Medicinal fungi

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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.

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History[edit]

Although fungal 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]

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[edit]

Cancer[edit]

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

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

11,11'-Dideoxyverticillin A, an isolate of marine Penicillium, was used to create dozens of semi-synthetic anticancer compounds.^[8] 11,11'-Dideoxyverticillin A, andrastin A, barceloneic acid A, and barceloneic acid B, are farnesyl transferase inhibitors that can be made byPenicillium.^[9] 3-O-Methylfunicone, anicequol, duclauxin, and rubratoxin B, are anticancer/cytotoxic metabolites of Penicillium.

Penicillium is a potential source of the leukemia medicine asparaginase.^[10]

Some countries have approved Beta-glucan fungal extracts lentinan, polysaccharide-K, and polysaccharide peptide as immunologic adjuvants.^[11] There is some evidence of this use having effectiveness 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".^[12] According to Cancer Research UK, "there is currently no evidence that any type of mushroom or mushroom extract can prevent or cure cancer".^[13]

Anti bacterial agents (antibiotics)[edit]

Alexander Fleming led the way to the beta-lactam antibiotics with the Penicillium mould 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[edit]

Statins are an important class of cholesterol-lowering drugs; the first generation of statins were derived from fungi.^[14]

The red yeast rice fungus,Monascus purpureus, can synthesize 3 statins.

The Pravastatin precursor mevastatin can be extracted from Penicillium. Lovastatin, the first commercial statin, was extracted from a fermentation broth of Aspergillus terreus.^[14] Industrial production is now capable of producing 70 mg lovastatin per kilogram of substrate.^[15] The red yeast rice fungus, Monascus purpureus, can synthesize lovastatin, mevastatin, and the simvastatin precursormonacolin J. Zaragozic acids were isolated from ascomycota. Nicotinamide riboside, a cholesterol biosynthesis inhibitor, is made bySaccharomyces cerevisiae.

Other compounds include Simvastatin, a semi-synthetic derivative of Lovastatin.^[14]

Antifungals[edit]

Griseofulvin, caspofungin, strobilurin, azoxystrobin, micafungin, and echinocandins, are all extracted from fungi. Anidulafungin is a derivative of an Aspergillus metabolite.

Immunosuppressants[edit]

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.^[16] Other compounds include mizoribine.

Malaria[edit]

Codinaeopsin, efrapeptins, zervamicins, and antiamoebin,^[17] are made by fungi.

Diabetes[edit]

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.^[18] Aspergillusol A is an alpha-glucosidase inhibitor made by Aspergillus. Sclerotiorin is an aldose reductase inhibitor made by Penicillium.

Psychotropic effects[edit]

A number of fungi have well documented psychotropic effects, some of them severe and associated with sometimes acute and life-threatening side-effects.^[19] Well known amongst these is Agaricus muscarius, 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.^[20]

Psychotropic compounds created from ergot alkaloids also include cafergot, 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 have been induced to produce ergot alkaloids including species of Aspergillus and Penicillium.

Vitamins[edit]

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).^[21]

Phytase[edit]

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[edit]

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.^[22]^[23] Research and small clinical studies demonstrated A. subrufescens extracts have antihyperglycemic and anticancer activities.^[24]^[25]^[26]^[27] 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.^[28]

Cordyceps sinensis is an entomopathogenic fungi collected on the Tibetan Plateau. The immunosuppressant ciclosporin was originally isolated from Cordyceps subsessilis. Theadenosine analog cordycepin was originally isolated from Cordyceps. Other Cordyceps isolates include, cordymin, cordycepsidone, and cordyheptapeptide.^[29] 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. ^[30]

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.^[11]

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

Ustilago maydis (Mexican truffle, huitlacoche, corn fungus) synthesises ustilagine and ustilagic acid.^[31]

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 asganoderic acids.^[32]

Hydnellum peckii has yielded Atromentin, an anticoagulant isolated from the mycorrhiza.^[33]^[34]

Schizophyllum commune (Split gill) has yielded Schizophyllan (SPG, sizofiran, sonifilan) which has been researched clinically for anticancer activity.^[35] 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.^{[citation needed]}

Yeasts[edit]

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.^[36] 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.