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===Laccases=== ===Laccases===
-''Laccases'' belong to a large family of multicopper containing enzymes. They are mainly found in Fungi and some high order plants. First explained in 1883 makes it one of the oldest known enzymes. Their wide range of activities comes from their Electron Transfer abilities, they are best known for their importance in the delignification process of white rot fungi. Their diverse range of functions specially in pathogenic Fungi make them an ideal enzyme to be studied in order to envestigate the mechanism of which a pathogenic Fungi behaves one inside its host environment. Another use for Laccases is role in Drug Analysis. A new enzymatic method based on laccase has been developed to distinguish morphine from codeine simultaneously in drug samples, employing the enzyme's oxidizing abilities. Laccase is able to oxidize morphine but not codeine. This method is proven to be fast and efficient which makes it quite useful in the massive industry pain killers. <ref>Mayera, Alfred M., and Richard C. Staples. "Laccase: new functions for an old enzyme." 60.6 (2002): 551-65.</ref>+''Laccases'' belong to a large family of multicopper containing enzymes. They are mainly found in Fungi and some high order plants. First explained in 1883 makes it one of the oldest known enzymes. Their wide range of activities comes from their Electron Transfer abilities, they are best known for their importance in the delignification process of white rot fungi. Their diverse range of functions specially in pathogenic Fungi make them an ideal enzyme to be studied in order to envestigate the mechanism of which a pathogenic Fungi behaves one inside its host environment. Another use for Laccases is role in Drug Analysis. A new enzymatic method based on laccase has been developed to distinguish morphine from codeine simultaneously in drug samples, employing the enzyme's oxidizing abilities. Laccase is able to oxidize morphine but not codeine. This method is proven to be fast and efficient which makes it quite useful in the massive industry of pain killers. <ref>Mayera, Alfred M., and Richard C. Staples. "Laccase: new functions for an old enzyme." 60.6 (2002): 551-65.</ref>
===Griseofulvin=== ===Griseofulvin===

Revision as of 17:25, 21 March 2013

Contents

Introduction

Fungal Pharmaceuticals

Over the past century fungi have been found to be extremely useful organisms in biotechnology. Fungi have so many unique complex molecules and yet many of its biologically active compounds have been discovered and used in the field of medicine. The role of fungi was established very early in history. During the beginning of civilization yeast has been used in the making of bread and alcohol. In more modern times the discovery of penicillin began the development of a new approach to microbial diseases in humans. Fungi and their metabolites have been immensely important in medicine and pharmaceutics. Since the discovery of penicillin by Alexander Fleming in 1928, there has been an increasing number of investigations seeking to exploit fungal metabolic pathways for potential novel drugs. In the following years, important antimicrobial pharmaceuticals such as Griseofulvin (derived from Penicillium griseofulvum) and Cephalosporin (Acremonium) were discovered [1]. The importance of fungi is being expanded way beyond its capacity to transform and protect.

History

Ever since the 18th and 19th century fungi in pharmaceuticals have a been vigorously studied. There are over 200 different fungi's, however only 74% are used in antimicrobial activity. Basidiospores, have a long history of medical uses. The tendor polypore,Fomes Fomentarius, was used in hemostatic dressing and bandages. Dioscorisdes- a Greek physician discovered the use of Fomitopsis(Polyporus) officinalis that was used to treat tuberculosis. That very same polypore was found in the body of a 5300 year old Ice-Man. SInce bacteria were very successful organisms that are widespread and adaptable something needed to be done. Life for humans was not easy and the development of penicillium was a tremendous breakthrough. Penicillin production was triumph in both scientific and technological terms.

It was in the year 1928, that Penicillium- most widely used fungi was discovered by accident at the St.Mary's Hospital in London by Alexander Fleming. Mr.Fleming left culture dishes of the pathogenic bacterium,Staphylococcus aureus on his work bench and upon his returned from a brief holiday, to his surprise a fungus colony had been found. Fleming identified the contaminating fungus-Penicillin. During the 1930's he continued to study the fungus but was unsuccessful at purifying and stabilizing it. However, he did not let them discourage him for he knew of the potential that penicillin could have both on the clinical and large scale.

Besides Alexander there were other "founding fathers" involved in the discovering and potential of penicillium. In 1940, Howard Flowery and Ernst Chain conducted a survey to show effective penicillin is in chemotherapeutic properties. In 1941, development of penicillin use in fermentation was discovered in the USA. Dorothy Hodgkin and Barbara Law established the β-lactam structure of penicillin by the use of X-ray crystallography. in 1956, John Sheehan used chemical synthesis to produced penicillin.



Fungal products found in pharmaceuticals

Taxol

Chemical structure of taxol.
Chemical structure of taxol.

Originally isolated in 1971, Taxol, or Paclitaxe as it is now referred to as, was found to have anti-tumour properties and is an important agent in chemotherapy [2]. It helps prevent the growth of tumours by disrupting microtubule formation, preventing proper cell division from occurring[3]. Taxol was first harvested from yew trees, Taxus brevifolia, from the inner bark, however, the demand caused a marked rise in price. As a result, alternative means for producing taxol were explored; one being production of taxol from microbial cultures. The fungi, Pestalotiopsis microspora, collected from Taxus wallachiana, was found to produce taxol in culture [4]. P. microspora was able to produce 60-70 μg of taxol per litre of fungal culture. Its production peaked at roughly the 3 week mark and declined drastically at 5 weeks. Although the amount of taxol produced was one order of magnitude less than that harvested from T. brevifolia, the accessibly of growing a fungal culture in terms of space and time far exceeds that of harvesting from yew trees.


Biochemical pathway of cholesterol synthesis and effect of statins on pathway.
Biochemical pathway of cholesterol synthesis and effect of statins on pathway.

Statins

Statins are a group of secondary metabolites that are used to lower low-density lipoprotein (LDL) cholesterol. It is the most widely used pharmaceutical drug in the world. This ability is very important for combating coronary disease since two-thirds of the total cholesterol in an individual is synthesised in the body, with the other third from dietary sources[5]. Therefore, suppressing de novo synthesis of cholesterol is a significant method to lower cholesterol levels in an individual with hypercholesterolemia. Mevastatin was the first statin to be isolated in 1976 from Penicillium citrinum and P. brevicompactum. These compounds work by inhibiting 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, which is the rate-limiting enzyme for cholesterol synthesis[6]. Lovastatin was the first of these compounds to be approved for medical use in 1980. Since then, other statins that have been isolated or synthesized including fluvastatin, pravastatin and simvastatin, which all act in similar fashions to lower LDL cholesterol [7]. These pharmaceutical products have been extremely important to pharmaceutical companies, especially one statin derivative, atorvastatin, generating sales revenues of roughly 7 billion USD in 2005[8].




Cryptocandin

Some diseases that humans are susceptible to are those from fungi and can cause serious problems, especially since infections tend to target immunocompromised patients. To combat this, fungi themselves have been turned to as select strains produce antifungal agents that can be utilized against pathogenic fungi. One such agent is cryptocandin which was isolated from Cryptosporiopsis quercina[9]. This compound works most effectively against Trichophyton which a common fungi in skin infections such as athlete's foot and ringworm. [10]. Cryptocandin was also found to be as effective as amphotericin B, a common antifungal agent, at inhibiting Histoplasma capsulatum and Candida albicans, which can cause pulmonary and oral infection, respectively. [10]. Since it effects Trichophyton most heavily, cryptocandin is an effective antifungal agent for skin and nails diseases.


Cephalosporin

Chemical structure comparisons between Cephalosporin and Penicillin.
Chemical structure comparisons between Cephalosporin and Penicillin.


Cephalosporin was first discovered from Acremonium chrysogenum in 1953. Cephalosporin compounds were first isolated from cultures by an Italian scientist Giuseppe Brotzu in Sardinia in 1948. This fungal species served great purpose in the production of several antibiotics including Cephalosporin C, Cephalosporin P1-P5 and Penicillin N. This species of Cephalosporin is one of the most widely used and prescribed antibiotics which contains 29% of the antibiotic market [11]. The structure of Cephalosporin as well as its mode of action, is very similar to that of Penicillin such as their beta-lactam ring which contribute to their bactericidal action of kiiling bacteria. Cephalosporin is very valuable due to their low toxicity and their broad spectrum of action against various diseases. This species will affect bacterial growth by inhibiting cell wall synthesis in gram-positive and negative bacteria [12]. The mode of action as stated previously of Cephalosporin are bactericidal agents. This species similar to Penicillin will disrupt the synthesis of the peptidoglycan layer of the bacterial cell walls, which in turn, causes the walls to break down and eventually the cell to die [13].

Mushrooms

Mushrooms have a high medical impact for pharmaceutical products[14]. Due to mushrooms having a high tolerance with the chemotherapy and radiotherapy the products obtained from it are used for cancer therapies. Mushrooms fruiting bodies and their extracts are very effective and is an economically option due to the faster growth of the fruiting body. There are few prominent mushrooms having pharmacological properties and they are: Agaricus brasiliensis, Ganoderma lucid,lentinula edodes'' and Grifola frondosa. Other biologically active substances found in mushroom includes immunosuppressants such as,nematicide,antimicrobial,antiviral and hypocholesterolemic agents. Black tea fermented with dabaryomyces hansenii contains lots of major vitamins such as A,B1,B2,B12 and C. It also results in reduction of caffeine and tannins in significant amount.

Laccases

Laccases belong to a large family of multicopper containing enzymes. They are mainly found in Fungi and some high order plants. First explained in 1883 makes it one of the oldest known enzymes. Their wide range of activities comes from their Electron Transfer abilities, they are best known for their importance in the delignification process of white rot fungi. Their diverse range of functions specially in pathogenic Fungi make them an ideal enzyme to be studied in order to envestigate the mechanism of which a pathogenic Fungi behaves one inside its host environment. Another use for Laccases is role in Drug Analysis. A new enzymatic method based on laccase has been developed to distinguish morphine from codeine simultaneously in drug samples, employing the enzyme's oxidizing abilities. Laccase is able to oxidize morphine but not codeine. This method is proven to be fast and efficient which makes it quite useful in the massive industry of pain killers. [15]

Griseofulvin

Griseofulvin.
Griseofulvin.


Griseofulvin was first discovered in the early 1960's and was the first orally effective antibiotic that was used for dermatophytosis management and later broad-spectrum agents arrived. It is the only broadly useful antifungal agent and it's original source was Penicillium griseofulvin.This commercial production of Griseofulvin was derived from a much mutated strain of P. patulum. It is used for the treatment of dermatophytes,as it accumulates in the hair and skin following topical application.Furthermore, it is the antibiotic is the only antibiotic that is effective against fungal infections of skin, athlete's foot, and ringworm. Griseofulvin is an antifungal antibiotic that will fight against infections caused by fungus. This antifungal drug inhibits mitosis in fungal cells and weakly in mammalian cells by afecting mitotic spindle microtubule function [16]. Analysis of Griseofulvin has shown to have the ability to inhibit cell proliferation and mitosis as well as, the inhibition of cell-cycle progression at prometaphase/anaphase of mitosis [17]. Griseofulvin only inhibits fungal growth but does not kill fungi, this antifungal agent affects a wide range of fungi but is limited to those with chitinous cell walls [18].

Cyclosporin

Tolypocladium inflatum.
Tolypocladium inflatum.
Cyclosporin's mode of action.
Cyclosporin's mode of action.


Cyclosporin is a drug obtained from a type of soil fungus found in Norway called Tolypocladium inflatum. Jean-Francois Borel, a microbiologist working for a labratory in Switzerland, discovered Cyclosporin in 1969 when he was vacationing in Norway [19]. This drug is fairly new and was brought to North America by the U.S. Food and Drug Administration in 1983 [20]. Cyclosporin is one of the most commonly used immunosuppressant drug in organ transplants. Its function is to suppress the action of certain cells in the body's immune system that can reject the transplanted organ, as well as, let the bulk of the body's immune system function normally and fight general infection [21]. Cyclosporin was found to inhibit the activity of white blood cells, the specific part of the immune system that starts the process of detecting and attacking foreign invaders. This prevents the attacks of cells called T-cells.




Cilofungin

Cilofungin is the first clinically applied member of antifungal drugs which was derived from a fungus in the genus Aspergillus [22]. This antibiotic is specifically produced to treat and effect Candida albicans. Cilofungin is a lipopeptide antifungal agent active against several species of Candida, and acts as a beta glucan synthase inhibitor [23]. This antibiotic utilizes phagocytosis and intracellular killing of Candida albicans blastospores by glass-adherent human neutrophils as well as interfering with an invading fungus' ability to synthesize the cell wall [24]. However, this drug was discontinued due to the incidence of metabolic acidosis.


Processes Involved

Penicillium chrysogenum

Penicillium chrysogenum is a common species used in the production of penicillin because it has an improved product accumulation and improved cycles of mutations. The amino acids inolved in producing penicillin are cysteine, and valine and the third compound involved is aminoadipic acid. This makes penicillin a tripeptide. The primary enzyme involved in penicillin biosynthesis is ACV-synthetase, which helpts to form the tripeptide ACV from the three fundamental amino acids. The second step in the biosynthesis process is the formation of β-lactam ring from ACV by the enzyme isopenicillin-N synthetase. It is important to note that oxygen is involved in the ring closure process but is not incorporated into the ring structure itself. The final step includes adding or exchanging side chains by acyteyl CoA. This is a two-step process which involves, firstly, the release of isopenicillin-N side chain to yield α-aminoadipate and 6-aminopenicillanic acid, and secondly, the addition of the new side chain and release of acetyl CoA. [25].

Terms and Definitions

  • Crystallography: The branch of science concerned with the formation, properties, and structure of crystals.
  • De novo synthesis: Refers to the synthesis of complex molecules from simple molecules such as sugars or amino acids, as opposed to their being recycled after partial degradation.
  • Dermatophytosis: An infection of the skin, hair, or nails caused by a dermatophyte and characterized by redness of the skin, small papular vesicles, fissures, and scaling.
  • Endophytic: Endophytic refers to fungi or bacteria that lives symbiotically with plants without causing any harmful effects to the plant.
  • Hypocholesterolemic agents: Hypocholesterolemia is a condition characterized by very low cholesterol levels without the assistance of medications used to lower cholesterol.
  • Peptidoglycan layer: The dense material consisting of cross-linked polysaccharide chains present in the cell wall of most bacteria.
  • T-cells are a type of lymphocyte that are produced or processed by the thymus gland and actively participating in the immune response.

Notes and References

  1. ↑ Amal, A., Debbab, A., Proksch, P. (2011) Fifty years of drug discovery from fungi. Fungal Diversity, 50: 3-19.
  2. ↑ Wani, M., Taylor, H., Wall, M., Coggon, P., & McPhail, A. (1971). Plant antitumour agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. Journal of the American Chemical Society, 93(9), 2325-2327.
  3. ↑ Horwitz, S. B. (1994). Taxol (paclitaxel): mechanisms of action. Annals of Oncology 5, S3-S6.
  4. ↑ Strobel, G., Yang, X., Sears, J., Kramer, R., Sidhu, R., & Hess, W. (1996). Taxol from Pestalotiopsis microspora, and enndophytic fungus of Taxis wallachiana. Microbiology, 142, 435-440.
  5. ↑ Manzoni, M. & Rollini, M. (2002). Biosynthesis and biotechnological production of statins by filamentous fungi and application of these cholesterol-lowering drugs. Journal of Applied Microbiology and Biotechnology. 58, 555-564.
  6. ↑ Manzoni, M., Bergomi, S., Rollini, M., & Cavazzoni, V. (1999). Production of statins by filamentous fungi. Biotechnology Letters, 21, 253-257.
  7. ↑ Endo, A. (2004). Statins is also used to treat diabetes, aging problems and heart disease. Just like many other medical drugs, too much of statin can be detrimental to ones health. Sideeffects of statins are headache,nausea,weakness, rash and even constipation.The origin of statins. International Congress Series, 1262, 3-8.
  8. ↑ Moorman, P. & Hamilton, R. (2007). Statins and cancer risk: What do we know and where do we go from here? Epidemiology, 18, 194-196
  9. ↑ Strobel, G., Daisy, B., Castillo, U. & Harper, J. (2004). Natural products from endophytic microorganisms. Journal of Natural Products. 67(2), 257-268.
  10. ↑ 10.0 10.1 Strobel, G., Miller, V., Martinez-Miller, C., Condron, M., Teplow, D. & Hess, W. (1999). Cryptocandin, a potent antimycotic from the endophytic fungus Cryptosporiopsis cf. quercina. Microbiology. 145, 1919-1936.
  11. ↑ Smith,A. Bailey, P. (1985). Production of Cephalosporin by fermentation. Glaxo Group Limited, 631-639
  12. ↑ Thompson, R L; Wright, A J. (February 1983). Cephalosporin antibiotics. National Library of Medicine;; 2 79-87
  13. ↑ O'Callaghan, C H; Sykes, R B; Staniforth, S E. (August 1976). National Library of Medicine. Antimicrobial agents and chemotherapy, 2: 245-248
  14. ↑ Wasser,S.P., & Weiss,A.L.(1999).Medicinal properties of substances occurring in higher Basidiomycetes mushroom:International Journal of Medicinal Mushrooms,1,31-62
  15. ↑ Mayera, Alfred M., and Richard C. Staples. "Laccase: new functions for an old enzyme." 60.6 (2002): 551-65.
  16. ↑ Panda, D. Rathinasamy, K. Santra, M. Wilson, L. (2005). Kinetic suppression of microtubule dynamic instability by griseofulvin. University of California, Santa Barbara, CA, 102, 9878-9883
  17. ↑ Panda, D. Rathinasamy, K. Santra, M. Wilson, L. (2005). Kinetic suppression of microtubule dynamic instability by griseofulvin. University of California, Santa Barbara, CA, 102, 9878-9883
  18. ↑ Haofan, J. Atsuya, Y. Shinya, M. Pinting, Y. Limin, H. (2008). Griseofulvin, an oral antifungal agent, suppresses hepatitis C virus replication in vitro. Hepatology Reseach, 38,9 909-918
  19. ↑ Henry,T. (1998). The discovery and development of Cyclosporin. Wolfson college, Cambridge, 12, 20-30.
  20. ↑ Henry,T. (1998). The discovery and development of Cyclosporin. Wolfson college, Cambridge, 12, 20-30.
  21. ↑ Kahan,B.(2003). Individuality: the barrier to optimal immunosuppression. Natures Review Immunology, 3, 831-838.
  22. ↑ Ko,Y. Ludescher,R. Frost,D. Wasserman,B. (1994). Use of cilofungin as direct fluorescent probe for monitoring antifungal drug-membrane interaction. Antimicrob Agents Chemother, 38, 1378-1385.
  23. ↑ Meshulam T, Levitz SM, Diamond RD, Sugar AM. (1989). Effect of cilofungin (LY121019), a fungal cell wall synthesis inhibitor, on interactions of 50 strains of Candida albicans with human neutrophils. US National Library of Medicine, National Institute of Health, 24, 741-745.
  24. ↑ Richardson,M. Scott,G. Shankland,G. (1992). Effect of cilofungin on phagocytosis and intracellular killing of Candida albicans by human neutrophils. European Journal of Clinical Microbiologyand Infectious Diseases, 11, 22-36.
  25. ↑ Moore,D., Robson,G.,& Trinci,T.(2013). 21st century guidebook to fungi. Cambridge Pr.

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