Objective Plasmodium falciparum causes severe malaria and about 2 million human deaths annually. The main obstacle to combat the disease is increasing resistance of the parasites to existing drugs and the lack of a protective vaccine. Therefore, it is imperative that new suitable drug targets in the parasite?s metabolism are identified, assessed and validated. The availability of the parasite's genome sequence offers an excellent tool to identify metabolic pathways potentially essential for parasite survival. Scrutinising the Plasmodium genomes revealed that they possess biosynthetic pathways for vitamins. Vitamins are organic compounds required in small amounts to ensure normal metabolic functions. Since they are not synthesized by humans, they need to be supplied via nutrients in trace amounts. The absence of vitamin biosynthesis in humans suggests that specific targeting of these parasite pathways with inhibitors is feasible and thus vitamin biosynthesis of Plasmodium might offer excellent potential for the development of novel chemotherapeutics against malaria with specific toxicity towards the parasites without affecting the host's metabolism. In the first instance we will focus on vitamin B6 biosynthesis, as this important nutrient is required as a co-factor for a wide variety of essential metabolic functions in protein and amino acid metabolism and also has been implicated in the defence against oxidative stress in other eukaryotes. Using reverse genetic approaches we will validate the suitability of two of the vitamin B6 synthesising enzymes Pdx1 and Pdx2 respectively, as drug targets. In addition, their precise biological functions and potential interactions with other cellular components will be analyzed. Further the biochemical, biophysical and structural features of both enzymes will be assessed in order to be able to rationally design specific inhibitors that interfere with the parasite's proteins activities and functions. Fields of science medical and health sciencesbasic medicinepharmacology and pharmacydrug discoverymedical and health scienceshealth sciencesinfectious diseasesmalariamedical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsvaccinesmedical and health sciencesbasic medicinephysiologyhomeostasisnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Keywords Malaria Plasmodium falciparum novel drug target vitamin B6 vitamin biosynthesis Programme(s) FP6-LIFESCIHEALTH - Life sciences, genomics and biotechnology for health: Thematic Priority 1 under the Focusing and Integrating Community Research programme 2002-2006. Topic(s) LIFESCIHEALTH-2.3.0 - Developing new promising candidate vaccines and therapies Call for proposal FP6-2003-LIFESCIHEALTH-3 See other projects for this call Funding Scheme STREP - Specific Targeted Research Project Coordinator UNIVERSITÄTSKLINIKUM HEIDELBERG EU contribution No data Address Im Neuenheimer Feld 672 HEIDELBERG Germany See on map Links Website Opens in new window Total cost No data Participants (4) Sort alphabetically Sort by EU Contribution Expand all Collapse all UNIVERSITY OF GLASGOW United Kingdom EU contribution No data Address University Avenue GLASGOW See on map Links Website Opens in new window Total cost No data EIDGENÖSSISCHE TECHNISCHE HOCHSCHULE ZÜRICH Switzerland EU contribution No data Address Raemistrasse 101 ZÜRICH See on map Links Website Opens in new window Total cost No data TECHNISCHE UNIVERSITÄT GRAZ Austria EU contribution No data Address Rechbauerstr. 12 GRAZ See on map Links Website Opens in new window Total cost No data RUPRECHT-KARLS-UNIVERSITÄT HEIDELBERG Germany EU contribution No data Address Seminarstr. 2 HEIDELBERG See on map Links Website Opens in new window Total cost No data
