Medicinal fungi

Medicinal fungi are those fungi which produce medically significant metabolites or can be induced to produce such metabolites using biotechnology. The range of medically active compounds that have been identified include antibiotics, anti-cancer drugs, cholesterol inhibitors, psychotropic drugs, immunosuppressants and even fungicides. Although initial discoveries centred on simple moulds of the type that cause spoilage of food, later work identified useful compounds across a wide range of fungi.

History

Although fungi products have been used in traditional and folk medicines, probably since pre-history, the ability to identify beneficial properties and then extract the active ingredient started with the discovery of penicillin by Alexander Fleming in 1928. Since that time, many additional antibiotics have been discovered and the potential for fungi to synthesize biologically active molecules useful in a wide range of clinical therapies has been extensively exploited.

Pharmacological research has now isolated antifungal, antiviral, and antiprotozoan, isolates from fungi.[1]

The fungus with probably the longest record of medicinal use, Ganoderma lucidum, is known in Chinese as líng zhī ("spirit plant"), and in Japanese as mannentake ("10,000-year mushroom"). In ancient Japan, Grifola frondosa was worth its weight in silver, although no significant therapeutic benefits have been demonstrated in humans.[2]

Studies have shown another species of Ganoderma genus, Ganoderma applanatum, contains compounds with anti-tumor and anti-fibrotic properties.

Inonotus obliquus was used in Russia as early as the 16th century, and it featured in Alexandr Solzhenitsyn's 1967 novel Cancer Ward.[3]

Lichens have also been used in many folk medicine traditions to treat a wide range of ailments.[4] Research has demonstrated a range of therapeutically significant compounds in a range of lichen species[4] but none are currently believed to be in use in mainstream medicine.

Applications

Cancer

40x brightfield microscopy of Pestalotia/Pestalotiopsis spores. Note the appendages. Some strains (Pestalotiopsis pauciseta) produce taxol.[5][6]

Paclitaxel is synthesised using Penicillium raistrickii and plant cell fermentation. Fungi can synthesize other mitotic inhibitors including vinblastine, vincristine, podophyllotoxin, griseofulvin, aurantiamine, oxaline, and neoxaline.[7][8]

11,11'-Dideoxyverticillin A, an isolate of marine Penicillium, was used to create dozens of semi-synthetic anticancer compounds.[9] 11,11'-Dideoxyverticillin A, andrastin A, barceloneic acid A, and barceloneic acid B, are farnesyl transferase inhibitors that can be made by Penicillium.[10] 3-O-Methylfunicone, anicequol, duclauxin, and rubratoxin B, are anticancer/cytotoxic metabolites of Penicillium.

Penicillium is a potential source of the leukemia medicine asparaginase.[11] The endophytic fungus Aspergillus flavus can produce a potent anticancer metabolite called solamargine.[12]

Some countries have approved Beta-glucan fungal extracts lentinan, polysaccharide-K, and polysaccharide peptide as immunologic adjuvants.[13] Evidence suggests this use as effective in prolonging and improving the quality of life for patients with certain cancers, although the Memorial Sloan-Kettering Cancer Center observes that "well designed, large scale studies are needed to establish the role of lentinan as a useful adjunct to cancer treatment".[14] According to Cancer Research UK, "there is currently no evidence that any type of mushroom or mushroom extract can prevent or cure cancer".[15] Fungal metabolites such as ergosterol, clavilactones, and triterpenoids are efficient Cdk inhibitors that lead to G1/S or G2/M arrest of cancer cells. Other metabolites, such as panepoxydone, are inhibitors of NF-κB. Fucose and mannose fragments of fungal cell wall are antagonists of VEGF-receptors [16]

Antibacterial agents (antibiotics)

Alexander Fleming led the way to the beta-lactam antibiotics with the Penicillium mold and penicillin. Subsequent discoveries included alamethicin, aphidicolin, brefeldin A, Cephalosporin, cerulenin, citromycin, eupenifeldin, fumagillin, fusafungine, fusidic acid, itaconic acid, MT81, nigrosporin B, usnic acid, verrucarin A, vermiculine and many others.

Ling Zhi-8, an immunomodulatory protein isolated from Ganoderma lucidum

Antibiotics retapamulin, tiamulin, and valnemulin are derivatives of the fungal metabolite pleuromutilin. Plectasin, austrocortilutein, austrocortirubin, coprinol, oudemansin A, strobilurin, illudin, pterulone, and sparassol are antibiotics isolated from basidiomycete species.

Cholesterol biosynthesis inhibitors

Statins are an important class of cholesterol-lowering drugs; the first generation of statins were derived from fungi.[17]

The red yeast rice fungus, Monascus purpureus, can synthesize three statins.

The Pravastatin precursor mevastatin can be extracted from Penicillium. Lovastatin, the first commercial statin, was extracted from a fermentation broth of Aspergillus terreus.[17] Industrial production is now capable of producing 70 mg lovastatin per kilogram of substrate.[18] The red yeast rice fungus, Monascus purpureus, can synthesize lovastatin, mevastatin, and the simvastatin precursor monacolin J. Zaragozic acids were isolated from ascomycota. Nicotinamide riboside, a cholesterol biosynthesis inhibitor, is made by Saccharomyces cerevisiae.

Other compounds include Simvastatin, a semi-synthetic derivative of Lovastatin.[17]

Antifungals

Some antifungals are derived or extracted from other fungal species. Griseofulvin is derived from a number of Penicillium species, caspofungin is derived from Glarea lozoyensis.[19] Strobilurin, azoxystrobin, micafungin, and echinocandins, are all extracted from fungi. Anidulafungin is a derivative of an Aspergillus metabolite.

Immunosuppressants

Ciclosporin, was discovered in Tolypocladium inflatum. Bredinin was discovered in Eupenicillium brefeldianum. Mycophenolic acid was discovered in Penicillium stoloniferum. Thermophilic fungi were the source of the fingolimod precursor myriocin. Aspergillus synthesizes immunosuppressants gliotoxin and endocrocin. Subglutinols are immunosuppressants isolated from Fusarium subglutinans.[20] Other compounds include mizoribine.

Malaria

Codinaeopsin, efrapeptins, zervamicins, and antiamoebin,[21] are made by fungi.

Diabetes

Many fungal isolates act as DPP-4 inhibitors, alpha-glucosidase inhibitors, and alpha amylase inhibitors in vitro. Ternatin is a fungal isolate that suppresses hyperglycemia.[22] Aspergillusol A is an alpha-glucosidase inhibitor made by Aspergillus. Sclerotiorin is an aldose reductase inhibitor made by Penicillium.

Psychotropic effects

A number of fungi have well documented psychotropic effects, some of them severe and associated with sometimes acute and life-threatening side-effects.[23] Well known amongst these is Amanita muscaria, the fly agaric. More widely used informally are a range of fungi collectively known as "magic mushrooms", which contain psilocybin and psilocin.

The history of bread-making is also peppered with references to deadly ergotism caused by ergot, most commonly Claviceps purpurea, a parasite of cereal crops. A number of therapeutically useful drugs have subsequently been extracted from ergot including ergotamine, pergolide and cabergoline.[24]

Psychotropic compounds created from ergot alkaloids also include dihydroergotamine, methysergide, methylergometrine, hydergine, nicergoline, lisuride, bromocriptine, cabergoline, pergolide. Polyozellus multiplex synthesizes prolyl endopeptidase inhibitors polyozellin, thelephoric acid, kynapcins. Neurotrophic fungal isolates include L-theanine, tricholomalides, scabronines, termitomycesphins. Many fungi synthesize the partial, non-selective, serotonin receptor agonist/analog psilocin.

A number of other fungal species, including species of Aspergillus and Penicillium, have been induced to produce ergot alkaloids.

Vitamins

The photochemistry of Vitamin D biosynthesis

Fungi are one source of vitamin D. Fungi can synthesize vitamins D2 (ergocalciferol), D4 (22-dihydroergocalciferol), and D1 (Lumisterol+D2).[25]

Phytase

Aspergillus niger is used to produce recombinant phytase, an enzyme added to animal feeds to improve absorption of phosphorus.

Edible species with medically significant metabolites

Many edible species have been shown to produce medically significant metabolites. However eating fungi with such properties is most unlikely to result in any medically beneficial effect. Most compounds of interest when used for medical purposes are synthesized on an industrial scale and are packaged and administered in ways that maximise the potential benefit.

Those fungi listed below have been shown to have significant effect as evidenced by human clinical trials published in peer reviewed papers and quoted in secondary sources.

Agaricus subrufescens (Agaricus blazei/brasiliensis, almond mushroom) is a fungus associated with Brazil and Japan.[26][27] Research and small clinical studies demonstrated A. subrufescens extracts have antihyperglycemic and anticancer activities.[28][29][30][31] Brefeldin A and blazein were isolated from A. subrufescens.

Boletus badius has been shown to synthesize theanine which is claimed to have mild psychoactive properties.[32]

Cordyceps sinensis is an entomopathogenic fungi collected on the Tibetan Plateau. The immunosuppressant ciclosporin was originally isolated from Cordyceps subsessilis. The adenosine analog cordycepin was originally isolated from Cordyceps. Other Cordyceps isolates include, cordymin, cordycepsidone, and cordyheptapeptide.[33] CS-4 is commercially sold as C. sinensis, but Cs-4 has recently been confirmed to be a different species from the Cordyceps species used in traditional Chinese medicine. CS-4 is properly known as Paecilomyces hepiali. Hirsutella sinensis is the accepted asexual form of C. sinensis.[34]

Lentinula edodes (Shiitake) has been used as a source of Lentinan, AHCC, and eritadenine. In 1985 Japan approved lentinan as an adjuvant for gastric cancer. Studies there indicate prolonged survival and improved quality of life when gastric cancer patients with unresectable or recurrent diseases are treated with lentinan in combination with other chemotherapies.[13]

Morchella esculenta (Morel) contains the amino acid, cis-3-amino-L-proline.

Ustilago maydis (Mexican truffle, huitlacoche, corn fungus) synthesises ustilagine and ustilagic acid.[35]

Ganoderma lucidum (Ling zhi, mannentake, reishi) has a long record of medicinal use. It contains p-hydroxybenzoic acid, cinnamic acid, and lanostane-type triterpenoids such as ganoderic acids.[36]

Hydnellum peckii has yielded atromentin, an anticoagulant isolated from the mycorrhiza.[37][38]

Schizophyllum commune (Split gill) has yielded schizophyllan (SPG, sizofiran, sonifilan) which has been researched clinically for anticancer activity.[39] Hydrophobins were originally isolated from S. commune. A chemically analogous polysaccharide, scleroglucan, is an isolate of Sclerotium rolfsii.

Trametes versicolor (Coriolus versicolor, yun zhi, kawaratake, turkey tail) have produced protein-bound polysaccharides PSK and PSP (polysaccharopeptide) from different mycelia strains. In Japan, PSK is a gastric cancer adjuvant. Japan began using PSK in 1977, while China began using PSP in 1987.[40]

Yeasts

Saccharomyces is used industrially to produce the amino acid lysine, as well as recombinant proteins insulin and Hepatitis B surface antigen. Transgenic yeast are used to produce artemisinin, as well as a number of insulin analogs.[41] Candida is used industrially to produce vitamins ascorbic acid and riboflavin. Pichia is used to produce the amino acid tryptophan and the vitamin pyridoxine. Rhodotorula is used to produce the amino acid phenylalanine. Moniliella is used industrially to produce the sugar alcohol erythritol.

See also

References

  1. ↑ Engler M, Anke T, Sterner O (1998). "Production of antibiotics by Collybia nivalis, Omphalotus olearis, a Favolaschia and a Pterula species on natural substrates.". Z Naturforsch C. 53 (5–6): 318–24. PMID 9705612.
  2. ↑ "Maitake Mushroom". Complementary and Alternative Medicine : Diet and Nutrition. American Cancer Society. 2008. Retrieved 2011-03-08.
  3. ↑ Zheng, Weifa; Miao, Kangjie; Liu, Yubing; Zhao, Yanxia; Zhang, Meimei; Pan, Shenyuan; Dai, Yucheng (2010). "Chemical diversity of biologically active metabolites in the sclerotia of Inonotus obliquus and submerged culture strategies for up-regulating their production". Applied Microbiology and Biotechnology. 87 (4): 1237–54. PMID 20532760. doi:10.1007/s00253-010-2682-4.
  4. 1 2 S Malhotra, R Subban, A Singh (2007). "Lichens – Role in Traditional Medicine and Drug Discovery". The Internet Journal of Alternative Medicine. 5 (2). doi:10.5580/3d9.
  5. ↑ Bemani E, Ghanati F, Rezaei A, Jamshidi M (2013). "Effect of phenylalanine on Taxol production and antioxidant activity of extracts of suspension-cultured hazel (Corylus avellana L.) cells.". J Nat Med. 67 (3): 446–51. PMID 22847380. doi:10.1007/s11418-012-0696-1.
  6. ↑ Gangadevi V, Murugan M, Muthumary J (2008). "Taxol determination from Pestalotiopsis pauciseta, a fungal endophyte of a medicinal plant.". Sheng Wu Gong Cheng Xue Bao. 24 (8): 1433–8. PMID 18998547. doi:10.1016/s1872-2075(08)60065-5.
  7. ↑ Rosaria Nicoletti; Maria Letizia Ciavatta; Elisabetta Buommino; Maria Antonietta Tufano (2008). "Antitumor extrolites produced by Penicillium species" (PDF). International Journal of Biomedical and Pharmaceutical Sciences. 2 (1): 1–23. Archived from the original (PDF) on 26 December 2014. Retrieved 26 August 2016.
  8. ↑ "Antitumor extrolites produced by Penicillium species" (PDF). Archived from the original (PDF) on December 26, 2014. Retrieved August 17, 2014.
  9. ↑ "Research update: Chemists find help from nature in fighting cancer - MIT News Office". Web.mit.edu. 2013-02-27. Retrieved 2013-12-17.
  10. ↑ Overy DP, Larsen TO, Dalsgaard PW, Frydenvang K, Phipps R, Munro MH, et al. (2005). "Andrastin A and barceloneic acid metabolites, protein farnesyl transferase inhibitors from Penicillium albocoremium: chemotaxonomic significance and pathological implications.". Mycol Res. 109 (Pt 11): 1243–9. PMID 16279417. doi:10.1017/S0953756205003734.
  11. ↑ Shrivastava A, Khan AA, Shrivastav A, Jain SK, Singhal PK (2012). "Kinetic studies of L-asparaginase from Penicillium digitatum.". Prep Biochem Biotechnol. 42 (6): 574–81. PMID 23030468. doi:10.1080/10826068.2012.672943.
  12. ↑ El-Hawary, S.s.; Mohammed, R.; AbouZid, S.f.; Bakeer, W.; Ebel, R.; Sayed, A.m.; Rateb, M.e. (2016-04-01). "Solamargine production by a fungal endophyte of Solanum nigrum". Journal of Applied Microbiology. 120 (4): 900–911. ISSN 1365-2672. doi:10.1111/jam.13077.
  13. 1 2 Ina, K; Kataoka, T; Ando, T (2013). "The use of lentinan for treating gastric cancer". Anti-cancer agents in medicinal chemistry. 13 (5): 681–8. PMC 3664515 Freely accessible. PMID 23092289. doi:10.2174/1871520611313050002.
  14. ↑ "Lentinan". Memorial Sloan-Kettering Cancer Center. 27 February 2013. Retrieved 26 August 2016.
  15. ↑ "Mushrooms and cancer". Cancer Research UK. Retrieved 26 August 2016.
  16. ↑ Zmitrovich IV (2015). "Anti-cancer metabolites of Basidiomycota and their molecular targets. A review." (PDF). Vestnik Permskogo Universiteta. Biologiya. 2015 (3): 264–86.
  17. 1 2 3 Tolbert, Jonathan A. (2003). "Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors". Nature Reviews Drug Discovery. 2: 517–526. PMID 12815379. doi:10.1038/nrd1112.
  18. ↑ Jahromi, M.F.; Liang, J.B.; Ho, Y.W.; Mohamad R.; Goh, Y.M.; Shokryazdan, P. (2012). "Lovastatin production by Aspergillus terreus using agro-biomass as substrate in solid state fermentation.". J Biomed Biotechnol. 2012: 196264. PMC 3478940 Freely accessible. PMID 23118499. doi:10.1155/2012/196264.
  19. ↑ Richardson, Malcolm D.; Warnock, David W. Fungal Infection Diagnosis and Management. ISBN 1-4051-15785.
  20. ↑ Kim H, Baker JB, Park Y, Park HB, DeArmond PD, Kim SH, et al. (2010). "Total synthesis, assignment of the absolute stereochemistry, and structure-activity relationship studies of subglutinols A and B.". Chem Asian J. 5 (8): 1902–10. PMID 20564278. doi:10.1002/asia.201000147.
  21. ↑ Nagaraj, G.; Uma, MV.; Shivayogi, MS.; Balaram, H. (January 2001). "Antimalarial activities of peptide antibiotics isolated from fungi". Antimicrobial Agents and Chemotherapy. NCBI. 45 (1): 145–9. PMC 90252 Freely accessible. PMID 11120957. doi:10.1128/aac.45.1.145-149.2001.
  22. ↑ Lo, HC; Wasser, SP (2011). "Medicinal mushrooms for glycemic control in diabetes mellitus: History, current status, future perspectives, and unsolved problems (review)". International journal of medicinal mushrooms. 13 (5): 401–26. PMID 22324407. doi:10.1615/intjmedmushr.v13.i5.10.
  23. ↑ Hoegberg LC; Larsen L; Sonne L; Bang J; Skanning PG (2008). "Three cases of Amanita muscaria ingestion in children: two severe courses [abstract]". Clinical Toxicology. 46 (5): 407–8. PMID 18568796. doi:10.1080/15563650802071703.
  24. ↑ Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E (January 2007). "Dopamine agonists and the risk of cardiac-valve regurgitation". The New England Journal of Medicine. 356 (1): 29–38. PMID 17202453. doi:10.1056/NEJMoa062222.
  25. ↑ Keegan RJ, Lu Z, Bogusz JM, Williams JE, Holick MF (Jan 1, 2013). "Photobiology of vitamin D in mushrooms and its bioavailability in humans". Dermatoendocrinol. 5 (1): 165–76. PMC 3897585 Freely accessible. PMID 24494050. doi:10.4161/derm.23321.
  26. ↑ Takaku, Takeshi; Kimura, Yoshiyuki; Okuda, Hiromichi (May 2001). "Isolation of an antitumor compound from Agaricus blazei Murill and its mechanism of action". The Journal of Nutrition. 131 (5): 1409–13. PMID 11340091.
  27. ↑ Hyodo, I.; Amano, N; Eguchi, K; Narabayashi, M; Imanishi, J; Hirai, M; Nakano, T; Takashima, S (2004). "Nationwide Survey on Complementary and Alternative Medicine in Cancer Patients in Japan". Journal of Clinical Oncology. 23 (12): 2645–54. PMID 15728227. doi:10.1200/JCO.2005.04.126.
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  29. ↑ Ahn, W.-S.; Kim, D.-J.; Chae, G.-T.; Lee, J.-M.; Bae, S.-M.; Sin, J.-I.; Kim, Y.-W.; Namkoong, S.-E.; Lee, I. P. (2004). "Natural killer cell activity and quality of life were improved by consumption of a mushroom extract, Agaricus blazei Murill Kyowa, in gynecological cancer patients undergoing chemotherapy". International Journal of Gynecological Cancer. 14 (4): 589–94. PMID 15304151. doi:10.1111/j.1048-891X.2004.14403.x.
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  32. ↑ "l-theanine". drugs.com. The chemical has also been isolated from the edible mushroomBoletus badius.
  33. ↑ Khan, Md.Asaduzzaman; Tania, Mousumi; Zhang, Dian-Zheng; Chen, Han-Chun (2010). "Cordyceps Mushroom: A Potent Anticancer Nutraceutical". The Open Nutraceuticals Journal. 3: 179–83. doi:10.2174/1876396001003010179.
  34. ↑ Chen, Yue-Qin; Wang, Ning; Qu, Liang-Hu; Li, Tai-Hui; Zhang, Wei-Ming (2001). "Determination of the anamorph of Cordyceps sinensis inferred from the analysis of the ribosomal DNA internal transcribed spacers and 5.8S rDNA". Biochemical Systematics and Ecology. 29 (6): 597–607. ISSN 0305-1978. PMID 11336809. doi:10.1016/S0305-1978(00)00100-9.
  35. ↑ Juárez-Montiel M, Ruiloba de León S, Chávez-Camarillo G, Hernández-Rodríguez C, Villa-Tanaca L (2011). "Huitlacoche (corn smut), caused by the phytopathogenic fungus Ustilago maydis, as a functional food.". Rev Iberoam Micol. 28 (2): 69–73. PMID 21352944. doi:10.1016/j.riam.2011.01.001.
  36. ↑ Liu D, Gong J, Dai W, Kang X, Huang Z, Zhang HM, et al. (2012). "The genome of Ganoderma lucidum provides insights into triterpenes biosynthesis and wood degradation [corrected].". PLoS ONE. 7 (5): e36146. PMC 3342255 Freely accessible. PMID 22567134. doi:10.1371/journal.pone.0036146.
  37. ↑ Khanna, Jatinder M.; Malone, Marvin H.; Euler, Kenneth L.; Brady, Lynn R. (1965). "Atromentin. Anticoagulant from Hydnellum diabolus". Journal of Pharmaceutical Sciences. 54 (7): 1016–20. PMID 5862512. doi:10.1002/jps.2600540714.
  38. ↑ Zheng, Chang-Ji; Sohn, Mi-Jin; Kim, Won-Gon (2006). "Atromentin and Leucomelone, the First Inhibitors Specific to Enoyl-ACP Reductase (FabK) of Streptococcus pneumoniae". The Journal of Antibiotics. 59 (12): 808–12. PMID 17323650. doi:10.1038/ja.2006.108.
  39. ↑ Mantovani G, Bianchi A, Curreli L, Ghiani M, Astara G, Lampis B, et al. (1997). "Clinical and immunological evaluation of schizophyllan (SPG) in combination with standard chemotherapy in patients with head and neck squamous cell carcinoma.". Int J Oncol. 10 (1): 213–21. PMID 21533366. doi:10.3892/ijo.10.1.213.
  40. ↑ Piotrowski, J.; Jędrzejewski, T.; Kozak, W. (21 January 2015). "Immunomodulatory and antitumor properties of polysaccharide peptide (PSP)". Postepy Hig Med Dosw (Online). 69: 91–97. PMID 25614677. doi:10.5604/17322693.1137086.
  41. ↑ Mark Peplow. "Sanofi launches malaria drug production | Chemistry World". Rsc.org. Retrieved 2013-12-17.
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