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Higher Basidiomycota as a Source of Antitumor and Immunostimulating Polysaccharides (Review)
Writer: Solomon P. Wasser / Date :2002-11-01 (taken from MushWorld site)
Activation of Mushroom Polysaccharides by Chemical Modification
Several trials have been conducted to Improve the antitumor activity of mushroom polysaccharides by chemical modification. The most successful schemes for chemical improvement of mushroom polysaccharides were developed for Ganoderma lucidum Grifola frondosa, and leucopaxillus giganteus (= Tricholoma gigantea). These schemes include two main procedures : modification of mushroom polysaccharides by
Smith degradation (oxydo-reducto-hydrolysis) and activation by the method of formolysis (Mizuno, 1996; Mizuno et al., 1996). Five polyaldehydes and 10 polyalcohols were prepared by Smith degradation from five polysaccharide fractions previously obtained from Grifola frondosa liquid culture mycelium. For this reason the original polysaccharide solutions were first oxidized to polyaldehydes using 0.1 M NaIO4 in the dark, then converted into polyalcohols by reduction of NaBH4 in alkaline media adjusted to pH8 with 2 M NaOH, and hydrolyzed using 1 M H2SO4 at room temperature (Zhuang et al., 1994b).
Chemical activation of mushroom polysaccharides by formolysis Includes degradation of polysaccharides by formic acid in a 99% solution of HCOOH, then the reaction solution is precipitated with 99% EtOH, and one-half of the precipitate is lyophilized after dialysis, while the other part if dissolved in hot water and additional fractions are obtained by alcohol precipitation(Zhuang et al., 1994b). Four formylated polysaccharides and four formolysis products of polysaccharides were prepared using this method from four polysaccharide fractioned from obtained from four Grifola frondosa liquid culture mycelium.
Although two of the original polysaccharides had no activity, their Polyaldehyde polyol, formylated, and formolysis derivatives showed significant activity. Polyaldehyde and polyol-polysac-charides prepared from a polysaccharide with low antitumor activity showed activity higher than the original polysaccharide (Zhuang et al.,1994b), As all original polysaccharide fractions showing elevated activity levels by chemical modification were β-glucan or xyloglucan, it was suggested that the sugar chain under treatment was changed or eliminated, resulting In improved ,solubility and activity (Mizuno, 1996).
Carboxymethylation is another chemical method that performed transformation of β-glucans into water-soluble form. For example, whole fruiting bodies of Pleurotus ostreatus Pleurotus ostreatus or their Stipes homogenate were treated with 0.15 M sodium hydroxide solution at 95'C for 2 h. The residue collected was washed with water until neutral, then suspended in 0.06% sodium chlorite solution, adjusted to pH4.5 with acetic acid, and stirred for 6 h at 50'C. The polysaccharide obtained was
β-(1→3)-linked glucan, every fourth glucopyranosyl residue was substituted at 0-6 with single D-glucopyranosyl groups. The heterogeneous etherification of the particulate glucan with monochloroacetic acid (C2H3CIO2) in alkaline medium gave the sodium Salt of the water-Sol-uble O-(carboxymethyl) glucan derivative (Ku-niak et al., 1993; Karacsonyi and Kuniak, 1994). carboxymethylated glucan from P ostreatus(Pleuran) demonstrated immunomodulatory effects, especially increased phagocytic activity (Paulic et al., 1996).
In a similar manner, water-insoluble, alkali-soluble linear α-(1→3)-glucans obtained from fruiting bodies of Amanita muscaria and Agrocybe aegerita (=A. Cylindracea) had little or no antitumor effect, while their carboxymethylated products showed potent antitumor activity (Kiho et al., 1994; Yoshida et al., 1996).
Chemical modification of branched mushroom polysaccharides that resulted in side chain reduction can be developed not only by Smith degradation but also by enzymatic reactions. A novel linear polysaccharide comprising α-(1→4)-bonded α-D-glucose units of molecular mass 500-10,000 was developed after successive enzymatic treatment of submerged culture broth by amylase, cellulase, and protease (Kosuna. 1998).
It was stated that hot water extracts of many mushrooms contain α-D-glucan (glycogen-like polysaccharide mycodextrin), however, this compound showed no antitumor activity (Mizuno and Zhuang, 1995). The extracellular polysaccharides produced in liquid cultures of many special from the genus Pleurotus Include minor water-Solu-ble fraction with α-(1→4)-linked glucose units in the backbone. These polysaccharides are bound with proteins rich in amide- and hydroxyl-con-taining residues, which can be involved in pro-tein-polysaccharide linkages (Gutierrez et al., 1996).
Linear low molecular weight α-(1→4)-glu-cans obtained after enzymatic reduction of side chains and protein components [active hexose correlated compounds (AHCCs)] were demonstrated as having immunomodulatory and anti-cancer properties (Ghoneum et al., 1995; Matsushita et al., 1998). In 1992, a trial was conducted in Japan to evaluate the preventive of effect of AHCCS against recurrence of hepatocellular carcinoma following surgical resection (Kidd, 2000).
Sulfated homo- and heteropolysaccharides possessing antiviral activity are widespread in algae, especially in sea algae (Schaeffer and Krylov, 2000), but do not occur naturally in higher Basid-iomycota mushrooms. Chemically sulfated schizophyllans with different sulfur contents were obtained from β-(1→3)-glucan produced by Schizophyllum commune (Itoh et al., 1990; Hirata et al., 1994), It was Suggested that the sulfur content in schizophyllan is the most important factor for inhibiting growth of human immunodeficiency virus (HIV), rather than molecular weight or kinds of sugar component (Itoh et al., 1990). The medicinal tests indicate that sulfated schizophyllan with sulfur content of 5% can be useful as an anti-HIV agent for treatment of HIV-infected hemophiliacs (Hirata et al., 1994).
Higher Basidiomycota mushrooms are unlimited sources of anticancer and immunostimulatingpolysaccharides. Many if not all Basidiomycota mushrooms contain biologically active polysaccharides. Six hundred and fifty-one species and 7 infraspecific taxa from 182 genera of higher Hetero-and Homobasidiomycetes were demonstrated to possess pharmacologically active polysaccharides in their fruiting bodies, culture mycelia, or culture broth. These polysaccharides are of different chemical composition; the biochemical mechanisms for mediating their biological activity are still not clearly demonstrated (Belchers et al., 1999).
The antitumor polysaccharides from various mushrooms are characterized by their molecular weight, degree of branching, and higher (tertiary)structure. A triple-helical tertiary conformation of medicinal mushroom β-(1→3)-glucans is known to be important in their immunostimulating activity. When lentinan was denatured with dimethyl sulfoxide, urea, or NaOH, the tertiary structure was lost, while the primary structure was not affected, but tumor inhibition properties were lowered with progressive denaturation (Maeda et al., 1988). The same results, which confirmed a correlation between antitumor activity and triple helix structure, were obtained in investigations on schizophyllan (Yanaki et al., 1983, 1986).
Unlike β-(1→3)-glucans, with medicinal properties that are strongly dependent on high molecular mass ranging from 500 to 2000 kDa(Mizuno, 1996).
α-(1→3)-glucuronoxylomannans, which are characteristic of jelly mushrooms, are not strongly dependent on molecular weight. Thus, Gao and co-workers (1996 a) reported that even acidic hydrolysate fractions of T. fuciformis fruiting body glucuronoxylomannans with a molecular mass from 53 to 1 kDa induce human monocytes to produce interleukin-6 (IL-6) as efficiently as the nonhydrolyzed heteropolysaccharide. This indicates that the activity may be caused by a common structure α-(1→3)-mannan back-bone, and the change of molecular weight had no obvious influence on the activity of the heteroglycans (Gao et al., 1996b). The products of Smith degradation and lithium degradation of T. fuciformis heteroglycan with molecular mass of 400 kDa or the product of deacetylation also induced monocytes to secrete IL-1 as efficiently as the original polysaccharide, indicating that xylose and glucuronic acid residues as well as acetyl groups are not important in the side chains for promoting cytokine-stimulating activity (Gao et al., 1997).
Mushroom β-(1→3)-glucans exhibit a variety of biological and immunopharmacological activities, and many of the activities, such as nitrogen oxide synthesis of macrophage and limulus factor G activation, were dependent on the triple helix conformation, but others were independent, such as interferon-U and colony stimulating factor syn- theses (Yadomae, 2000). Acidic glucuronoxylomannan isolated from the fruit body of Tremella fuciformis was also demonstrated as having a left-handed, threefold helical backbone conformation (Yui et al., 1995), thus indicating that the α- (1→3)-mannan backbone structure is more important than the tertiary structure of the molecule.
A wide range of biologically active polysaccharides is found among higher Basidiomycota mushrooms, and their practical application is dependent not only on unique properties but also on biotechnological availability. Mycelia formed by growing pure cultures in submerged conditions are of constant composition, and submerged culture is the best technique for obtaining consistent and safe mushroom products (Wasser et al., 2000).