The malaria plastid organelle: a potential drug target

Lead Research Organisation: MRC National Inst for Medical Research

Abstract

Malaria remains one of the primary parasitic diseases of the world. It causes deaths of millions of people each year in endemic areas. In addition, malaria poses a hazard for international travellers and military personnel operating overseas. Drug resistance has become a major problem and effective vaccines are yet unavailable. Therefore, we are trying to find new targets for therapeutic intervention. Nearly a decade ago we discovered an unusual organelle within the parasite. The organelle is derived from an ancient algal cell taken up by the parasite and still involved in non-photosynthetic plant-type reactions in the parasite today. Because these reactions are essential for the parasite but are absent from humans, they may form targets for parasite-specific intervention. Our studies are directed at exploring the functions of this organelle so as to find new inhibitors that can act as lead compounds for drug development.

Technical Summary

Malaria continues to be a massive and growing world health problem due to the spread of drug resistance and lack of a vaccine. Our work is directed at finding new targets for therapeutic intervention. Nearly a decade ago we discovered at NIMR that the malaria parasite and the AIDS-associated pathogen Toxoplasma gondii carry a novel plastid organelle derived from an ancient algal cell. Being essential for the survival of these parasites, the plastid is a prime target for intervention. Our work is directed at finding out the functions of this organelle of the human malaria parasite Plasmodium falciparum by molecular genetic and biochemical means. We are examining genes and their products from two sources: those from the plastid genome itself and those from the nucleus where many genes that once belonged to the ancient alga now reside. The malaria plastid genome encodes a component of a particular type of iron-sulphur cluster metabolic pathway that is present in bacteria and plants but not in humans. The parasites nuclear genome encodes genes specifying remaining components of the pathway and we have already confirmed that most of them are targeted to the plastid. The function of the proteins involved in this pathway is being investigated biochemically and biophysically. The same pathway has been shown to be essential for the survival of mycobacteria and could form a target for both malaria and tuberculosis therapy. It has long been known that the malaria parasite depends on de novo haem biosynthesis, and there is a theory that the metabolism makes use of enzymes recruited from the hosts red cell. However, the parasites nuclear genome encodes a set of enzymes that comprise a complete de novo haem biosynthetic pathway of its own. One of the parasites own enzymes, namely PfPBGS, has been demonstrated to be catalytically functional and localized to the plastid. Interestingly, PfPBGS exhibits a substantially different sensitivity against several synthetic inhibitors from the human PBGS. Other enzymes involved in the pathway are being investigated in a similar way. As the plastid is absent from the human cell, housekeeping factors of the organelle itself, such as chaperones and DNA/RNA metabolic enzymes, and coordination of this organelle with other part of the cell such as the mitochondrion, also have potential as new drug targets and are the subject of our research. We hope this project will open the way to intervention against malaria by use of specific inhibitors

Publications

10 25 50
 
Description PHYSICAL BIOCHEMISTRY 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Public 
PI Contribution Parasitology
Collaborator Contribution Biochemistry and enzymology
Impact 16431905, 18413861
 
Description TOKYO 
Organisation University of Tokyo
Department Biomedical Chemistry
Country Japan 
Sector Academic/University 
PI Contribution parasite genetic manipulation
Collaborator Contribution biochemistry and enzymology
Impact 17289446, 19358847
 
Description Seminars 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Provided overview of activities to interested lay-people

Increased general level of awareness
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010