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UK funding (£388,895): Synthetic probes of natural product biosynthesis: implications for synthetic biology and drug discovery. Ukri1 Jul 2012 UK Research and Innovation, United Kingdom
Overview
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Synthetic probes of natural product biosynthesis: implications for synthetic biology and drug discovery.
| Abstract | Natural products represent a major source of powerful agents for the treatment of human, animal and plant diseases. Indeed the most potent antibiotics, anticancer agents, antiparasitic agents and pesticides in use today are natural substances produced in microorganisms and plants by dedicated sets of enzymes. Natural products owe their extraordinary bioactivity to their highly complex chemical structures, which still constitute a challenge for chemical synthesis. Intriguingly microorganisms and plants have the ability to produce these products from very simple precursors (e.g. acetate, amino acids and sugars) for their survival. Advances in research have increased our knowledge of the bacterial, fungal and plant enzymes and the genes responsible for their existence; however little is known about the chemical details of their biosynthesis. This is because the biosynthetic processes comprise of multiple transformations that take place in rapid succession and for which we currently have no generic and straightforward method of investigation. The limited amount of information obtained so far in relation to the number and the complexity of the existing natural product pathways prevent us from fully understanding and utilizing these pathways for improving the production of known products (via the metabolic engineering of microorganisms) and the generation of new ones (via synthetic biology approaches aimed at new drug discovery). At the present time these are extremely desirable goals in view of the many global challenges in health, environment, sustainability and energy that the scientific and the nonscientific communities face. This research project aims at developing a novel and general methodology for the study of natural product biosynthesis based of the use of synthetic probes. These are chemically prepared compounds that mimic the basic precursors utilized in natural product formation and interfere in the pathways leading to the natural product assembly, 'catching' and retrieving the intermediate species from complex biological mixtures and throughout their processing. The pathways targeted in this research project are those leading to polyketide and nonribosomal peptide products, among which we count many commercially and industrially relevant products such as the blockbuster cardiovascular statin drugs and the antibiotics of last resort vancomycin and teicoplanin. To develop this 'chemical' methodology, which is of general applicability and is capable of providing immediate answers to complex mechanistic issues, we have identified specific research objectives concerning (1) the development of synthetic probes of improved bioavailability for the study of polyketide biosynthesis 'in vivo' (meaning directly in live microorganisms); (2) the design, the development and the validation of putative probes of nonribosomal peptide biosynthesis, and (3) the application of the polyketide and nonribosomal peptide probes to elucidate poorly understood pathways leading to products of commercial and industrial interest. The main outcomes of this research will be (a) powerful yet very practical tools capable of providing unique mechanistic insights into biological processes, whose beneficiaries include researchers in the broad area of biosciences; (b) new understanding of natural product biosynthesis, which will constitute the basis of for the biosynthetic engineering of new products. The major beneficiary of this research outside the academic community will therefore be the biotechnology industry, who is going to utilize the information gained through our methodology to develop new products for the nation's health and for the growth of the UK economic competitiveness. |
| Category | Research Grant |
| Reference | BB/J007250/1 |
| Status | Closed |
| Funded period start | 01/07/2012 |
| Funded period end | 31/01/2016 |
| Funded value | £388,895.00 |
| Source | https://gtr.ukri.org/projects?ref=BB%2FJ007250%2F1 |
Participating Organisations
| University of Warwick | |
| Aalborg University | |
| University of Milan | |
| Wuhan University | |
| European Cooperation in Science and Technology (COST) | |
| Leibniz Association | |
| University of Warwick | |
| UNIVERSITY OF CAMBRIDGE | |
| Monash University |
The filing refers to a past date, and does not necessarily reflect the current state. The current state is available on the following page: University of Warwick, Coventry.
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