Journal of Medicinal Plants Research Vol. 5(19), pp. 4696-4703, 23 September, 2011 Available online at http://www.academicjournals.

org/JMPR ISSN 1996-0875 2011 Academic Journals

Review

Ellagitannins: Biosynthesis, biodegradation and biological properties

Juan A. Ascacio-Valds1, Jos J. Buenrostro-Figueroa1, Antonio Aguilera-Carbo2, Arely Prado-Barragn3, Ral Rodrguez-Herrera1 and Cristbal N. Aguilar1*
Department of Food Science and Technology, School of Chemistry, Universidad Autnoma de Coahuila, Saltillo, 25280, Coahuila, Mexico. 2 Department of Food Science and Technology, Universidad Autnoma Agraria Antonio Narro, Buenavista, Saltillo, 25000, Coahuila, Mexico. 3 Department of Biotechnology, Universidad Autonoma Metropolitana Iztapalapa, 09340, Mexico D. F, Mexico.
Accepted 22 July, 2011
1

From the antiquity, the ellagitannins have formed an important part of human diet. With a great relevancy in the field of science and technology, several studies have reported the important benefits of ellagitannins to human and animal health. However, the knowledge and application of these compounds is seriously limited due to their complexity and diversity. One of the unknown facts of ellagitannins is their biodegradation, but it is well known through this process that it is possible to get the monomeric unit, the ellagic acid, which is a product from the hydrolysis of ellagitannins and represents a high added value compound due to its biological properties. The general outline of this work includes information on ellagitannins, their classification and properties, biosynthesis, biodegradation, ellagic acid production and potential applications. Special attention has been focused on the biological properties of ellagitannins. Key words: Ellagitannins, biosynthesis, biodegradation, ellagic acid, biological properties. INTRODUCTION The ellagitannins (ETs) are water-soluble hydrolysable polyphenolic compounds (Wilson and Hagerman, 1990). ETs are no nitrogenous compounds with a molecular weight between 300 and 20,000 da (Khanbabaee and Van Ree, 2001), amorphous, with astringent flavor, act as weak acids and are considered secondary metabolites found in cytoplasm and cell vacuoles (Khadem and Marles, 2010). They are classified in different groups (Figure 1). ETs are formed from gallotannins (GTs), particularly from the oxidative coupling of two galloyl units in the carbon 6, forming a unit of hexahydroxydifenic acid (HHDP) and generating a monomeric ellagitannin (Kaponen et al., 2007). They have important functions in plant physiology, because they provide protection against microbial decay; this microbial resistance is attributed to the ability to form strong complexes with proteins and polysaccharides thus inhibiting microbial growth (Haslam, 1996). ETs are nutrient of high relevance in human diet and there is evidence of their key activity in the prevention of degenerative diseases such as cancer and cardiovascular diseases due their antioxidant properties (Manach and Scalbert, 2004; Madrigal-Carballo et al., 2009). Antioxidant activity of polyphenolic compounds is due principally to their redox properties, this is important in the absorption and neutralization of free radicals (Osawa and Walsh, 1993; Fukuda et al., 2003; Olsson et al., 2004). This activity provides a great phytochemical relevance to the ellagitannin molecule, since they have important benefits to the human health. When the ETs are exposed to acids or bases, the ester bounds are hydrolyzed and HHDP group is released (Figure 2), however, this is a non-stable group requiring a lactonization step to move on to a stable form, leading to the formation of monomer with high antioxidant activity (Aguilera-Carb et al., 2008a). Ellagitannins biosynthesis The ETs are part of the group known as hydrolysable

*Corresponding author. E-mail: cristobal.aguilar@uadec.edu. mx. Tel: +86-25-854-82463. Fax: (8625) 854-82463.

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Figure 1. Tannin classification (Khanbabaee and van Ree, 2001).

Figure 2. Hydrolytic scheme of Ellagitannins (Aguilera-Carb et al., 2008a).

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Figure 3. ETs biosynthesis pathway: a) Galloylation of glucose C-1 and b) Oxidation of PGG to synthesize the ellagitannin known as tellimagrandin II (Salminen et al., 2004; Barbehenn et al., 2006; Niemetz and Gross, 2003).

Table 1. Ellagitannins distribution in vegetal kingdom (Swain, 1979).

Group Psilopsida Lycopsida Sphenopsida Hypolepidaceae Angiospermas Dicotiledoneae Monocotiledoneae

Condensed tannins (CTs) (%) 0 0 28 92 54 62 29

Hidrolysable tannins (GTs and ETs) (%) 0 0 0 0 13 18 0

tannins (HTs), also the gallotannins (GTs). Information about ETs biosynthesis is limited and confused, however, it is known that the biosynthesis begins when a glucose molecule forms a complex with a gallic acid (GA) molecule, the complex is formed in glucose C-1, forming 1-O-galloylglucose (Figure 3a) (Salminen et al., 2004). Later four galloylation consecutive reactions are carried out to form its 1,2,3,4-penta-O-galloyl--D-glucopiranose (pentagalloyl glucose, PGG). Many GTs and ETs derive from the same predecessor, PGG. For GTs biosynthesis, this ester group with additional galloyl units forms complex metabolites which can have ten or more galloyl units (Barbehenn et al., 2004). On the other hand, ETs come from the result of the molecular oxidations between residues of galloyl and PGG generating the formation of 3,4,5,3',4',5'hexahidroxidifenol (HHDP), typical unit of ETs; the PGG oxidation is carried out by action of polyphenoloxidase enzyme (Niemetz and Gross, 2003). However, it is necessary for further studies to elucidate the routes and

the mechanism of ETs biosynthesis, since the information is not well- understood. Sources of ellagitannins ETs presence has been described in different plant tissues, principally in leaves, stalks, husks of some fruits, fruits, etc. The ETs concentration in vegetable source is established by quantification of ellagic acid (EA) previous ETs hydrolysis, also the free EA is quantified to obtain the total content. Table 1 shows the percentage of ETs distribution in some families of the vegetal kingdom (Swain, 1979). On the other hand, the plant tissues examination can reveal the influence of tannins on the plant metabolism, for example, young oak leaves contain mainly ETs; while in fresh bark there is a mix of ellagitanninsproantocyanidins and in acorns principally proantocyianidins are present (Lei et al., 2001).

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Table 2. Ellagitannins sources (Vattem and Shetty, 2003).

Scientific name Vitis vinifera Juglans regia Castanea sativa Fragaria ananassa Rubus idaeus Rubus occidentalis Bertholletia excelsa Carya illinoinensis Punica granatum

Common name Grape walnut Chesnut Strawberry Cranberry Blueberry Brasilian nut Pecan nut Pomegranate

In recent works, the presence of these compounds has been established in vegetal species from the Mexican semidesert, particularly from Creosote bush (Larrea tridentata), tarbush (Fluorensia cernua), candelilla (Euphorbia antisyphilitica), dragons blood (Jatropha dioica) and pomegranate (Punica granatum) (AguileraCarb et al., 2008b). Occurrence of ellagitannins in foods The presence of ETs and EA acid has been determined in food of vegetal origin, for example cranberry, raspberry and pomegranate [Clifford and Scalbert, 2000; Vattem and Shetty, 2003; Seeram et al., 2005, 2006). Table 2 shows some of principal sources for ellagitannin obtention. The occurrence of ETs in the human diet is determinant, and, in many countries the ingest of meals with high ETs content is customary (Lee et al., 2004). Nowadays, it is well known that the ETs are promoters of good health, then the vegetal ETs sources have received great attention (Seeram et al., 2005). The mentioned health activities of these molecules will be described subsequently. ELLAGITANNINS PROPERTIES ETs are of great importance for their properties to eliminate or reduce major chronic diseases and improve the health of the customer, either naturally or concentrates from plants, then describes some of these properties. Antioxidant property Oxidative stress plays a major role in the development of cancer and suffering from inflammatory diseases, cardiovascular and neurodegenerative diseases, (Faria et al., 2007). Reactive oxygen species (ROS) and reactive

nitrogen species (RNS) are generated within cells by exposure to different endogenous or exogenous agents, causing damage to important biomolecules (DNA) involved in different human diseases (Priyadarsini et al., 2002). Other causes of the formation of ROS include exposure to ionizing radiation, ultraviolet rays, pollution, cigarette smoke, some drugs, hyperoxia, excessive exercise and ischemia, and even during the food digestion (Cuzzocrea, 2006). Free radicals are produced in presence of oxygen during respiration, and although essential oxygen for life, also produces a reactive molecules such as superoxide anion, superoxide radical and hydroxyl radical (O2-, ROO, OH), which react to produce adverse health effects due to its ability to alter the DNA, lipids and protein oxidation. Over the years, free radicals can produce genetic alteration of cell division process contributing to the risk of cancer (Amakura et al., 2000). Overall, the ETs and EA preventing the free radicals formation and its reaction and damage of cells organism (Amakura et al., 2000; Priyadarsini et al., 2002; Cuzzocrea, 2006). Antimutagenic, properties antitumoral and anticarcinogenic

The coordinated reaction between ETs and carcinogen benzo [a] pyrene-7,8-diol-9,10-epoxide (BPDE), test these as chemopreventive agents against cancers caused by polycyclic aromatic hydrocarbons (PAHs) (Huetz et al., 2005), inhibiting a mutation of healthy cells, initial step in cancer development (Smith et al., 2004). ETs reduced the incidence of colon tumors and bladder carcinoma in mice when oral administered in the diet (Kellof et al., 1994). ETs are known for their action to modulate the activation of carcinogenesis by inhibition of the enzymatic cytochrome P450 phase 1 and inducing the enzymes involved in the carcinogenic detoxification from phase 2. At concentrations around 1 to 100 mM/L, shows strong anti-proliferative activity against cancer cells in colon, lung and prostate (Castonguay et al., 1998;

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Losso et al., 2004). ETs strengthen the connective tissue and avoid the spread of cancer cells; moreover, they reduce the negative effects from chemotherapy and radiation (Varadkar and Dubey, 2001). Reports related ETs to the inhibition malignant cells in skin cancer (melanome) breast, stomach, lung, esophagus, liver and others are found in literature (Kashiwada et al., 1992; Clifford and Scalbert, 2000; Kaur et al., 2006; Seeram et al., 2006). Antiviral properties ETs precursors and EA have been reported as potent antiviral against herpes simplex virus (anti-HSV) (Kurokawa et al., 2001), especially Eugenin ellagitannin extracted from Geun japonicum y Syzygium aromaticum, (Jassim and Naji, 2003). The EA precursor, eugenin, exhibits antiviral activity against herpes simplex type-1 (HSV-1). Infected rats treated with 50 mg/Kg both, topical and oral supply showed reduced virus titles on skin and brain (Kurokawa et al., 2001). Furthermore, EA and ETs are widely studied for their ability to inhibit the replication of human immunodeficiency virus (HIV). Geranin and corilagin, two ETs extracted and purified from Phyllanthus amarus (Notka et al., 2004) restrained by 50% the interaction of glycoprotein 120 of HIV-1 at concentrations from 2.65 to 0.48 g/mL on the primary cellular receptor CD4 by 50%. The inhibition was stronger for HIV-1 integrase enzyme (0.48 to 0.16 g/ml), the reverse transcriptase (8.17 to 2.53 g/ml) and protease (21.80 to 6.28 g/ml) concentrations of geranin and corilagin, respectively. This research was conducted in vitro and in vivo, with an oral administration of effective anti-HIV in blood, thereby obtaining a reduction from 5 to 30% of HIV replication. Studies conduced in vitro to evaluate (Haidari et al., 2009) the major polyphenol present in pomegranate extracts, such as ellagic acid, caffeic acid, luteolin and punicalagin, showed that the ellagitannin punicalagin, blocks the replication of influenza virus A human and has a virucidal effect, then a major inhibitor effect is observed. These studies support the conclusion that ETs have an inhibitory effect on some virus not only in vitro but also in vivo, reducing the spread of HIV in the body of infected persons (Ruibal, 2003). Antimicrobial properties

Salmonella typhi and Salmonella pyogenes (Atta-UrRahman et al., 2001). Extracts from Punica granatum L. showed the ability to inhibit the growth of Pseudomonas aeruginosa and Bacillus subtilis at concentrations of 70 mg/ml (Nascimento et al., 2000). Fractions obtained from extracts of Punicalagin ellagitannin, (Punica granatum L.), showed a clear inhibition zone of 20 mm of susceptibility against strains of methicillin-resistant Staphylococcus aureus (MRSA), at a minimum inhibitory concentration (MIC) of 61.5 g.ml-1 (Machado et al., 2002). By purification of pomegranate peels extracts (Seeram et al., 2005), punicalagin, punicalin, gallagic and ellagic acid, which exerted an effect on the growth of bacteria such as E. coli, Candida albicans and Crypotococcus neoformans as well as the fungus Aspergillus fumigatus, were obtained (Nascimento et al., 2000). The phenolic compounds extracted from pomegranate have the ability to inhibit gram negative and gram-positive bacteria (Naz et al., 2007), as well as present bioinsecticide activity (Abo-Moch et al., 2010). The ellagitannin tellimagrandin II; extracted from a Brazilian popular plant (Ocotea odorifera) used for the cure of skin exhibited potent inhibitory activity against the yeast C. parasilopsis with a MIC of 1.6 ml. The extract also showed low cytotoxicity in vitro and in vivo, without mutagenic effects in mice (Ueda-Yamaguchi et al., 2011). The use of EA at different concentrations in edible films for subsequent application in avocados reduces changes in the appearance of solid content, pH, aw, lightness and weight loss; furthermore, maintains quality and extends shelf life of avocados inoculated with high loads of the fungus Colletotrichum gloeosporioides (Saucedo et al., 2007). In addition, the use of extract with 13% of EA inhibits in vitro growth of Propionibacterium acnes and Staphylococcus epidermis, which cause skin diseases like acne (Panichayupakaranant et al., 2010). Antiparasitic activity The effect of ETs evaluated on the parasite Leishmania donovan, showing antileishmanial activity against intracellular amastigotes, avoiding the activation of macrophages at half maximum effective concentration (EC50) of 0.4 to 12.5 mg/ml, thus preventing the development of disease (Kolodziej et al., 2001; Reddy et al., 2007).

Glycemic regulator activity Both ETs and EA precursors are reported as antimicrobials because their inhibitory effect over bacteria, fungi and parasites. It has been shown that some plant extracts from Pteleopsis hylodendron containing mainly EA derivatives, are active against certain pathogenic bacteria such as Klebsiella pneumoniae, Bacillus cereus, Escherichia coli, Lagestroemin ellagitannin was isolated from Lagerstroemia speciosa (Hayashi et al., 2002) and studied both in vivo and in vitro showed to activate the transport of glucose. Lagestroemin helps to control diabetes and obesity, reducing up to 10% of body weight in obese mice using a 5% plant extracts (Klein et al.,

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2007). Berry fruit or tree shrubs are the most common food sources of EA, among them it is the raspberry (Rubus idaeus) with EA content of 3.3 mg/g (Haslam, 1996) and blackberry (Rubus occidentalis ) with 1.5 to 2.0 mg/g of EA (Bianco et al., 1998) among other sources. Ellagitannin ocurrence ETs and EA have been found as natural components in 46 different foods, being identified, the red raspberry (Rubis idaeus) as a major source of EA. However, EA can be found as a free molecule or HTs (ETs). Because of its chemical stability, EA can be absorbed through the gastrointestinal system in mammals, including humans (Hakkinen, 2000). ELLAGITANNINS BIODEGRADATION There are few studies on biodegradation of ETs requiring more research to clearly understand the mechanisms of biodegradation of ETs (Scalbert, 1992; Vivas et al., 2004). However, there are few reports on the enzymatic biodegradation by fugal enzymes. Yoshida et al. (1999) reported two compounds, novotanin O and P, with high tannin concentration. Those were extracted from Tiouchina multiflora. These compounds were subjected to enzymatic hydrolysis using a tannase enzyme producing by Aspergillus niger and the released compounds were monitored by high performance liquid chromatography (HPLC). EA was not released because tannase enzyme did not hydrolyzate HHDP bounds although acid gallic released by tannase enzyme was detected. By enzymatic hydrolysis (Vattem and Shetty, 2002, 2003), researchers have worked with cranberry pomace, an agroindustrial waste obtained after juice extract; they used a GRAS fungal strain, Lentinus edodes in solid state fermentation. Results showed an increase on polyphenols concentration associated to the glucosidase enzyme produced during the fungal fermentation. However, the association of the ETs enzymatic hydrolysis was not clearly defined. Thereafter, the enzymatic hydrolysis of ETs from oak by fungal enzyme named valonia tannin hydrolase producing for A. niger SHL 6 was reported (Huang et al., 2005). However, results were evaluated only with tannase activity, so this cannot ensure that ellagitannin hydrolysis was made by the enzyme. In studies on enzyme hydrolysis, they fermented valonia extracts with A. niger and C. utilis and reported that the EA accumulation was due to the tannase activity from A. niger and the polyphenol oxidase from C. utilis (Shi et al., 2005). Agree on the need of more search on ETs biodegradation in order to clearly elucidate its metabolic pathway (Saavedra et al., 2005); with this

information the recovery process of EA will be enhanced. Attending the recommendation was reported that tannase enzyme is responsible of GTs hydrolysis producing GA, and ETs producing HHDP, the last can be metabolized to EA by lactonization. Another way to obtain EA from GA catalyzed by PPO enzyme (Li et al., 2006), although this way is in controversy. Advancement in the research of unclear points of the metabolic pathway has been increased; researchers found that tannase do not catalyze the EA accumulation (Lee and Talcot, 2004). The results showed that the reaction was catalyzed by a -glucosidase enzyme, but it was only a hypothesis, because more investigation is needed. There are some studies where ellagic acid production and accumulation as result of ETs hydrolysis by a new enzyme different to tannase from A. niger GH1, a fungus with high potential to degradate polyphenols has been reported (Aguilera-Carb et al., 2007). One assay evaluated hydrolyzed activity from an enzyme named ellagitanin acil hydrolase obtained in a fermented enzymatic extract (Huang et al., 2007a, b). However, this extract was not purified, so this hypothesis is unclear. There is evidence of a band in polyacrylamide electrophoresis gel (SDS-PAGE) from a purified enzymatic extract produced in solid state fermentation by A. niger GH1 (Hernndez-Rivera, 2008), molecular weight of this band was 200 kDa. This enzyme can be responsible of catalysis of HHDP hydrolysis reaction in ETs to obtain EA, because of that the putative enzyme was named ellagitanin acil hidrolase or ellagitannase. However, it is necessary to generate more results to support this metabolic pathway. ELLAGIC ACID As already mentioned, the ETs are precursors of a molecule with high antioxidant capacity, with applications in different areas of industry and high added value, EA. This molecule has a molecular weight of 338.2 g/mol. It is highly thermostable (melting point 359 C) (Bala et al., 2006) due to the four rings that give it a lipophilic property and two lactones that can act as hydrogen-forming and electron acceptors, respectively, which gives a hydrophilic characteristic (Salminen et al., 2004). Has important biological activities as antitumor (Okuda et al., 1993; Castonguay et al., 1998), antiviral (Ruibal, 2003), antioxidant (Vattem and Shetty, 2002, 2003), antimicrobial (Atta-Ur-Rahman et al., 2001) and anticancer (Losso et al., 2004; Huang et al., 2005), which gives it high value and added the great interest in its production and recovery. For quantifying have been developed spectrophotometric methods (Khanbabaee and Van Ree, 2001; Hartzfeld et al., 2002), however, is very evident that few spectrophotometric measurement techniques by

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the complexity involved in the treatment of this compound to carry out reactions that are detected by a spectrophotometer. That is why the more specific and reliable techniques are chromatographic, as in the case of HPLC with that due to its high sensitivity for the detection of compounds such as EA, have developed different techniques to quantify (Scalbert, 1991; Bianco et al., 1998; Hakkinen, 2000) and recently a protocol for recovery (AscacioValds et al., 2010). ETs and EA have proved to be very important compounds, which can be exploited in the cosmetic industry, pharmaceutical, nutraceutical and beverages. However, it is necessary to develop ecological biotechnology processes to enable the production of these compounds, reducing costs and increasing production yields.

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