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Pyrophosphate and polyphosphate metabolism in Plasmodium falciparum
Dissertation

Pyrophosphate and polyphosphate metabolism in Plasmodium falciparum

Ikechukwu Chidiebere Nwankwo
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2026
DOI:
https://doi.org/10.17918/00011338
pdf
Nwankwo_Ikechukwu_20264.75 MB
PDF Embargoed Access, Embargo ends: 31 May 2027

Abstract

Apicoplasts Mitochondria Plasmodium falciparum Polyphosphates Pyrophosphates Malaria
Pyrophosphate (PPi) and polyphosphate (polyP) are central metabolites across all life forms including malaria parasites, which infect millions of people and kill approximately 600,000 lives per year. To understand PPi and polyP metabolism, this study focuses on Plasmodium falciparum, the deadliest malaria parasite, and characterizes soluble pyrophosphatases (sPPases) and polyphosphate metabolic enzymes, including exopolyphosphatase (PPX1) and vacuolar transport chaperon subunit 4 (VTC4). Using comprehensive approaches such as CRISPR-Cas9 mediated genetics, biochemical analysis, and cell biological tools, we demonstrate that the parasite encodes two sPPase isoforms arising from a single genetic locus, PfsPPase1 and PfsPPase2, which differ in subcellular targeting and function. PfsPPase1 localizes exclusively to the cytosol, whereas PfsPPase2, containing an N-terminal targeting peptide, is distributed to the mitochondrion and the apicoplast. Functional analyses reveal that PfsPPases are essential for parasite survival, highlighting the critical requirement for PPi hydrolysis in maintaining metabolic flux and supporting rapid proliferation. This dual-localization strategy in P. falciparum represents a unique evolutionary adaptation compared to other eukaryotes, which typically encode compartment-specific sPPases from distinct genetic loci. In contrast, characterization of polyP metabolism through the analysis of PfPPX1 and PfVTC4 indicates a more limited role of polyP during asexual and sexual blood stages. PfPPX1 localizes primarily to the cytosol with potential to an organelle, while PfVTC4 is organelle associated but expressed at low levels. Conditional depletion of either protein does not impair parasite growth, stress tolerance, or gametocyte formation. Collectively, these results highlight an essential role for PPi metabolism in parasite survival, while suggesting that polyP metabolism may be dispensable during blood stages but important in other lifecycle phases. The essentiality and divergence of soluble pyrophosphatases underscore their potential as targets for antimalarial drug development.

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