8 October 2013
By Alena PanceOne of the great difficulties with malaria is that, despite sequencing of the Plasmodium genome and intense research, close to 50 per cent of the genome in all Plasmodium species remains annotated as hypothetical proteins, for which there is no experimental evidence. Understanding the functions of these proteins is imperative to finding vulnerabilities in the parasite that could be exploited for the development of new strategies to fight the disease.
Transposons, genomic curiosities that are often called ‘jumping genes’, have been used to develop a novel technology to perform genetic screens on a large scale. Transposons are movable DNA elements that are introduced into cells and made to jump randomly throughout the genome. The result is the disruption of the genes where they integrate, which can change the make-up and behaviour of the cells. These changes can be identified and linked to a particular gene, thereby providing an insight into the biology of the cell and the function of individual genes.
The use of this strategy in Plasmodium falciparum, the most lethal human malaria parasite, has started revealing some of its fundamental components. The most recent gene unveiled by this technique is an unusual enzyme that regulates the life cycle of the parasite. When it is disrupted, this enzyme delays parasite growth in the blood, potentially having an impact on the infection.
Enzymes such as this one are important because they are part of signalling pathways within cells that, like a control panel, modify cell behaviour and function by modifying other proteins. One of the most widespread modifications is phosphorylation, which consists in the addition of phosphate groups to specific aminoacids to alter the activity of a target protein.
Strikingly however, a comparison of the Plasmodium enzyme identified here with similar proteins found in other organisms, showed that its activity, if any, is very low. The regulatory mechanism of these phosphatases (enzymes), known as pseudophosphatases, might rely on trapping phosphoproteins or protecting them from de-phosphorylation (where phosphates are removed). As a consequence, the target protein is either prevented from working or left switched on, disrupting the normal behaviour of the cell.
The identification of proteins with enzymatic activity is very exciting precisely because some of them might have crucial differences as compared with the human counterparts. These differences can be modelled and used to design specific molecules that could interfere with the activity of the Plasmodium enzyme without affecting similar proteins in the host.
In this way, it is possible to devise strategies to target such components of the parasite while minimising the effects of the potential drug on the patient.
Alena Pance is a staff scientist in the Malaria Programme, where she works with Julian Rayner to develop a stem cell-based system to study the host component of malaria infection.
- Balu, B., Campbell, C., Sedillo, J., Maher, S., Singh, N., Thomas, P., Zhang, M., Pance, A., Otto, T.D., Rayner, J.C., Adams, J.H. (2013) Atypical Mitogen-Activated Protein Kinase Phosphatase Implicated in Regulating Transition from Pre-S-Phase Asexual Intraerythrocytic Development of Plasmodium falciparum Eukaryotic Cell. PMID:23813392