Mitochondrial Spermidine Synthase is Essential for Blood-stage growth of the Malaria Parasite

Kamil, Mohd; Kına, Ümit Yaşar; Deveci, Gözde; Akyuz, Sevim N.; Yilmaz, Ilknur; Aly, A. S.

doi:10.1016/j.micres.2022.127181

Cited by 4 publications

(2 citation statements)

References 41 publications

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“…Further sporozoites were incubated with the 50 nm ER‐Tracker for 30 min at 37°C in dark. The sporozoites were washed with PBS by centrifugation at 8000 rpm for 3 min (Kamil, Kina, et al., 2022).…”

Section: Methodsmentioning

confidence: 99%

Endoplasmic reticulum localized TMEM33 domain‐containing protein is crucial for all life cycle stages of the malaria parasite

Kamil,

Kina,

Atmaca

et al. 2024

Molecular Microbiology

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Endoplasmic reticulum (ER) plays a pivotal role in the regulation of stress responses in multiple eukaryotic cells. However, little is known about the effector mechanisms that regulate stress responses in ER of the malaria parasite. Herein, we aimed to identify the importance of a transmembrane protein 33 (TMEM33)‐domain‐containing protein in life cycle of the rodent malaria parasite Plasmodium berghei. TMEM33 is an ER membrane‐resident protein that is involved in regulating stress responses in various eukaryotic cells. A C‐terminal tagged TMEM33 was localized in the ER throughout the blood and mosquito stages of development. Targeted deletion of TMEM33 confirmed its importance for asexual blood stages and ookinete development, in addition to its essential role for sporozoite infectivity in the mammalian host. Pilot scale analysis shows that the loss of TMEM33 results in the initiation of ER stress response and induction of autophagy. Our findings conclude an important role of TMEM33 in the development of all life cycle stages of the malaria parasite, which indicates its potential as an antimalarial target.

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Section: Methodsmentioning

confidence: 99%

Endoplasmic reticulum localized TMEM33 domain‐containing protein is crucial for all life cycle stages of the malaria parasite

Kamil,

Kina,

Atmaca

et al. 2024

Molecular Microbiology

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“…Both enzymes of the hypusine pathway have been cloned and characterized and have shown to be vital genes in murine blood-stages [48] using reverse genetics similar to homologous recombination techniques, suggesting the importance of the pathway for infection. Moreover, a recent targeting of SpdS in P. yoelii, by deletion/complementation analyses, demonstrated the gene to be essential for blood-stage growth [49]. Interestingly, SpdS was located in the mitochondria of blood-stages and sporozoites pinpointing its role as a drug candidate of interest.…”

Section: Spermidine As a Hallmark In The Apicomplexan Parasite P Falc...mentioning

confidence: 99%

The Role of Spermidine and Its Key Metabolites in Important, Pathogenic Human Viruses and in Parasitic Infections Caused by Plasmodium falciparum and Trypanosoma brucei

Kaiser

2023

Biomolecules

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The triamine spermidine is a key metabolite of the polyamine pathway. It plays a crucial role in many infectious diseases caused by viral or parasitic infections. Spermidine and its metabolizing enzymes, i.e., spermidine/spermine-N1-acetyltransferase, spermine oxidase, acetyl polyamine oxidase, and deoxyhypusine synthase, fulfill common functions during infection in parasitic protozoa and viruses which are obligate, intracellular parasites. The competition for this important polyamine between the infected host cell and the pathogen determines the severity of infection in disabling human parasites and pathogenic viruses. Here, we review the impact of spermidine and its metabolites in disease development of the most important, pathogenic human viruses such as SARS-CoV-2, HIV, Ebola, and in the human parasites Plasmodium and Trypanosomes. Moreover, state-of-the-art translational approaches to manipulate spermidine metabolism in the host and the pathogen are discussed to accelerate drug development against these threatful, infectious human diseases.

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In silico prediction and in vitro assessment of novel heterocyclics with antimalarial activity

Orozco,

Moreno,

Guevara

et al. 2023

Parasitol Res

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The development of new antimalarials is paramount to keep the goals on reduction of malaria cases in endemic regions. The search for quality hits has been challenging as many inhibitory molecules may not progress to the next development stage. The aim of this work was to screen an in-house library of heterocyclic compounds (HCUV) for antimalarial activity combining computational predictions and phenotypic techniques to find quality hits. The physicochemical determinants, pharmacokinetic properties (ADME), and drug-likeness of HCUV were evaluated in silico, and compounds were selected for structure-based virtual screening and in vitro analysis. Seven Plasmodium target proteins were selected from the DrugBank Database, and ligands and receptors were processed using UCSF Chimera and Open Babel before being subjected to docking using Autodock Vina and Autodock 4. Growth inhibition of P. falciparum (3D7) cultures was tested by SYBR Green assays, and toxicity was assessed using hemolytic activity tests and the Galleria mellonella in vivo model. From a total of 792 compounds, 341 with good ADME properties, drug-likeness, and no interference structures were subjected to in vitro analysis. Eight compounds showed IC50 ranging from 0.175 to 0.990 µM, and active compounds included pyridyl-diaminopyrimido-diazepines, pyridyl-N-acetyl- and pyridyl-N-phenyl-pyrazoline derivatives. The most potent compound (UV802, IC50 0.178 µM) showed no toxicophoric and was predicted to interact with P. falciparum 1-cysperoxidredoxin (PfPrx1). For the remaining 7 hits (IC50 < 1 μM), 3 showed in silico binding to PfPrx1, one was predicted to bind the haloacid dehalogenase-like hydrolase and plasmepsin II, and one interacted with the plasmodial heat shock protein 90.

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Mitochondrial Spermidine Synthase is Essential for Blood-stage growth of the Malaria Parasite

Cited by 4 publications

References 41 publications

Endoplasmic reticulum localized TMEM33 domain‐containing protein is crucial for all life cycle stages of the malaria parasite

Endoplasmic reticulum localized TMEM33 domain‐containing protein is crucial for all life cycle stages of the malaria parasite

The Role of Spermidine and Its Key Metabolites in Important, Pathogenic Human Viruses and in Parasitic Infections Caused by Plasmodium falciparum and Trypanosoma brucei

In silico prediction and in vitro assessment of novel heterocyclics with antimalarial activity

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