Abstract
Effective malaria control and elimination in hyperendemic areas of the world will require treatment of the Plasmodium falciparum (Pf) blood stage that causes disease as well as the gametocyte stage that is required for transmission from humans to the mosquito vector. Most currently used therapies do not kill gametocytes, a highly specialized, non-replicating sexual parasite stage. Further confounding next generation drug development against Pf is the unknown metabolic state of the gametocyte and the lack of known biochemical activity for most parasite gene products in general. Here, we take a systematic activity-based proteomics approach to survey the activity of the large and druggable ATPase family in replicating blood stage asexual parasites and transmissible, non-replicating sexual gametocytes. ATPase activity broadly changes during the transition from asexual schizonts to sexual gametocytes, indicating altered metabolism and regulatory roles of ATPases specific for each lifecycle stage. We further experimentally confirm existing annotation and predict ATPase function for 38 uncharacterized proteins. By mapping the activity of ATPases associated with gametocytogenesis, we assign biochemical activity to a large number of uncharacterized proteins and identify new candidate transmission blocking targets.
Highlights
Despite tremendous treatment and control efforts, malaria continues to be the world’s most devastating parasitic dis
Most drugs that are effective against the asexual blood stages are ineffective against gametocytes, suggesting that a better understanding of the distinct biology of gametocytes is important for the identification of transmission-blocking drug targets [4]
ATP-activity Based Probe (ABP) Labels Many Plasmodium falciparum (Pf) Proteins—To test the reactivity of the ATP activity based probe (ATP-ABP) (Fig. 1A, [13]) in the proteome of asexual erythrocytic schizonts and sexual gametocytes of Pf strain NF54, we labeled lysates of each with the ATP-ABP followed by conjugation with a fluorophore by click chemistry
Summary
Despite tremendous treatment and control efforts, malaria continues to be the world’s most devastating parasitic dis-. Sequence-based annotation predicts functions for large numbers of gene products, species-specific proteins often remain uncharacterized. We used ABPP with an ATP-based activity probe in combination with quantitative mass spectrometry to survey the ATPase activity in the proteome of Plasmodium falciparum (Pf), the most important human malaria pathogen.
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