Keywords: Malaria; Plasmodium falciparum; vitamine biosynthesis; vitamin B6; drug; target; antimalarial drug development
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 synthesised 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. 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 has 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 analysed. 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.
As P. falciparum, the most dangerous human malaria parasite, is rapidly developing resistances against most of the currently available drugs, there is an urgent need to identify new targets in Plasmodium metabolism that can be specifically inhibited without affecting the human host. One of these might be vitamin biosynthesis. Vitamins belonging to the vitamin B complex such as thiamine (B1), riboflavin (B2), pyridoxine (B6) and cobalamin (B12) cannot be synthesised by mammals and have to be taken up in their diet. In contrast, micro-organisms, including the malarial parasites, fungi and plants, possess de novo biosynthetic pathways that provide these organisms with an intrinsic source of these essential compounds. Of all the water-soluble vitamins that are present in blood plasma, the only one for which the intracellular parasite apparently has an absolute requirement and for which the parasitised cell must consequently have the appropriate uptake system, is B5, the precursor of coenzyme A. Therefore, there is a hypothesis that the parasites most likely possess biosynthetic pathways for the other water-soluble vitamins. This hypothesis is supported by the presence of genes in the parasite genome that encode proteins and enzymes necessary for the biosynthesis of a number of vitamins, including those for lipoic acid synthesis, the vitamin and coenzyme precursor chorismate and vitamin B6 biosynthesis.
Validation of vitamin B 6 biosynthesis as the novel target for antimalarial drug development.
Antimalarial and possibly anti-apicomplexan drug development.
Im Neuenheimer Feld 324
Tel: +49 6221 561774
Fax: +49 6221 564643
|Official Address||Other Information|
|2||Sylke Müller||Institute of Biomedical and Life Sciences |
Division of Infection and Immunity
UK-G12 8QQ Glasgow
|Tel: +44 141 330 2383 |
Fax: +44 141 330 4600
|3||Teresa Fitzpatrick||Department of Biology and Department of Agricultural and Food Sciences Institute of Plant Sciences |
|Tel: +41 1 632 3841 |
Fax: +41 1 632 1041
|4||Peter Macheroux||Institute of Biochemistry |
|Tel: +43 316 873 6450 |
Fax: +43 316 873 6952
|5||Ivo Tews||Department of Structural Biology |
Biochemie-Zentrum Heidelberg (BZH)
Im Neuenheimer Feld 328
|Tel: +49 6221 544788 |
Fax: +49 6221 544790