In nature, algae are an ancient form of existing for photosynthetic organisms that belong to the plant kingdom and make up its largest group. Along with that, they constitute a considerable part of human diet in many parts of the globe, mainly in Southeast Asian countries. Since prehistoric times, seaweeds have been widely used as an alternative medicine for different purposes. Besides, they are a source of polysaccharides with potentially active biological compounds. Brown algae fucoidan, is the most widely studied type of polysaccharide so far (Ale and Meyer, 2013; Ermakova et al., 2015; Biancarosa et al., 2018; Quitério et al., 2021). However, alginate is the most used polysaccharide in the industry. In general, the brown algae Ectocarpales and Laminariales can evolve polysaccharides with a structure consisting of 1 → 3-α-L-Fucp residues. Fucales is the main chain of fucoidan within the brown alga; it consists of linked 1 → 3 and 1 → 4 residues of α-L-fucoidan (Kusaykin et al., 2008; Holtkamp et al., 2009; Usov and Bilan, 2009; Hentati et al., 2020; Shiau et al., 2022). It (fucoidan) has a higher degree of polymerization. Therefore, depolymerization is required for fucoidan before medical or downstream applications. Enzymes that degrade polysaccharides have practical application in science, i.e. in structural studies, bioactivity studies, and drug manufacturing industries (Kusaykin et al., 2006; Drira et al., 2021).

Fucoidan is exposed to hydrolyze of some chemicals such as acids and bases, but enzymatic hydrolysis by fucoidanase is believed to be the main functional process involved in various biological activities towards sulfated polysaccharides. Till date, fucoidanase enzyme has only been described in a few or limited studies. It might be due to several factors, including a small number of a quantitative method for determining fucoidanase hydrolyzing activity, as well as the study’s use of structurally uncharacterized or partially purified fucoidan as a substrate (Hentati et al., 2020; Drira et al., 2021).

Fucoidanases are a collective name for the enzymes involved in the hydrolysis of polysaccharides and fucoidan. This group includes fucoidanase (EC 3.2.1.44, α-L- fucosidase, poly(1,2-α-L-fucoside-4- sulfate) glycanohydrolase), an endoenzyme that catalyzes the hydrolysis of the (1→2)-α-L-fucoidan bond by retaining sulfate in fucoidan, while alpha-L-fucosidase (EC 3.2.1.51) contain L-fucose and α(1→ 3)-, α(1→ 4)-, α(1→ 2)-O-fucosyl bond. Various microbial fucoidanases promoted the degradation of algal fucoidan from different sources, resulting in a variety of degradation patterns and product structures. Enzymatic hydrolysis of fucoidan is generally considered to be an advanced sustainable green technology because it does not allow to hydrolyze fucoidan in chemically (Sørensen et al., 2007; Dobrinčić et al., 2020; Mikkelsen et al., 2021).

Such studies need to consider the structural diversity of fucoidan. In the case of source, bacteria that can hydrolyze fucoidan molecules has been under investigation since 1959 (Yaphe and Morgan, 1959) when Fucoidanase was discovered in the Haliotis sp. (Thanassi and Nakada, 1967; Zayed and Ulber, 2020). In addition to the marine bacteria (Bakunina et al., 2000; Descamps et al., 2006; Silchenko et al., 2013; Trang et al., 2022) and marine invertebrates (Kitamura et al., 1992; Daniel et al., 1999; Kusaykin et al., 2003; Bilan et al., 2005), fucoidanase was also found in some listed fungi (Rodríguez-Jasso et al., 2010; Cui et al., 2018). Though, fucoidanase obtained from such agents, is comparatively far less common that the other enzymes like glycosidases produced from cellulases, amylases, laminarinases. Fucoidanases (formerly known as α-L-fucosidases) can be extracted as an intracellular as well as an extra-cellular metabolite. The information concerning the fermentative power of fucoidanases i.e. site of dissociation of glycoside bond in fucoidan, the coalition in their catalytic action, can rarely be found. Even though the sequence of genes affecting the structure of fucoidanase has been reported, and the specific amino acid structure of fucoidanases isolated from Mariniflexile fucanivorans SW5 (Silchenko et al., 2013) and Alteromonas sp. SN-1009, however, endofucosidase does not yet exist in the commercial form. Since, fucoidanases are less studied enzymes therefore, actual mode of action is still unclear (Birolli et al., 2019).

Hence, the present article has been designed to highlight the fucoidans, generated by specifically brown seaweed, along with to discuss new information or data on the fucoidanase enzyme hydrolyzing fucoidan, as well as to determine its properties and biological activity for possible downstream applications.

To date, enzymes that decompose fucoidan are produced by a wide range of living organisms (marine bacteria, seaweed, sea urchins). The fucoidanase enzyme was produced by marine bacteria, seaweeds, and sea urchins as a result of the formation of fucoidan during their vital activity, which is cleaved by fucoidanase to ensure the metabolism of these organisms. List of organisms producing fucoidannase are presented in Table 1 .

To date, there are several studies have highlighted about the isolation and characterization of fucoidanase including various possible methods for isolating and purifying fucoidanase. The general protocols followed for isolation and purification of some fucoidanases producing organisms from different marine sources are summarized in the Table 2 .

So far, different marine ecosystems such as Busan coast at South Korea (Manivasagan and Oh, 2015); Aomori at Japan (Sakai et al., 2004); Sewha Beach, Jeju Island at Korea (Kim et al., 2008); Baltic Sea and North Sea at Germany (Qianqian et al., 2011; Wu et al., 2011) have been studied with the aim to determine isolation of fucoidanases producing by marine organisms. Mentioned bacteria and fungi producing fucoidanase enzymes have been isolated from marine sediment (Manivasagan and Oh, 2015), seawater (Sakai et al., 2004), brown algae F. evanescens L. (Silchenko et al., 2013), sea sand (Furukawa et al., 1992; Qianqian et al., 2011; Wu et al., 2011), and mollusks and sea urchin producing fucoidanase enzymes have been isolated from digestive glands (Silchenko et al., 2014), hepatopancreas (Kitamura et al., 1992), and digestive tract (Sasaki et al., 1996).

Due to the complex structure of fucoidans, which are heteropolysaccharides, fucoidanases are difficult to be classified correctly. Fragmentary data on the structures of fucoidans lead to an incorrect classification of fucoidanases. For example, fucoidan isolated from F. vesiculosus L. was determined incorrectly as a unit with structure 1→2-α-L-fucan. This definition led to the incorrect assignment of fucoidanases to EC 3.2.1.44. Subsequently, the structure of the enzyme was refined and assigned to α-1→3- and α-1→4 bond residues of fucose. However, there is a lack of knowledge for a complete and correct classification of fucoidanases. In addition, it is noted that enzymes that hydrolyze any glycosidic bonds in fucanes (polysaccharides from fucose residues) are called fucanases rather than fucoidanases (Kusaykin et al., 2016).

Comparison of amino acid sequences has led to an alternative classification of fucoidanases based on hydrolyzed bond types. The classification by carbohydrate active enzymes or CAZy (www.cazy.org) is called homologous. According to CAZy, glycoside hydrolase (GH) enzymes are divided into 133 classes (GH classes). Peptides with unknown properties can be found in each class, if they are similar in amino acid structure and sequence, they can also be classified by CAZy. CAZy can be used to predict the catalytic and molecular properties of fucoidanases (Gebler et al., 1992) and the structural geometry of cleavable glycosidic bonds (Henrissat et al., 1995). The CAZy system includes 133 GH classes united into 14 families of closely related classes. Due to the presence of sites that belong to several classes, some GHs are multifunctional enzymes. By applying this classification, fucoidanases can be assigned to class 107 GH. Fucoidanase FcnA isolated from the marine bacterium M. fucanivorans strain SW5T is one of the first members of this class. A comparative analysis of the secondary structure elements of the fucoidanase FcnA and other known fucoidanases subsequently made it possible to state that this entire class contains data on four sequences: FcnA (CAI47003.1) from M. fucanivorans SW5T, Fda1 (AAO00508.1) and Fda2 (AAO00509.1) from Alteromonas sp. SN-1009 and gene SVI_0379 (BAJ00350.1) from Shewanella violacea DSS12T (Kusaykin et al., 2016).

Significant interest in health-promoting properties of polysaccharide bio-macromolecules of marine origin, particularly acidic polysaccharides, has been sparked by developments particularly in biopharmaceutical and genetic engineering techniques. Fucoidan is one of these and is thought to be promising (Wang et al., 2019). The structure of these polysaccharides is so irregular that it is difficult to study them chemically and analyze their structure in detail (Sergeevich and Olegovna, 2015). To address this issue, specific enzymes capable to hydrolyze complex fucoidan molecules are required.

Fucoidanase catalyzes the O-glycosidic bond hydrolysis in the main chain of the fucoidan molecule, while exhibiting biological activity. Moreover, fucoidanase is a rare and little-studied enzyme. To date, there is no information or very scanty information on the complete structure of fucoidanase, active sites, substrate binding sites, secondary and tertiary structures. The mechanism of fucoidanase action has not yet been completely understood. Moreover, due to their heterogeneity, fucoidans are still largely underutilized as a base of pharmaceuticals despite having a wide range of biological activity and being non-toxic when taken orally (Kusaykin et al., 2016). Therefore, one possible solution to address such issue is to define the sequence of amino acid in fucoidanase and obtain enough recombinant enzymes to study the enzyme’s properties and spatial structure (Tran et al., 2022a).

There was determined the sequence of amino acid in fucoidanase isolated from the marine bacterium Formosa algae. They were obtained by recording the nucleotide sequence of the F. algae genome and homologs of gene products contained in the genome of algae were found (Sergeevich and Olegovna, 2015). As a result, it can be concluded that, the algae genome contains two genes encoding fucoidanase (FFA1 and FFA2) and the review of the amino acid sequences of FFA1 and FFA2 by multiple alignment showed 57% identity. The amino acid sequence of FcnA is 67% and 57% identical for FFA1 and FFA2, respectively.

Cadherin-like domains were found in bacterial enzymes that accelerate decomposition of various compounds (proteins, carbohydrates, nucleic acids) and lectins that bind to anionic polysaccharides (Abdian et al., 2013). It should be noted that the functions of these domains described in the literature are common for binding to one or another biopolymer using calcium ions (calcium dependent binding).

The gene construct encodes full-length fucoidanases (FFA1 and FFA2) and their truncated derivatives without the C-terminal domain of FFA1-SD and FFA2-SD, and without the cadherin-like repeating domain of FFA2-KD and FFA1-KD, containing nucleotide sequences (Sergeevich and Olegovna, 2015).

The full-length recombinant fucoidanase and all its truncated derivatives catalyze the breakdown of fucoidan. The fucoidanase activity of recombinant and native enzymes is manifested only if there are ions of certain divalent metals. The presence of fucoidanase activity in recombinant FFA1-SD fucoidanase and truncated FFA2-SD derivatives suggests that the C-terminal domain may not be involved in catalysis. So, it could be stated that, fucoidanase FFA1-KD and FFA2-KD also have the ability to hydrolyze fucoidan, but to a much lesser extent. This modification of the protein can reduce its ability to bind to substrate molecules. If the cadherin-like domain plays a stabilizing role, then similar results can be achieved by decreasing the molecule stability (Abdian et al., 2013; Silchenko et al., 2013).

Nonetheless, both the enzymes rapidly hydrolyze fucoidan. The fucoidan chain alternates with residues of sulfated fucose that are linked to α-1 → 3 and α-1 → 4. The obtained data shows that both fucoidanases are specific for splitting of the α-1 → 4-glycosidic bond within residues of sulfated fucose (Tran et al., 2022a).

At present, three principal mechanisms of fucoidan modifying enzymes have been identified and listed below: a-L-fucosidase acts as a catalyst for the degradation of the a-L-fucosyl linkages at the nonreducing ends, thereby liberating fucose units from the major backbone of fucose in fucoidans ( Figure 1 ).

While the other type of fucoidanase causes random endo-type hydrolysis of glycosidic linkages (both α (1→3)-, and α (1→4)-) found in the fucose ( Figure 1 ).

The study (Silchenko et al., 2017a) observed the anticancer activity of fucoidan from S. horneri var. densum C.Agardh, described its structure and established the process of its transformation under the action of fucoidanases. The gene encoding fucoidanase from the marine bacterium F. algae was identified and cloned; subsequently FFA1 was generated in Escherichia coli. The product of gene FFA1 had a molecular weight of 111 kDa. Amino acid sequence analysis indicated that the FFA1 fucoidanase belongs to the class of glycoside hydrolases GH107 (CAZy). The resulting recombinant fucoidanase FFA1 was used to obtain fucooligosaccharides. NMR spectroscopy was used to determine the structure of 5 sulfated oligosaccharides with a degree of polymerization of 4–10. It was shown that the fucoidan extracted from S. horneri var. densum C.Agardh was an almost pure fucane (Silchenko et al., 2017a).

The marine organisms serve as producers of bioactive compounds in a large amount and diversity presenting elements and compounds of different chemical classes (Barzkar et al., 2017; Barzkar et al., 2018; Jahromi and Barzkar, 2018a; Jahromi and Barzkar, 2018b; Barzkar, 2020; Barzkar and Sohail, 2020; Barzkar et al., 2021a; Barzkar et al., 2021b; Barzkar et al., 2021c; Barzkar et al., 2022a; Barzkar et al., 2022b). Meanwhile, seaweeds play the fundamental role in oxygen producing in the aquatic media, being prolific sources of bioactive agents (Barzkar et al., 2019). Seaweed polysaccharides such as brown algae fucoidan are of value and it is a negatively charged hygroscopic molecule that is chemically saturated with fucose and sulfated polysaccharides, mainly from the extracellular matrix of brown seaweeds. Fucoidan enzymes are a group of hydrolases that hydrolyze complex fucoidan polymers to produce low molecular weight fucoidan.

To date, only the basic principles of the construction of fucoidan molecules have been established. Chemical studies of these polysaccharides are difficult due to the extreme irregularity of their structure, and therefore a detailed analysis of the structure presents significant difficulties. Therefore, a reliable correlation between the chemical structure and the biological action of fucoidans has not yet been elicited. To solve these problems, it is important to use enzymes with established specificity and mechanism of action that can hydrolyze complex fucoidan molecules. A detailed analysis of the structure of small fragments of fucoidans will allow establishing the chemical structure of this polysaccharide. The use of fucoidan fragments of various structures will help to determine the relationship between certain structural elements and their biological action.

Enzymes that use fucoidans as a substrate are called fucoidanases or fucanases. These enzymes act as a hydrolysis catalyst for O-glycosidic bonds within the main chain of fucoidan molecules (EC 3.2.1.44, GH107 (CAZy database)). Fucoidanases are rare and poorly studied enzymes. To date, there is no information on the structural organization of fucoidanases, sizes of active centers, substrate-binding sites, secondary and tertiary structures. Fucoidanases presented a particularly not studied mechanism of action. Such a small number of publications on the structure of fucoidanases and their catalytic properties is due to the low content of these enzymes in organisms used as sources. One solution is to determine the sequences of amino acids inside fucoidanases and obtain recombinant enzymes in sufficient quantities to study specific properties and spatial structure of enzymes (Bakunina et al., 2000).

Fucoidans fermented by fucoidanase can be absorbed into the blood in a small amount and have a direct effect on the circulatory system (Tokita et al., 2010; Nagamine et al., 2014). Nagamine et al. (Nagamine et al., 2014) picturized that low molecular weight fucoidan oligo- and polysaccharides supplied with food are cleaved into small soluble fragments of about 3 kDa and secreted into the extracellular space. Further, these fragments can bind to receptors on the membranes of target cells, mediating effects similar to those during parenteral administration of high molecular weight polysaccharides (Nagamine et al., 2014).

Thus, both direct and indirect biological effects can be expected from fermented fucoidans (Trang et al., 2022). As in the case when fucoidan with low molecular weight fermented by fucoidanase causes a prebiotic effect that can be considered as a direct effect, while the anti-inflammatory effect can be considered as indirect and implemented through an improvement in the composition of the intestinal microflora, an increase in the proportion of symbiotic, and a decrease in the proportion of facultative microflora that has an anti-inflammatory effect (Luthuli et al., 2019; Wang et al., 2019). Fucoidanases can be engaged in the process of sulfated fucooligosaccharides’ production (in biotechnology), thus it has potential applications as biologically active additives and drugs.So, the collection of information on this subject indeed need-based attempt or research, and there is an ample scope to explore such enzyme or bioactive compounds for many beneficial purposes, including health, biomedical, bioengineering and life-science research. Hence, the future research strategies may be adopted or designed by the researchers with such latest updated information mentioned in this review article.

Conceptualization and writing original draft, NB. Editing, QL, STJ, VR and RD. Review and funding acquisition, SS, OB All authors contributed to the article and approved the submitted version.