, number of sulfate, and acetyl groups and
moreover, molecular mass. Fucans can differ in structure
among algal species and can vary even within the same
species. Because of the heterogeneity in structures within
the seaweed, differing extraction conditions used by
researchers can give rise to the isolation of distinct fucan
forms, thus need to establish any systematic correspondence between structure and algal order (Li et al. 2008). All
fucoidans show a wide spectrum of biological action (Fitton
2005), which seems to be determined by their degree of
sulfatation, fine structure, monosaccharide composition,
and molecular weight. In general, Fucans have been
classified into two groups. One group includes the fucans
from Laminaria saccharina, Laminaria digitata, A. japonicus, C. okamuranus, and C. filum that have their central
chains composed of (13-L-fucopyranose residues. A
second group included fucans isolated from A. nodosum
and Fucus species that have their central chains composed
of repeating (13)- and (14 residues (Jiao et al. 2011;
Ushakova et al. 2009; Li et al. 2008). However, many
studies have revealed more complex fucans, some with
branching structures. Fucoidans of various structures are of
doubtless interest for a comparative study of differential

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Appl Microbiol Biotechnol (2012) 93:7182

Table 1 Structural properties of some fucoidans from different sources

Sr. Source

Chemical composition

Adenocytis utricularis

Analipus japonicus

Ascophyllum nodosum

A. nodosum

Chorda filum

Dictyota menstrualis

Ecklonia kurome

Fucose, galactose, mannose,

and sulfate
Fucose, xylose, galactose, mannose,
and sulfate
Fucose (49%), xylose (10%),
GlcA (11%), and sulfate
Fucose (49%), xylose (10%),
GlcA (11%), and sulfate
Fucose/xylose/mannose/glcose/
galtose (1.0:0.14:0.15:0.40:0.10)
andsulfate
Fucose/xylose/uronic acid/
galactose/
sulfate (1/0.8/0.7/0.8/0.4) and
(1/0.3/0.4/1.5/1.3)
Fucose, galactose, mannose,
xylose, GlcA, and sulfate
Fucose/sulfate/acetate (1/1.21/0.08)

Fucoidan structure

Reference

3 (4Fucp) and 1 (2Fucp) per 10 (13)-a-L

-Fucp(2/4SO3-) residues
(13)--L-Fucp and a few (14)--L-Fucp with
(13)--L-(2and/or 4 Fucp)
3)--L-Fucp(2SO3-)-(14)--L-Fucp
(2,3-diSO3-)-(1
-[3)--L-Fucp-(1-]33)--L-Fucp
(2Fucp)-(1

Bilan et al. (2007)

Marais and Joseleau (2001)
Chevolot et al. (2001)
Chizhov et al. (1999)

Bilan et al. (2007)

3)--L-Fucp-(2,4-diSO3)-(14)--L-Fucp
-(2SO3)-(1
Bilan et al. (2006)
9 Fucus evanescens c. Ag. Fucose/sulfate/acetate (1/1.23/0.36) 3)--L-Fucp(2SO3-)-(14)--L-Fucp
(2SO3-)-(1
Bilan et al. (2006)
10 Fucus serratus L.
Fucose/sulfate/acetate (1/1/0.1)
3)--L-Fucp(2R1,4R2)-(14)--L-Fucp(2SO3)
-(1a. (50%): R1 =SO3, R2 =H b. (50%): R1 =H,
R2 =-L-Fucp-(14)--Fucp(2SO3)-(13)--L
-Fucp(2SO3)-(1
11 Fucus vesiculosus
Fucose and sulfate
8

F. distichus

12 Himanthalia lorea and

Bifurcaria bifurcate
13 Hizikia fusiforme
14 Laminaria angustata

Fucose, xylose, GlcA, and sulfate

Fucose, galactose, mannose,
xylose, GlcA, and sulfate
Fucose/galactose/sulfate (9/1/9)

(12)- and (13)-linked fucose residues with sulfation

at C-4
Li et al. (2006)
2)--D-Man(1and4)--D-GlcA(1alternately,
while a little4)--D-Gal(1

16 Lessonia vadosa

Fucose, xylose, mannose, glcose,

3)--L-Fucp(4SO3-)-(1and additionally3)
and galctose (30.8:1.4:2.1:0.9:7.9) --L-Fucp(4SO3- or2Fucp)-(1
Fucose/sulfate (1/1.12)

17 Macrocytis pyrifera

Fucose/galactose (18/1) and sulfate

18 Padina pavonia

Fucose, xylose, mannose, glucose, 12 linked fucose; 14 linked GlcA, mannose

galactose, and sulfate
and glucose
Fucose/galactose (10/1) and sulfate

15 Laminaria saccharina

19 Pelvetia wrightii

20 Sargassum stenophyllum Fucose, galactose, mannose, GlcA,

glucose, xylose, and sulfate
21 Spatoglossum
Fucose/xylose/galactose/sulfate
schroederi
(1/0.5/2/2)
22 Stoechospermum
Fucose, galacturonic acid, xylose,
marginatum
galactose, and sulfate
23 Undaria pinnatifida
(Mekabu)

3)--L-Fucp(2/4SO3)-(1and4)
--L-Fucp
(2SO3)-(1
Fucose, galactose, mannose, xylose, 1,3-linked fucose and 1,3-, 1,4-,
and sulfate
and 1,
6-linked galactose

Adhikari et al. (2006)

Lee et al. (2004) and

Kim et al. (2007)

Glc glucose, Gal galactose, NAc N-acetyl amines, Man mannose, GlcA glucuronic acid

and functional biological activities. Thus, the investigation

of content and structural variability of fucoidan, synthesized
by seaweeds at their different life stages, is essential both
for seaweed biology and fucoidan utilization by the medical
industry. Applications of polysaccharide agents in medicine
have associated problems with standardization. One method
of standardization is a definition of the season characterized
by the maximum quantity of fucoidan with a fixed structure
and the highest biological activity (Skriptsova et al. 2010).

Therefore, this wonder molecule needs more extensive

study to establish the mechanisms of complexity in
structure, to produce at the large scale.
Bioactivities of fucoidan
Various researches to have done and many have to do with
fucoidan to evaluate the medicinal and cosmeceutical
potentials (Fitton and Dragar 2006; Holtkamp et al. 2009).

Appl Microbiol Biotechnol (2012) 93:7182

75

The literatures cited on the bioactivity ranges from

anticoagulant (Silva et al. 2005; Alekseyenko et al. 2007;
Gideon and Rengasamy 2008; Kwak et al. 2010; Cho et al.
2010), antiviral (Lapshina et al. 2006; Trinchero et al.
2009), and anti-tumoral to anti-inflammatory (Aisa et al.
2005; Lapshina et al. 2006; Raghavendran et al. 2011).
Furthermore, fucoidan promotes collagen gel contraction by
probably enhancing the surface integrin 21 expression
on fibroblasts and may therefore accelerate wound-healing
processes (Holtkamp et al. 2009). In spite of the mentioned
applications fucoidan shows, some other properties like
anti-mycotoxin (Angulo and Lomonte 2003), immunomodulatory (Raghavendran et al. 2011), antioxidant (Micheline
et al. 2007; Li et al. 2008; Wang et al. 2008; Jing et al.
2009), anticomplementary properties, hypoxic ischemic
brain injury (Luo et al. 2009), cardio protective (Thomes
et al. 2010), acting as an anti-inflammatory in the brain (Del
Bigio et al. 1999), as a neuroprotectant in ischemicreperfusion injury (Uhm et al. 2003), inhibitor of proinflammatory proteins, such as TNF-alpha or nitric oxide
(Mitrasinovic and Murphy 2002), uropathy, renal pathy
(Zhang et al. 2003), and a neuroprotective effect against
dopaminergic neurodegeneration (Luo et al. 2009). The
biological activity of fucoidan depends on its structure
(Boisson-Vidal et al. 2000) and sulphation content (Qiu et
al. 2006). The structural properties are highly governed by
climatic condition and time of collection. To determine and
correlate these complexities in structure of fucoidan contents is one of the most challenging tasks for researches.
According to these activities, fucoidan exhibits a high
pharmaceutical potential with possible applications. Here,

in this review, we tried to summarize some of the biological

activity and size effect of fucoidans reported from different
sources.
Size-dependent bioactivities of fucoidan
This molecule has various biological and medicinal
properties, as discussed above which have been explored
in vitro conditions. A major obstruction to the development
of its medicinal application is the poor knowledge of its
molecular structure and, as a result, of the structural basis of
its biological activities (Mulloy et al. 2000). Since 2000,
various developments have enhanced our knowledge about
fucoidan structures and structural diversity. One major issue
associated with this molecule is its higher size and seasonal
compositional variation; thus, to resolve the issue and
maintain the bioactivity, a prcised hydrolysis process
needs to be developed. Several attempts have been made
to generate oligo-polysaccharide by free radical, mineral
acid, organic acid, and enzymatic hydrolysis of fucoidan
(Table 2). Several attempts have been done by various
groups of researchers to develop a methodology to produce
a low molecular weight fucoidan (LMWF), like physical,
chemical, and enzymatic (Holtkamp et al. 2009). As we
have discussed, the bioactivity is highly dependent on
sulfate group; enzymatic hydrolysis prevents the loss of
sulfate group than the chemical hydrolysis. One wellknown enzyme for fucoidan hydrolysis is fucoidanases or
-L-fucosidases, distributed as extracellular as well as
intracellular among several organisms (Holtkamp et al.
2009). The producer range of the fucoidan-degrading

Table 2 Various methods used to prepare low molecular weight fucoidan and their bioactivities
Applications

Method

Source

Reference

Antithrombotic

Radical

Ascophyllum nodosum

Colliec-Jouault et al. (2003) and

Chabut et al. (2003, 2004)

Radical

A. nodosum

Durand et al. (2008)

Acid

Laminaria japonica

Zhu et al. (2010)

Acid

Egg jelly

Pomin et al. (2005)

Enzyme

Sporophyll of Undaria pinnatifida

Kim et al. (2010a, b)

Anticoagulant
Antioxidant

Gamma irradiation

Sigma fucoidan (Fucus vesiculosus)

Choi et al. (2009)

Antioxidant and anticoagulant

Acid

L. japonica

Wang et al. (2009)

Anticancer

Acid

Sporophyll from U. pinnatifida

Radical

A. nodosum

Alkhatib et al. (2006)

Radical

A. nodosum

Hlawaty et al. (2011)

Radical

A. nodosum

Bachelet et al. (2009)

Radical and acid

Pheophicae cell wall

Changotade et al. (2008)

Acid

F. vesiculosus

Azofeifa et al. (2008)

Wang et al. (2010)

Yang et al. (2008)
Cho et al. (2010)

Radical
Anti-inflammatory

Acid

Lake et al. (2006)

U. pinnatifida

Park et al. (2010)

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Appl Microbiol Biotechnol (2012) 93:7182

enzymes is wide enough, i.e., from bacteria to sea

cucumber, this enzyme is reported in higher vertebrates
also. The cleavage pattern by fucoidan-degrading enzyme
largely depends on the organism, but it has been broadly
classified in three groups: first is -L-fucosidase cleaves Lglucosyl linkage at non-reducing terminal while fucoidanases or fucansulphatehydrolases has two types of cleavage
pattern, one is an endo-cutter which produces oligomers;
another type is an exo-cutter and resulting monomers while
the exact mechanism is still unknown (Holtkamp et al.
2009; Wu et al. 2011). Most of the researcher worked on
the production study of fucosidases. The crystal structure
and extensive sequence analysis from microbial sources,
however, are limited (Rodrguez Jasso et al. 2008;
Descamps et al. 2006b; Wu et al. 2011). Looking at the
importance and perspectives of this enzyme, many more
research will be conducted in near the future. Some
important sources of fucoidan-degrading enzymes and
distribution are listed in Table 3. Here, in this review, we
have focused on important studies done on bioactivities
influenced by the molecular size of fucoidan.
Effect of LMWF as anticoagulant
As we mentioned that the prioritized research on
fucoidan was started in the 1990s, most of the paper
in the successive two decades was on screening and
structural analysis. A research by Colliec-Jouault et al.
in 2003 has pointed the size of fucoidan and their effect
on bioactivity (Colliec-Jouault et al. 2003). Chabut et al.

(2003) made a comparative study of heparin and

fucoidan on basic fibroblast growth factor (FGF-2).
They have reported that LMWF enhances the FGF-2induced tubular morphogenesis through overexpression
that was heparan sulfate dependent. Based on their
report, LMWFprevents arterial thrombus growth in
animals having low hemorrhagic propensity than heparin
and inhibits smooth muscle cell proliferation. After
myocardial infarction, endothelial cells increase expression of heparan sulfate proteoglycans, specifically at
ischemic sites. LMWF, being antithrombotic and potentially proangiogenic, could constitute an interesting drug
to initiate endothelial cell differentiation in revascularization of ischemic areas after myocardial infarction
(Chabut et al. 2004). Durand et al. (2008) have made a
comparative study of the antithrombotic and anticoagulant
activity of LMWF and LMWH in an experimental model
of arterial thrombosis due to endothelial apoptosis
(Durand et al. 2008). Deux et al. (2002) performed in
vitro growth inhibition experiments on vascular smooth
muscle cells, an in vivo pharmacokinetic study, and
locally delivered fluorescently labeled polysaccharides in
rabbit iliac arteries after angioplasty with a non-occlusive
catheter. They have reported that the low molecular weight
fraction of fucoidan as anti-in-stent restenosis after
angioplasty in rabbits (Deux et al. 2002). A similar study
done with different aspects of clinical and in vitro
evaluation of antithrombic activity of LMWF, supports
that the molecule can be exploited further (Zhu et al. 2010;
Kim et al. 2007, 2008, 2011b). The molecular weight and/

Table 3 Fucoidan-degrading enzyme sources and the nature of secretions

Sl. no.

Source organism

Nature

References

Alteromonadaceae sp.

Extracellular

Sakai et al. (2004)

Bacillus cereus

Extracellular

Miura et al. (2005)

Bifidobacterium bifidum
Lactobacillus sp.

Intracellular

Rodrguez-Daz et al. (2011) and Ashida et al. (2009)

Dendryphiella arenaria TM94

Extracellular

Wu et al. (2011)

Flavobacteriaceae sp.

Extracellular

Descamps et al. (2006a)

Flavobacterium CZ1127

Intracellular

Chang et al. (2010)

Flavobacterium sp. F-31

Intracellular

Ohshiro et al. (2011)

Fucophilus fucoidanolyticus

Intracellular

Sakai et al. (2003b)

Littorina kurila

Extracellular

Bilan et al. (2005)

10

Maribacter sp. KMM 6211

Gramella sp. KMM 6054

Intracellular

Urvantseva et al. (2006)

11

Pseudoalteromonas citrea strains KMM 3296 and KMM 3298

Bakunina et al. (2002)

12

Sphingomonas paucimobilis PF-1

Extracellular

Kim et al. (2008)

13

S. paucimobilis PF-1

Digestive

Kim et al. (2010a, b)

14

Streptomyces sp. OH11242

Extracellular

Goso et al. (2001)

15

Sulfolobus solfataricus

Intracellular

Cobucci-Ponzano et al. (2008)

16

Verrucomicrobia sp.

Digestive

Sakai et al. (2003a)

Appl Microbiol Biotechnol (2012) 93:7182

or degrees of sulfation of fucoidan are key factors for its

anticoagulating activity; therefore, enzymatically partial
digests could be a better tool for synthesis for LMWF
(Kim et al. 2010a, b)
Pomin et al. (2005) employed an apparently nonspecific
approach to cleave this polysaccharide based on mild
hydrolysis with acid and obtained low molecular weight
derivatives. They reported that the slight decrease in the
molecular size of the sulfated fucan dramatically reduces its
effect on thrombin inactivation mediated by heparin
cofactor II. Sulfated fucan with 45 tetrasaccharide
repeating units binds to heparin cofactor II but is unable
to link efficiently the plasma inhibitor and thrombin (Pomin
et al. 2005). In the same year, Matsubara et al. (2005)
have reported a comparative and comprehensive analysis
with various rages of LMWF as an inhibitor of for
inhibition human umbilical vein endothelial cells
(HUVEC) tube formation. They have reported that
LMWF with molecular weight ranges between 15 and
20 kDa, enhanced HUVEC migration but did not inhibit
HUVEC tube formation. Thus, 1520 kDa fucoidan would
have proangiogenic effect on angiogenesis. Their results
elucidated that 2030 kDa would be a critical point to
characterize the role of fucoidans on angiogenesis
(Matsubara et al. 2005).
Effect on endothelial cell migration
LMWF greatly enhances endothelial cells tube formation
in growth factor reduced Matrigel (Matsubara et al. 2005;
Lake et al. 2006). Luyt et al. (2003) have reported that a
LMWF can promote revascularization in rat critical
hindlimb ischemia. Previous studies have shown that it
can act as a potent inhibitor of vascular smooth muscle cell
proliferation in vitro (Lake et al. 2006) and prevent
neointimal hyperplasia of these cells during artery restenosis in vivo. Fucoidan is of particular pharmacological
interest because, in addition to its non-animal origin, it
exhibits anti-inflammatory activities, is a potent modulator
of connective tissue proteolysis but has low anticoagulant
activity compared with heparin. LMWF is also devoid of
direct antithrombin effect.
The vascular endothelial growth factor (VEGF) family
and its receptors are essential regulators of angiogenesis
and vascular permeability. LMWF is a strong enhancer of
VEGF165-induced EC chemotaxis but not proliferation
(Lake et al. 2006). While it was reported that LMWF was
not effective on VEGF121-induced EC migration, a VEGF
isoform that does not bind to heparan sulfate proteoglycans
(Lake et al. 2006). Surface plasmon resonance analysis
showed that LMWF binds with high affinity to VEGF165
(1.2 nM) and its receptors (520 nM) but not to VEGF121
(Lake et al. 2006). Overall, the effects of LMWF were

77

much more pronounced than those of LMWF heparin (Lake

et al. 2006).
LMWF as protective agent against alloimmune injury
The Graft vascular disease remains a major limitation to
long term organ graft survival, and conventional immunosuppressive agents fail to be effective for the treatment or
the prevention of allograft arteriosclerosis. In 2006, a study
reflected on the effect of LMWF on prevention of coronary
intimal proliferation in a rat cardiac allograft model, and it
has been reported that 5 mg kg1 day1 of LMWF prevents
coronary intimal lesion at 30-day post-transplantation. The
above model of heterotopic cardiac transplantation, allogeneic rejection is characterized by coronary intimal proliferation and myofibroblastic parenchymal remodelling
(Alkhatib et al. 2006). It was reported that on a daily basis,
injections of LMWF prevent intimal lesion, and myofibroblastic parenchymal remodelling treatment with LMWF
showed effective in the rat cardiac allograft model to
prevent arterial and parenchymal lesions occurring in
response to alloimmune injury. However, this protective
effect does not appear to depend on mobilization of bone
marrow-derived cells. It was also reported that high
molecular mass and viscous nature of these polysaccharides
has hampered their application, especially as a therapeutic
agent (Alkhatib et al. 2006). Thus, production and
optimization of single-type LMWF for proper function
and formulation is needed.
LMWF as anticancer agent
Yang et al. have studied the native and hydrolyzed fucoidan
from Undaira pinnatifida, as the anticancer agent. They
have shown that the anticancer activity was enhanced from
37.6% to 75.9% with a concentration of 1.0 mg/mL and
with native and hydrolyzed fucoidan, respectively (Yang et
al. 2008). This may be caused by the increased in molar
concentration and the enhanced mobility and diffusivity of
the partially hydrolyzed fucoidans. Yang et al. have
suggested that the anticancer activity of fucoidans could
be significantly improved by lowering their molecular
weight when they are depolymerized by mild hydrolysis
conditions without causing considerable desulfation (Yang
et al. 2008). Recently, Cho et al. have reported a
relationship between oversulfation and conformation of
LMWF and evaluation of their in vitro anticancer activity
(Cho et al. 2010).
LMWF as stumilant in 3D culture
Another interesting bioactivity of fucoidan was reported by
Changotade et al. (2008); when they have subjected the

78

LMWF (from pheophicae cell wall) on bi-dimensional

cultured normal human osteoblasts behaviors, they also
studied on, impregnation procedure of the bone biomaterials (Lubboc1) and explored the applicability of LMWF in
bone extracellular matrix context its capabilities to support
human osteoblastic behavior in 3D culture (Changotade et
al. 2008). The researchers have reported that LMWF is a
stimulant expression of osteoblastic markers differentiation
such as alkaline phosphatase activity, collagen type I,
expression, and mineral deposition; furthermore, cell
proliferation was enhanced as well (Changotade et al.
2008).
Effect of LMWF in treatment of cardiovascular desease
Inflammation of the vessel walls is a key player to be
initiated and the progression of cardiovascular diseases
(Bachelet et al. 2009). The inflammation, thrombosis, and
atherogenesis are successive phenomena, and platelets are
major components to co-ordinate the same (Gawaz et al.
2005; Bachelet et al. 2009). The activated platelets and
pathological endothelium prominently express the Pselectin, which has been described as a candidate target in
atherosclerosis (Bachelet et al. 2009). Using surface
plasmon resonance experiments, it observed that Pselectin binds to a synthetic dendrigraft polymer substituted
with sialic acid epitopes (Bachelet et al. 2009). In 1992,
Lindbom et al. reported that fucoidan can reduce the
leukocyte rolling on the vessel wall. Various reports on
LMWF as a revascularizing agent for cardiovascular
diseases (Lake et al. 2006; Bachelet et al. 2009) have been
archieved. It has been reported that in comparison to low
molecular weight heparin and dextran sulfate, the LMWF
more efficiently binds with the ligand of P-selectin. To
prove the same, they used binding assay, mass spectrometry, surface plasmon resonance, and flow cytometry on
human platelets (Bachelet et al. 2009). The inhibition of
SLex/P-selectin binding was quantified from binding assay
experiments, Bachelet et al. ranked polysaccharides as
follows (IC50): fucoidan (20 nM)>heparin (400 nM)>
dextran sulfate (25,000 nM) (Bachelet et al. 2009). Bachelet
et al. also reported that LMW fucoidan binds to activated
platelets and the level of binding was related to the degree
of platelet activation thus LMW fucoidan has an ability to
inhibit the binding of an anti-P-selectin antibody to activate
human platelets (Bachelet et al. 2009). According to
Bachelet et al., the LMWF could be used in the vascular
field as a targeting moiety in biomedical applications such
as drug-delivery systems or contrast media for molecular
imaging (Bachelet et al. 2009). Park et al. comparatively
analyze the effect of the high (HMWF; 1004 kDa),
medium (MMWF; 3.50.3), and LMWF (10.2 kDa)
molecular weight fucoidans on the progression of

Appl Microbiol Biotechnol (2012) 93:7182

collagen-induced arthritis (CIA). Their study concluded

that HMWF enhances arthritis through enhancing the
inflammatory activation of macrophages while LMWF
reduces arthritis through the suppression of Th1-mediated
immune reactions (Park et al. 2010).
Antioxidant activity of LMWF
As various studies suggest, fucoidan have been a great
potential as an antioxidant, in vitro. Fucoidan from L.
japonica can prevent the increase of lipid peroxide in
serum, liver, and spleen of diabetic mice obviously (Li et al.
2008). This fucoidan was reported as strong scavenging
effect on superoxide radical, while less effective on 1,1diphenyl-2-picryl-hydrazyl scavenging. The fucoidan can
inhabit H2O2-induced hemolysis of rat erythrocytes effectively and showed a significant protective effect on lipid
peroxidation of liver homogenate in rat induced by FeSO4ascorbic acid (Li et al. 2008). Micheline et al. reported that
fucoidan (homofucan) from F. vesiculosus and fucans
(heterofucans) from P. gymnospora had an inhibitory effect
on the formation of hydroxyl radical and superoxide radical
(Micheline et al. 2007). Similarly, various studies focus on
antioxidant properties of fucoidan in vitro (Micheline et al.
2007; Zhao et al. 2005; Li et al. 2006; Wang et al. 2008; Li
et al. 2004).
As it has been mentioned, the large size of this molecule
is a major concern with this molecule to be considered as a
drug. A little progress has been done in the direction of
sized selection of LMWF and enhancement of antioxidant
properties. A study done by Wang et al. (2009) and Choi et
al. (2009) in the direction of evaluation of antioxidant
activity of modified fucoidan is remarkable to understand
the size dependent antioxidant properties of fucoidan. They
have also explored the toxicity and activity level of
modified LMWF (Wang et al. 2009; Choi et al. 2009).
Some more studies yet to reveal for the establishment of
relation between size-dependent bioactivity of fucoidan are
still needed. Still, an intensive research is needed to develop
a safer and effective LMWF as an antioxidant.

Conclusions
In spite of their potential as biologically active compounds,
the high molecular mass and viscous natures of fucoidan
have hampered their applications, especially as a therapeutic agent. To obtain oligosaccharide with more diverse
bioactivities, LMWF can be prepared by chemical, radical,
or enzymatic means. Therefore, an extensive research
requires for boosting the generation of more and more
information regarding the LMWF as safer and enhanced
bioactivity without cross reactivity. This review is an

Appl Microbiol Biotechnol (2012) 93:7182

attempt to summarize the information regarding the

bioactivity of fucoidan and impact of molecular weight on
bioactivity of this marvel molecule. This molecule has more
hope as a medicine and may be in the future, the fabrication
of this molecule will be as smooth as required.
Acknowledgments This study was supported by a grant of the
Korea Healthcare Technology R&D Project, Ministry of Health &
welfare, Republic of Korea (Grant No. A103017). The work was also
supported in part by Inha University.

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