The protozoan parasite Leishmania donovani is the causative agent of visceral leishmaniasis, a devastating and often fatal disease in humans. A better understanding of the biochemical or metabolic differences between pathogen and host is needed for the development of more effective therapeutic drugs. This research proposal offers thorough characterization of two key enzymes of the polyamine pathway in Leishmania donovani: spermidine synthase (SPDSYN) and S-adenosylmethionine decarboxylase (ADOMETDC). A thorough biochemical and physicochemical characterization of recombinant SPDSYN and ADOMETDC as well as the initiation of structural analyses will be the main focus of the proposal. The metabolic contribution and importance of these proteins will be evaluated in SPDSYN and ADOMETDC deficient parasites, which have been created by targeted gene replacement. The nutritional requirement, growth rate and polyamine metabolism of the mutants will be investigated. As the polyamine pathway has been targeted in antiparasitic chemotherapies, this investigation provides a foundation for the validation of SPDSYN and ADOMETDC as potential therapeutic targets for the treatment of parasitic diseases.
