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Team:Cornell/project/future/pharmaceuticals
From 2013.igem.org
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Future Applications
- Overview
- Other Biomaterials
- Bioremediation
- Pharmaceuticals
Pharmaceuticals
Many clinically used drugs are derived from fungi. A few notable examples include the antibiotic penicillin, immunosuppressant cyclesporin A and the statins lovastatin and squalestatin, which act to reduce and remove low density lipoproteins from blood vessels and lower chance of heart attack, stroke and diabetes. Fungi are extremely useful in biotechnology efforts and pharmaceutical research because they are able to utilize many unique metabolic pathways to produce a wide array of bioactive compounds capable of producing many positive pharmacological effects [1]. The biocompounds synthesized our organism, Ganoderma lucidum, are capable of regulating the immune system, inhibiting platelet aggregation, reducing blood pressure, and lowering levels of cholesterol and sugars. In addition, Ganoderma lucidum has the potential to be used against the Human Immuno Virus (HIV), exhibits anti-tumor activity and can propagate anti-diabetic effects. [2]Ganoderma lucidum can also exhibit many immuno-modulating effects by activating T-cells and macrophages, which act as the body's first line of defense by releasing cytokines, nitric oxides (NO) and other mediators. These cytokines and NOs are important chemical messengers for inducing biological responses. In the case of Human Immuno Virus (HIV) and Acquired Immuno - Deficiency Syndrome (AIDS), Ganoderma lucidum produces many natural products that can serve as anti-HIV agents. Triterpenoids such as lucidenic acid O and lucidenic lactone inhibit HIV-1 Reverse Transcriptase, an enzyme encoded by HIV to aid in the reproduction of the virus and propagate mutations to develop polyproteins to create the main protein components of an infectious HIV virion [3, 4]
A G. lucidum polysaccharide GLB7 also decreases the production of oxygen free radicals and exerts an anti-mutagenic and anti-tumor effect. One major mechanisms of anti-tumor action includes polysaccharide -mediated potentiation of immune function, which is mostly due to beta-D glucans, which bind to leucocyte surfaces and serum-specific proteins and increase production of cytokines, interleukins and interferons, nitric oxides and antibodies [5-13]. Other mechanisms include suppressing the growth of leukemia cells and inducing differentiation into mature erythrocytic cells [14], inhibition of DNA polymerase and post-translational modification of oncoproteins [15-17].
Ganoderma lucidum’s anti-diabetic effects include hypoglycemic and hypolipidemic activities and inhibition of increased blood glucose without raising blood insulin levels [18]. This effect is supported by clinical tests in patients with confirmed type II diabetes mellitus who experienced lowered blood glucose concentrations after treatment with Ganopoly (polysaccharide fractions extracted from G. lucidum) [19]. Other effects of the fungi vary from anti-allergic to estrogenic and hepatoprotective; a thorough review of Ganoderma lucidum's possible pharmacological effects is available [2].
The various biocompounds synthesized from this strain of fungi poses many possibilities for pharmacological development. However, there are also many challenges present in this endeavor. Pharmaceutical exploitation is still very limited due to the limited quantity of Ganoderma lucidum found in nature. Polysaccharides, ganoderic acids and other metabolites have mostly been extracted from solid state cultivated fruit bodies but methods of extraction from liquid cultivated mycelium still need to be thoroughly investigated [2].
References
[1] Wainwright M. (1995) An Introduction to Fungal Biotechnology. Wiley, Chichester.
[2] Sanodiya, B.S.; Thakur, G.S.; Baghel, R.K.;Prasad, G.B.K.S.;Bisen, P.S. (2009) Ganoderma lucidum: A Potent Pharmacological Macrofungus. Current Pharmaceutical Biotechnology, 10, 717-742.
[3] Kartikeyan, S.; Bharmal, R.N.; Tiwari, R.P. and Bisen, P.S. (2007) HIV and AIDS: Basic Elements and Priorities, Springer Verlag: Dordrecht, The Netherlands.
[4] Menendez-Arias, L. (2002) Targeting HIV: antiretroviral therapy and development of drug resistance. Trends Pharmacol. Sci., 23, 381-388.
[5] Miyazaki, T. and Nishijima, M. (1981) Studies on fungal polysaccharides. XXVII. Structural examination of a water-soluble, anti- tumor polysaccharide of Ganoderma lucidum. Chem. Pharm. Bull., 29, 3611-3616.
[6] Usui, T.; Iwasaki, Y.; Hayashi, K.; Mizuno, T.; Tanaki, M.; Shinkai, K. and Arakawa, M. (1981) Antitumor activity of water- soluble beta-D-glucan elaborated by Ganoderma applanatum. Ag- ric. Biol. Chem., 45, 323-326.
[7] Usui, T.; Iwasaki, Y.; Mizuno, T.; Tanaki, M.; Shinkai, K. and Arakawa, M. (1983) Isolation and characterization of antitumor ac- tive beta-D-glucans from the fruit bodies of Ganoderma applanatum. Carbohydr. Res., 115, 273-280.
[8] Sone, Y.; Okuda, R.; Wada, N.; Kishida, E. and Misaki, A. (1985) Structural and anti-tumor activities of polysaccharides isolated from fruiting body and the growing culture of mycelium of Gano- derma lucidum. Agric. Biol. Chem<.i>., 49, 2641-2653.
[9] Kishida, E.; Okuda, R.; Sone, Y. and Misaki, A. (1988) Fractiona- tion structures and antitumor activities of the polysaccharides of Reishi, the fruiting body of Ganoderma lucidum. Osaka-Shiritsu Daigaku Seikatsukagakubu Kiyo, 35, 1-10.
[10] Konopski, Z.; Smedsrod, B.; Seljelid, R. and Eskeland, T. (1994) A novel immunomodulator soluble aminated ß-1,3-D-glucan: binding characteristics to mouse peritoneal macrophages. Biochem. Biophys. Acta, 1221, 61-65.
[11]Mueller, A.; Raptis, J.; Rice, P.J.; Kalbfleisch, J.H.; Stout, R.D.; Ensley, H.E.; Browder, W. and Williams, D.L. (2000) The influ- ence of glucan polymer structure and solution conformation on binding to (13)-beta-D-glucan receptors in a human monocyte- like cell line. Glycobiology, 10, 339-346.
[12] Battle, J.; Ha, T.Z.; Li, C.F.; Dellabeffa, V.; Rice, P.; Kalbfleisch, J.; Browder, W. and Williams, D. (1998) Ligand binding to the (13)-beta-D-glucan recpetor stimulates NF-kappa B activation, but not apoptosis in U937 cells. Biochem. Biophys. Res. Commun., 249, 499-504.
[13] Muller, A.; Rice, P.J.; Ensley, H.; Coogan, P.S.; Kalbfleisch, J.H.; Kelley, J.L.; Love, E.J.; Portera, C.A.; Ha, T.Z.; Browder, I.W. and Williams, D.L. (1996) Receptor binding and internalization of a water-soluble (13)-beta-D-glucan biologic response modifier in two monocyte macrophage cell lines. J. Immunol., 156, 3418-3425.
[14] Zhong, L.; Jiang, D.Z. and Wang, Q.R. (1999) Effects of Ganoderma lucidum (Leyss ex Fr) Karst compound on the proliferation and differentiation of K562 leukemic cells. J. Hunan Med. Univ., ,24, 521-524.
[15]Mizushina, Y.; Hanashima, L.; Yamaguchi, T.; Takemura, M.; Sugawara, F.; Saneyoshi, M.; Matsukage, A.; Yoshida, S. and Sakaguchi, K. (1998) A mushroom fruiting body-inducing sub- stance inhibits activities of replicative DNA polymerases. Biochem. Biophys. Res. Commun., 249, 17-22.
[16]Mizushina, Y.; Watanabe, I.; Togashi, H.; Hanashima, L.; Takemura, M.; Ohta, K.; Sugawara, F.; Koshino, H.; Esumi, Y.; Uzawa, J.; Matsukage, A.; Yoshida, S. and Sakaguchi, K. (1998) An ergos- terol peroxide, a natural product that selectively enhances the in- hibitory effect of linoleic acid on DNA polymerase beta. Biol. Pharm. Bull., 21, 444-448.
[17]Lee, S.; Park, S.; Oh, J.W. and Yang, C.H. (1998) Natural inhibi- tors for protein prenyltransferase. Planta Medica, 64, 303-308.
[18]Mohammed, A.; Adelaiye, A.B.; Abubakar, M.S. and Abdurahman, E.M. (2007) Effects of aqueous extract of Ganoderma lucidum on blood glucose levels of normoglycemic and alloxaninduced dia- betic wistar rats. J. Med. Plants Res., 1(2), 34-37.
[19]Gao, Y.; Lan, J.; Dai, X.; Ye, J. and Zhou, S.H. (2004) A phase I/II study of Ling Zhi mushroom Ganoderma lucidum. (W. Curt.: Fr.) Lloyd (Aphyllophoromycetideae) extract in patients with type II diabetes mellitus. Int. J. Med. Mushrooms, 6 (1), 33-39.
[2] Sanodiya, B.S.; Thakur, G.S.; Baghel, R.K.;Prasad, G.B.K.S.;Bisen, P.S. (2009) Ganoderma lucidum: A Potent Pharmacological Macrofungus. Current Pharmaceutical Biotechnology, 10, 717-742.
[3] Kartikeyan, S.; Bharmal, R.N.; Tiwari, R.P. and Bisen, P.S. (2007) HIV and AIDS: Basic Elements and Priorities, Springer Verlag: Dordrecht, The Netherlands.
[4] Menendez-Arias, L. (2002) Targeting HIV: antiretroviral therapy and development of drug resistance. Trends Pharmacol. Sci., 23, 381-388.
[5] Miyazaki, T. and Nishijima, M. (1981) Studies on fungal polysaccharides. XXVII. Structural examination of a water-soluble, anti- tumor polysaccharide of Ganoderma lucidum. Chem. Pharm. Bull., 29, 3611-3616.
[6] Usui, T.; Iwasaki, Y.; Hayashi, K.; Mizuno, T.; Tanaki, M.; Shinkai, K. and Arakawa, M. (1981) Antitumor activity of water- soluble beta-D-glucan elaborated by Ganoderma applanatum. Ag- ric. Biol. Chem., 45, 323-326.
[7] Usui, T.; Iwasaki, Y.; Mizuno, T.; Tanaki, M.; Shinkai, K. and Arakawa, M. (1983) Isolation and characterization of antitumor ac- tive beta-D-glucans from the fruit bodies of Ganoderma applanatum. Carbohydr. Res., 115, 273-280.
[8] Sone, Y.; Okuda, R.; Wada, N.; Kishida, E. and Misaki, A. (1985) Structural and anti-tumor activities of polysaccharides isolated from fruiting body and the growing culture of mycelium of Gano- derma lucidum. Agric. Biol. Chem<.i>., 49, 2641-2653.
[9] Kishida, E.; Okuda, R.; Sone, Y. and Misaki, A. (1988) Fractiona- tion structures and antitumor activities of the polysaccharides of Reishi, the fruiting body of Ganoderma lucidum. Osaka-Shiritsu Daigaku Seikatsukagakubu Kiyo, 35, 1-10.
[10] Konopski, Z.; Smedsrod, B.; Seljelid, R. and Eskeland, T. (1994) A novel immunomodulator soluble aminated ß-1,3-D-glucan: binding characteristics to mouse peritoneal macrophages. Biochem. Biophys. Acta, 1221, 61-65.
[11]Mueller, A.; Raptis, J.; Rice, P.J.; Kalbfleisch, J.H.; Stout, R.D.; Ensley, H.E.; Browder, W. and Williams, D.L. (2000) The influ- ence of glucan polymer structure and solution conformation on binding to (13)-beta-D-glucan receptors in a human monocyte- like cell line. Glycobiology, 10, 339-346.
[12] Battle, J.; Ha, T.Z.; Li, C.F.; Dellabeffa, V.; Rice, P.; Kalbfleisch, J.; Browder, W. and Williams, D. (1998) Ligand binding to the (13)-beta-D-glucan recpetor stimulates NF-kappa B activation, but not apoptosis in U937 cells. Biochem. Biophys. Res. Commun., 249, 499-504.
[13] Muller, A.; Rice, P.J.; Ensley, H.; Coogan, P.S.; Kalbfleisch, J.H.; Kelley, J.L.; Love, E.J.; Portera, C.A.; Ha, T.Z.; Browder, I.W. and Williams, D.L. (1996) Receptor binding and internalization of a water-soluble (13)-beta-D-glucan biologic response modifier in two monocyte macrophage cell lines. J. Immunol., 156, 3418-3425.
[14] Zhong, L.; Jiang, D.Z. and Wang, Q.R. (1999) Effects of Ganoderma lucidum (Leyss ex Fr) Karst compound on the proliferation and differentiation of K562 leukemic cells. J. Hunan Med. Univ., ,24, 521-524.
[15]Mizushina, Y.; Hanashima, L.; Yamaguchi, T.; Takemura, M.; Sugawara, F.; Saneyoshi, M.; Matsukage, A.; Yoshida, S. and Sakaguchi, K. (1998) A mushroom fruiting body-inducing sub- stance inhibits activities of replicative DNA polymerases. Biochem. Biophys. Res. Commun., 249, 17-22.
[16]Mizushina, Y.; Watanabe, I.; Togashi, H.; Hanashima, L.; Takemura, M.; Ohta, K.; Sugawara, F.; Koshino, H.; Esumi, Y.; Uzawa, J.; Matsukage, A.; Yoshida, S. and Sakaguchi, K. (1998) An ergos- terol peroxide, a natural product that selectively enhances the in- hibitory effect of linoleic acid on DNA polymerase beta. Biol. Pharm. Bull., 21, 444-448.
[17]Lee, S.; Park, S.; Oh, J.W. and Yang, C.H. (1998) Natural inhibi- tors for protein prenyltransferase. Planta Medica, 64, 303-308.
[18]Mohammed, A.; Adelaiye, A.B.; Abubakar, M.S. and Abdurahman, E.M. (2007) Effects of aqueous extract of Ganoderma lucidum on blood glucose levels of normoglycemic and alloxaninduced dia- betic wistar rats. J. Med. Plants Res., 1(2), 34-37.
[19]Gao, Y.; Lan, J.; Dai, X.; Ye, J. and Zhou, S.H. (2004) A phase I/II study of Ling Zhi mushroom Ganoderma lucidum. (W. Curt.: Fr.) Lloyd (Aphyllophoromycetideae) extract in patients with type II diabetes mellitus. Int. J. Med. Mushrooms, 6 (1), 33-39.
