The tetrameric structure of Plasmodium falciparum phosphoglycerate mutase is critical for optimal enzymatic activity

Tehlan, Ankita; Bhowmick, Krishanu; Kumar, Amarjeet; Subbarao, Naidu; Dhar, Suman Kumar

doi:10.1016/j.jbc.2022.101713

Cited by 3 publications

(2 citation statements)

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“…During the last years (2019-2022), several studies [14][15][16][17][18][19][20][21] were published discussing new approaches to identify novel drug targets for Plasmodium spp. Stanway et al [14] hypothesized that identifying genes encoding the high metabolic activities behind rapid development of a single sporozoite (invading the liver) into thousands of daughter-merozoites (invading RBCs) should reveal several potential drug targets.…”

Section: Drug Targets In Plasmodium Sppmentioning

confidence: 99%

“…The study characterized PfPGM1 structure that revealed its existence in tetramer form, and in-depth oligomerization analysis showed that this tetramerization contributed to the optimal enzymatic function in vitro, and in vivo. Understanding PGM enzymatic mechanism of action might provided a promising strategy to design and develop a specific inhibitor as novel antimalarial drug [21] .…”

Section: Drug Targets In Plasmodium Sppmentioning

confidence: 99%

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Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part IV. Plasmodium spp.

Abaza

2022

Parasitologists United Journal

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In the last two decades, transporters attracted much attention in identification of potential drug targets against intracellular protozoa. Several membrane molecules exhibit essential roles in trafficking pathways for nutrients, essential enzymes and virulence factors. In this context, P. falciparum possesses a complex of genomic plasticity-encoding transporters with high potentiality for aneuploidy, and gene expression modulation in response to drug exposure. Therefore, it is able to undergo gene mutations in enzymes controlling drug uptake, and evade host immune response by antigenic variations as well. The genetic mechanism of antimalarial drug resistance arises early with monotherapy using fast-acting drugs or a single targeting drug. Accordingly, combined therapy acting on multiple targets would decrease the emergence of drug resistance. Evolutionary technology on genetic approach enabled researchers to identify and propose novel Plasmodium drug targets. The main objective of this part is to review potential drug targets for apicomplexans and discuss recent approaches in identifying Plasmodium targets, as well as advances in the design and development of novel antimalarial drugs.

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Section: Drug Targets In Plasmodium Sppmentioning

confidence: 99%

Section: Drug Targets In Plasmodium Sppmentioning

confidence: 99%

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part IV. Plasmodium spp.

Abaza

2022

Parasitologists United Journal

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Plasmodium falciparum cysteine protease Falcipain 3: A potential enzyme for proteolytic processing of histone acetyltransferase PfGCN5

Nagar,

Bhowmick,

Chawla

et al. 2024

Biotech and App Biochem

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In spite of 150 years of studying malaria, the unique features of the malarial parasite, Plasmodium, still perplex researchers. One of the methods by which the parasite manages its gene expression is epigenetic regulation, the champion of which is PfGCN5, an essential enzyme responsible for acetylating histone proteins. PfGCN5 is a ∼170 kDa chromatin‐remodeling enzyme that harbors the conserved bromodomain and acetyltransferase domain situated in its C‐terminus domain. Although the PfGCN5 proteolytic processing is essential for its activity, the specific protease involved in this process still remains elusive. Identification of PfGCN5 interacting proteins through immunoprecipitation (IP) followed by LC‐tandem mass spectrometry analysis revealed the presence of food vacuolar proteins, such as the cysteine protease Falcipain 3 (FP3), in addition to the typical members of the PfGCN5 complex. The direct interaction between FP3 and PfGCN5 was further validated by in vitro pull‐down assay as well as IP assay. Subsequently, use of cysteine protease inhibitor E64d led to the inhibition of protease‐specific processing of PfGCN5 with concomitant enrichment and co‐localization of PfGCN5 and FP3 around the food vacuole as evidenced by confocal microscopy as well as electron microscopy. Remarkably, the proteolytic cleavage of the nuclear protein PfGCN5 by food vacuolar protease FP3 is exceptional and atypical in eukaryotic organisms. Targeting the proteolytic processing of GCN5 and the associated protease FP3 could provide a novel approach for drug development aimed at addressing the growing resistance of parasites to current antimalarial drugs.

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Revisiting the Plasmodium falciparum druggable genome using predicted structures and data mining

Godinez-Macias,

Chen,

Wallis

et al. 2024

Preprint

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The identification of novel drug targets for the purpose of designing small molecule inhibitors is key component to modern drug discovery. In malaria parasites, discoveries of antimalarial targets have primarily occurred retroactively by investigating the mode of action of compounds found through phenotypic screens. Although this method has yielded many promising candidates, it is time- and resource-consuming and misses targets not captured by existing antimalarial compound libraries and phenotypic assay conditions. Leveraging recent advances in protein structure prediction and data mining, we systematically assessed the Plasmodium falciparum genome for proteins amenable to target-based drug discovery, identifying 867 candidate targets with evidence of small molecule binding and blood stage essentiality. Of these, 540 proteins showed strong essentiality evidence and lack inhibitors that have progressed to clinical trials. Expert review and rubric-based scoring of this subset based on additional criteria such as selectivity, structural information, and assay developability yielded 67 high priority candidates. This study also provides a genome-wide data resource and implements a generalizable framework for systematically evaluating and prioritizing novel pathogenic disease targets.

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The tetrameric structure of Plasmodium falciparum phosphoglycerate mutase is critical for optimal enzymatic activity

Cited by 3 publications

References 83 publications

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part IV. Plasmodium spp.

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part IV. Plasmodium spp.

Plasmodium falciparum cysteine protease Falcipain 3: A potential enzyme for proteolytic processing of histone acetyltransferase PfGCN5

Revisiting the Plasmodium falciparum druggable genome using predicted structures and data mining

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