Functional consequences of perturbing polyamine metabolism in the malaria parasite, Plasmodium falciparum

Abstract

Inhibition of polyamine biosynthesis and/or the perturbation of polyamine functionality have been exploited with success against parasitic diseases such as Trypanosoma infections. However, when the classical polyamine biosynthesis inhibitor, alpha-difluoromethylornithine, is used against the human malaria parasite, Plasmodium falciparum, it results in only a cytostatic growth arrest. Polyamine metabolism in this parasite has unique properties not shared by any other organism. These include the bifunctional arrangement of the catalytic decarboxylases and an apparent absence of the typical polyamine interconversion pathways implying different mechanisms for the regulation of polyamine homeostasis that includes the uptake of exogenous polyamines at least in vitro. These properties make polyamine metabolism an enticing drug target in P. falciparum provided that the physiological and functional consequences of polyamine metabolism perturbation are understood. This review highlights our current understanding of the biological consequences of inhibition of the biosynthetic enzymes in the polyamine pathway in P. falciparum as revealed by several global analytical approaches. Ultimately, the evidence suggests that polyamine metabolism in P. falciparum is a validated drug target worth exploiting.

Protein S-nitrosylation in Plasmodium falciparum

“…Regarding the similar metabolic function and the presence of the same S-nitrosylation site in PfSAMS compared to rat SAMS, it is reasonable to speculate that SNO may affect the SAM biosynthesis in P. falciparum by influencing the PfSAMS activity. Because SAMS is a key precursor for polyamine biosynthesis, which is closely related to the proliferation of P. falciparum (12), SNO on PfSAMS may correlate with the growth arrest of Plasmodium parasites caused by NO, which has been observed in several studies (4,50). Of course, this hypothesis needs to be substantiated by further experiments.…”

Polyamines in Eukaryotes, Bacteria, and Archaea

“…The dcAdoMet is formed by the decarboxylation of AdoMet performed by S-adenosylmethionine decarboxylase (AdoMetDC) (14,15). ODC, AdoMetDC, and SpdSyn are the universal pathway for spermidine biosynthesis in eukaryotes, and the pathway has been characterized in trypanosomes (16), Leishmania (17), Plasmodium falciparum (18), and filamentous fungus Neurospora crassa (19,20), among others. Thus, the core pathway producing the triamine Spd has been characterized in the Excavata, SAR, and Opisthokonta supergroups.…”

Discovery of Novel Alkylated (bis)Urea and (bis)Thiourea Polyamine Analogues with Potent Antimalarial Activities

“…1 One class of promising antiparasitic agents include inhibitors of polyamine biosynthesis, 2 as well as polyamine analogues, 3 with ample evidence indicating that these rapidly dividing cells have an exquisite need for the presence of polyamines for a myriad of cellular functions during cell growth and division. 4,5 …”