Award details

The Biosynthesis of Artemisinin

Reference	BB/G008744/1
Principal Investigator / Supervisor	Dr Geoff Brown
Co-Investigators / Co-Supervisors
Institution	University of Reading
Department	Chemistry
Funding type	Research
Value (£)	387,616
Status	Completed
Type	Research Grant
Start date	08/06/2009
End date	07/12/2012
Duration	42 months

Abstract

Malaria is the most serious infectious disease in the World today, accounting for the deaths of one-two million people annually. The parasite which causes malaria has acquired resistance to many of the older generation of antimalarial drugs, such as chloroquine. Artemisinin, obtained from the medicinal plant Artemisia annua, is now the only drug which can treat multidrug-resistant falciparum malaria in several parts of the World. Currently researchers in the UK are attempting to increase the yield of artemisinin from A. Annua by a crop breeding programme. Over the past few years, researchers in the US have also been attempting to express the biosynthetic pathway to artemisinin in a microbial host, so far without success. One problem faced by both groups is that the complete sequence of intermediates involved in the biosynthesis of artemisinin has never been established by rigorous feeding experiments, involving labeled precursors. The aim of this proposal is therefore to completely determine the biosynthetic route to artemisinin in A. annua. This will be achieved by first synthesising hypothetical biosynthetic precursors incorporating a stable isotope label, such as deuterium or carbon-13. The selection of these precursors will be made with a view to filling in all the gaps in our knowledge of the biosynthetic pathway. In the second phase, each labelled precursor will be administered to living A. annua plants as a part of in vivo experiments designed to mimic metabolism in the native state. In the third and final phase, labelled compounds, produced by metabolism of each precursor, will be extracted from the plant and their structures determined using analytical techniques such as HPLC and NMR. By completely defining the biosynthetic pathway to artemisinin in this way, it is hoped to establish a solid foundation on which to build future attempts to produce this drug by the crop-breeding and microbial 'fermentation' strategies described above.

Summary

Malaria is currently responsible for one-two million deaths every year. Artemisinin is an antimalarial drug derived from the medicinal plant Artemisia annua. Because of increasing resistance to conventional malarial therapies, artemisinin is now the only drug which can treat the often fatal condition of cerebral malaria in many parts of the World. Artemisinin is produced on a multi-ton scale entirely from the plant source by pharmaceutical factories in China and Vietnam. Recently, there have been problems with both the cost and the supply of artemisinin. The most attractive approaches to address these issues are: i) to increase the yield of this antimalarial drug from the parent plant, A. annua, via a crop-breeding program; and, ii) to genetically engineer the pathway to artemisinin within a microbial host, in order to permit its production by fermentation. A complete understanding of the biosynthetic route to artemisinin, in which all of the biosynthetic intermediates have been unambiguously identified, is clearly the foundation of both approaches, since this provides the most secure basis on which to search for the relevant enzymes in that pathway. Surprisingly, however, the complete sequence of intermediates which are involved in the biosynthesis of this vitally important natural product has never been fully established. The aim of this proposal is to fill in the gaps in our knowledge of the biosynthetic pathway to artemisinin in A. annua by means of rigorous feeding experiments, involving labelled precursors, which will be produced by chemical synthesis. Particular emphasis will be placed on the later steps in the pathway, which are the least well understood.

Committee	Closed Committee - Biomolecular Sciences (BMS)
Research Topics	Crop Science, Industrial Biotechnology, Pharmaceuticals, Plant Science, Synthetic Biology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

I accept the terms and conditions of use (opens in new window)

export PDF file

back to list new search