A Global Survey of ATPase Activity in Plasmodium falciparum Asexual Blood Stages and Gametocytes

Abstract

Effective malaria control and elimination in hyperendemic areas of the world will require treatment of the () 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 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.

Who Is Metabolizing What? Discovering Novel Biomolecules in the Microbiome and the Organisms Who Make Them

“…In many cases, genes of unknown function are excluded from analysis because a method that requires mapping to an annotated genome is employed. ABPP can help address this challenge, as ABP-labeling directly signifies protein function (Adam et al, 2004 ; Kamat et al, 2015 ; Xu et al, 2015 ; Martell et al, 2016 ; Ortega et al, 2018 ; Elahi et al, 2019 ). This is especially true when accompanying metabolomics data can provide added confidence (Jansen et al, 2020 ).…”

The use of proteomics for the identification of promising vaccine and diagnostic biomarkers in Plasmodium falciparum

“…It has been shown that several proteins in P. falciparum gametocytes are able to potentially activate host immunological responses (Frimpong et al ., 2018). ATPase-activity altered in Plasmodium parasites from asexual schizonts to sexual gametocytes suggested the regulatory role of malarial-ATPases and the complex metabolism of malaria parasites in different stages (Ortega et al ., 2018). Therefore, the characterization of specific malarial-ATPases including Pfs48/45, Pfg27 and the plasma membrane-associated protein Pfs230 with gametocytogenesis might provide valuable information regarding the inhibition of malaria transmission (Simon et al ., 2016; Ortega et al ., 2018).…”

“…ATPase-activity altered in Plasmodium parasites from asexual schizonts to sexual gametocytes suggested the regulatory role of malarial-ATPases and the complex metabolism of malaria parasites in different stages (Ortega et al ., 2018). Therefore, the characterization of specific malarial-ATPases including Pfs48/45, Pfg27 and the plasma membrane-associated protein Pfs230 with gametocytogenesis might provide valuable information regarding the inhibition of malaria transmission (Simon et al ., 2016; Ortega et al ., 2018). Pfs48/45 is an important factor in the malaria parasite's adherence to host cells and was interestingly suggested as a possible vaccine candidate for blocking malaria transmission (Singh et al ., 2015).…”