Parasite Genomics
Parasitic organisms range from unicellular protozoans such as the Apicomplexa (e.g. plasmodium, toxoplasma and cryptosporidium) and Kinetoplastids (e.g. leishmania and trypanosomes) to multicellular worms (e.g. cestodes, trematodes and nematodes). The impact of each has enornomous implications to the healthcare systems of many developing countries. For example, Plasmodium is the etiological agent of malaria that affects over 300 million people worldwide and kills over 1 million children under the age of five annually. Toxoplasma, the causative agent of toxoplasmosis, infects nearly 1 in 3 of the adult population with severe implications for those living with HIV/AIDS and congenitally infected children. Parasitic nematodes such as roundworm (Ascaris) and Hookworms (e.g. Ancylostoma and Necator) are thought to infect over half the worlds population.
Despite their significance, it is perhaps surprising that relatively few effective treatments and vaccines are available to protect against these organisms. Furthermore, we are beginning to witness new strains of parasites resistant or tolerant to available prophylactics. For example the emergence of chloroquine and mefloquine resistance in P. falciparum and the rise of sulfonamide resistance in Toxoplasma. The development of new classes of effective therapeutics is therefore imperative. Since many of these diseases are associated with countries with poor economies, drug, vaccine and diagnostic development programs are largely dependent on non-profit making organizations. A recent study found that, of 1393 new chemical entities marketed between 1975 and 1999, only 13 were for tropical diseases. To meet this challenge, several international consortia have been initiated to generate vast amounts of sequence data for many of these parasites. Studies exploiting these exceptional sequence resources together with computational and functional genomics, and proteomics datasets are now starting to reveal specialized apicomplexan processes required for the establishment of parasite infections in animal hosts, driving new opportunities for designing potent anti-parasitic strategies. Applying our bioinformatics expertise in the collation and analysis of parasite sequence data, together with computational methods that we have previously applied in analyses of large scale interaction networks, we are undertaking an innovative program of research that combines sequence and functional genomic datasets to systematically explore the structure, organization and conservation of apicomplexan metabolism. Our goal is to identify enzymes and pathways in the Apicomplexa that are required for mediating parasite replication and persistence within the human host. In collaboration with Dr Michael Grigg at the NIH, we will exploit Toxoplasma gondii as a biochemically and genetically amenable model apicomplexan, for follow up in vitro and in vivo validation studies. Targets identified through these studies will lay the foundation for future programs of drug discovery. Current projects: apicomplexan phylogenomics
KEGG representation of the Arachidonic acid metabolic pathway. The Arachidonic acid pathway (formerly the Prostaglandin and Leukotriene pathway) was recently annotated by the Kyoto Encyclopaedia of Genes and Genomes (KEGG) in August 2006. Each enzyme in the pathway is represented by a colored box and is associated with an enzyme classification (EC) number, substrates are indicated by small circles. Blue boxes indicate presence of the enzyme in at least one apicomplexan, red boxes indicate no detectable enzyme in any apicomplexan. White boxes indicate enzymes which were not included in this analysis either due to the lack of examples to screen the database or ambiguity concerning their assignment through simple BLAST homology searches. The orange box highlights 1.13.11.33—15-lipoxygenase (15-LO), an enzyme activity which has been identified in Toxoplasma but without an identifiable gene [1]. Note how 15-LO links two highly connected substrates (Arachidonic acid and 15(S)-HPETE) involved in several alternative reactions. Two additional enzymes, 1.13.11.31 and 1.14.99.1, also link highly connected substrates (Arachidonic acid, 12(S)-HPETE and PGH2) and have also not been identified in any apicomplexan. The local connections of the three enzymes: 1.13.11.33 (15-LO), 1.13.11.31 and 1.14.99.1 suggest their involvement in multiple flux modes suggesting that they represent ‘critical’ enzymes within this pathway. Reference [1] Bannenberg, G. et al. Lipoxins and novel 15-epi-lipoxin analogs display potent anti-inflammatory actions after oral administration. Br J Pharmacol 143, 43-52 (2004).
