Abstract
ABSTRACTPolyamines are positively-charged organic molecules that are important for cellular growth and division. Polyamines and their synthesizing enzymes are particularly abundant in rapidly proliferating eukaryotic cells such as parasitic protozoa and cancer cells. Polyamine biosynthesis inhibitors, such as Elfornithine, are now being considered for cancer prevention and have been used effectively against Trypanosoma brucei. Inhibitors of polyamine biosynthesis have caused growth arrest of Plasmodium falciparum blood stages in vitro, but in P. berghei only partial inhibition has been observed. While polyamine biosynthesis enzymes are characterized and conserved in Plasmodium spp., little is known on the biological roles of these enzymes inside malaria parasite hosts. The bifunctional polyamine biosynthesis enzyme S-adenosyl methionine decarboxylase/ornithine decarboxylase (AdoMetDC/ODC) was targeted for deletion in P. yoelii. Deletion of AdoMetDC/ODC significantly reduced blood stage parasitemia but Anopheles transmission was completely blocked. We showed that male gametocytogenesis and male gamete exflagellation were abolished and consequently no ookinetes or oocyst sporozoites could be generated from adometdc/odc(–) parasites. Supplementation of putrescine and spermidine did not rescue the defective phenotypes of male gametocytes and gametes of the knockout parasites. These results highlight the crucial role of polyamine homeostasis in the development and functions of Plasmodium erythrocytic stages in the blood and in the mosquito vector and validate polyamine biosynthesis pathway enzymes as drug targeting candidates for malaria parasite transmission blocking.
Highlights
In spite of the reduction of malaria related deaths in sub-Saharan Africa in the last few years, continuous mosquito transmission of Plasmodium still poses a tremendous threat to malaria eradication efforts (Alonso et al, 2011)
Targeted deletion of the malaria parasite conserved AdoMetDC/ODC in P. yoelii Apart from the absence of a clear homologue for spermine synthase, all of the polyamine biosynthesis enzymes are conserved in Plasmodium genomes (Fig. 1A)
Alongside the intraerythrocytic asexually replicating parasites, intrinsic and extrinsic factors lead to the development of sexual stages that are only destined for transmission and continuation of the life cycle (Waters, 2016)
Summary
In spite of the reduction of malaria related deaths in sub-Saharan Africa in the last few years, continuous mosquito transmission of Plasmodium still poses a tremendous threat to malaria eradication efforts (Alonso et al, 2011). No specific molecular physiological roles have yet been assigned to polyamines They are known to be important for cell growth and division in eukaryotic cells (Birkholtz et al, 2011; Pegg, 2009; Wallace, 2009). Elfornithine was used against P. falciparum and showed very promising growth inhibiting effects in vitro (Assaraf et al, 1984) It was not effective against intraerythrocytic stages of the murine malaria model P. berghei (Bitonti et al, 1987). Elfornithine blocked malaria parasite transmission to the mosquito and liver stage development of P. berghei (Gillet et al, 1983; Hollingdale et al, 1985)
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