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From BIOL 2P96 Jan 2013 Group 06

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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 grisefulvin (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].

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.

notes

Can everyone add their names and emails to the discussion, just so we can organize the work and what not better.

I was thinking we could split this page into three sections: First being a brief introduction/history, probably talk about penicillin since that's the most commonly known use then become more specific with the other two sections. The other two could be techniques to extract fungal products for pharmaceuticals and the last section could be specific examples of fungi, what they're used for, how they create the substance of interest, etc. Thoughts?

Judith, can you copy and paste your section from "new page" to the main page? I would do it, but they look at the history for marking and I don't want to take your credit :P And do you have references for the info??

If anyone wants to work on processes involved I found this article that might help.