Main Page

From BIOL 2P96 Jan 2013 Group 06

Revision as of 16:51, 19 March 2013

Introduction

Fungal Pharmaceuticals

Over the past half century, 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].

New page

Fungal products found in pharmaceuticals

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.

Statins

Statins are a group of secondary metabolites that are used to lower low-density lipoprotein (LDL) cholesterol. 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.

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. ^[11].

History

Terms and Definitions

• Endophytic: Endophytic refers to fungi or bacteria that lives symbiotically with plants without causing any harmful effects to the plant.

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). 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. ↑ Moore,D., Robson,G.,& Trinci,T.(2013). 21st century guidebook to fungi. Cambridge Pr.