Structural Analysis of Plasmodium falciparum Hexokinase Provides Novel Information about Catalysis Due to a Plasmodium-Specific Insertion

Dillenberger, Melissa; Werner, Anke-Dorothee; Velten, Ann-Sophie; Rahlfs, Stefan; Becker, Katja; Fritz-Wolf, Karin

doi:10.3390/ijms241612739

Cited by 2 publications

(2 citation statements)

References 59 publications

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“…The role of protein PTMs has already been established for numerous enzymes, while for others, this role must still be determined. Some promising enzymes in this regard include oxidative stress-related enzymes [ 369 , 370 , 371 ], cytochromes P450 and NADPH hemoprotein reductases [ 372 ], nucleotide biosynthesis-related [ 373 , 374 ], ion homeostasis-related, and energy metabolism-related enzymes [ 375 , 376 , 377 , 378 , 379 , 380 ].…”

Section: Discussionmentioning

confidence: 99%

Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle

Schwarzer,

Skorokhod

2024

IJMS

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Post-translational modifications (PTMs) are essential for regulating protein functions, influencing various fundamental processes in eukaryotes. These include, but are not limited to, cell signaling, protein trafficking, the epigenetic control of gene expression, and control of the cell cycle, as well as cell proliferation, differentiation, and interactions between cells. In this review, we discuss protein PTMs that play a key role in the malaria parasite biology and its pathogenesis. Phosphorylation, acetylation, methylation, lipidation and lipoxidation, glycosylation, ubiquitination and sumoylation, nitrosylation and glutathionylation, all of which occur in malarial parasites, are reviewed. We provide information regarding the biological significance of these modifications along all phases of the complex life cycle of Plasmodium spp. Importantly, not only the parasite, but also the host and vector protein PTMs are often crucial for parasite growth and development. In addition to metabolic regulations, protein PTMs can result in epitopes that are able to elicit both innate and adaptive immune responses of the host or vector. We discuss some existing and prospective results from antimalarial drug discovery trials that target various PTM-related processes in the parasite or host.

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Section: Discussionmentioning

confidence: 99%

Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle

Schwarzer,

Skorokhod

2024

IJMS

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“…This allowed for the development of a starting framework to identify the location of these residues; our laboratory is pursuing testing to determine whether they have a key role in the proposed inhibitor binding sites. Structural insight can also be gained by comparing solved hexokinase structures of other parasitic protozoa, such as Plasmodium vivax hexokinase (PDB entry 6VYG) [34] and Plasmodium falciparum hexokinase (PDB entry 7ZZI) [35].…”

Section: T Brucei Biological Assaymentioning

confidence: 99%

Discovery of Strong 3-Nitro-2-Phenyl-2H-Chromene Analogues as Antitrypanosomal Agents and Inhibitors of Trypanosoma cruzi Glucokinase

Carey,

O’Neill,

Conner

et al. 2024

IJMS

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Chagas disease is one of the world’s neglected tropical diseases, caused by the human pathogenic protozoan parasite Trypanosoma cruzi. There is currently a lack of effective and tolerable clinically available therapeutics to treat this life-threatening illness and the discovery of modern alternative options is an urgent matter. T. cruzi glucokinase (TcGlcK) is a potential drug target because its product, d-glucose-6-phosphate, serves as a key metabolite in the pentose phosphate pathway, glycolysis, and gluconeogenesis. In 2019, we identified a novel cluster of TcGlcK inhibitors that also exhibited anti-T. cruzi efficacy called the 3-nitro-2-phenyl-2H-chromene analogues. This was achieved by performing a target-based high-throughput screening (HTS) campaign of 13,040 compounds. The selection criteria were based on first determining which compounds strongly inhibited TcGlcK in a primary screen, followed by establishing on-target confirmed hits from a confirmatory assay. Compounds that exhibited notable in vitro trypanocidal activity over the T. cruzi infective form (trypomastigotes and intracellular amastigotes) co-cultured in NIH-3T3 mammalian host cells, as well as having revealed low NIH-3T3 cytotoxicity, were further considered. Compounds GLK2-003 and GLK2-004 were determined to inhibit TcGlcK quite well with IC50 values of 6.1 µM and 4.8 µM, respectively. Illuminated by these findings, we herein screened a small compound library consisting of thirteen commercially available 3-nitro-2-phenyl-2H-chromene analogues, two of which were GLK2-003 and GLK2-004 (compounds 1 and 9, respectively). Twelve of these compounds had a one-point change from the chemical structure of GLK2-003. The analogues were run through a similar primary screening and confirmatory assay protocol to our previous HTS campaign. Subsequently, three in vitro biological assays were performed where compounds were screened against (a) T. cruzi (Tulahuen strain) infective form co-cultured within NIH-3T3 cells, (b) T. brucei brucei (427 strain) bloodstream form, and (c) NIH-3T3 host cells alone. We report on the TcGlcK inhibitor constant determinations, mode of enzyme inhibition, in vitro antitrypanosomal IC50 determinations, and an assessment of structure–activity relationships. Our results reveal that the 3-nitro-2-phenyl-2H-chromene scaffold holds promise and can be further optimized for both Chagas disease and human African trypanosomiasis early-stage drug discovery research.

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Structural Analysis of Plasmodium falciparum Hexokinase Provides Novel Information about Catalysis Due to a Plasmodium-Specific Insertion

Cited by 2 publications

References 59 publications

Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle

Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle

Discovery of Strong 3-Nitro-2-Phenyl-2H-Chromene Analogues as Antitrypanosomal Agents and Inhibitors of Trypanosoma cruzi Glucokinase

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