A5000567573- Biochemical and Molecular Research
- Malaria Research and Control
- HIV/AIDS drug development and treatment
- Enzyme Structure and Function
- Computational Drug Discovery Methods
- Folate and B Vitamins Research
- Amino Acid Enzymes and Metabolism
- Trypanosoma species research and implications
- RNA Research and Splicing
- Ubiquitin and proteasome pathways
- Pharmaceutical studies and practices
- Peroxisome Proliferator-Activated Receptors
- HIV-related health complications and treatments
- Pneumocystis jirovecii pneumonia detection and treatment
- Asthma and respiratory diseases
- Muscle metabolism and nutrition
- Zebrafish Biomedical Research Applications
- Protein Structure and Dynamics
- Cancer-related gene regulation
- Sulfur Compounds in Biology
- Drug Transport and Resistance Mechanisms
- Drug-Induced Adverse Reactions
- Pancreatic function and diabetes
- Phenothiazines and Benzothiazines Synthesis and Activities
- SARS-CoV-2 and COVID-19 Research
University of Groningen
2014-2022
European Molecular Biology Laboratory
2012
Malaria remains a major threat to human health, as strains resistant current therapeutics are discovered. Efforts in finding new drug targets hampered by the lack of sufficiently specific tools provide target validation prior initiating expensive discovery projects. Thus, approaches that can rapidly enable significant interest. In this manuscript we present crystal structure malate dehydrogenase from Plasmodium falciparum (PfMDH) at 2.4 Å resolution and structure-based mutagenic experiments...
Aspartate transcarbamoylase catalyzes the second step of de-novo pyrimidine biosynthesis. As malarial parasites lack salvage machinery and rely on production for growth proliferation, this pathway is a target drug discovery. Previously, an apo crystal structure aspartate from Plasmodium falciparum (PfATC) in its T-state has been reported. Here we present structures PfATC liganded R-state as well complex with novel inhibitor, 2,3-napthalenediol, identified by high-throughput screening. Our...
The de novo pyrimidine-biosynthesis pathway of Plasmodium falciparum is a promising target for antimalarial drug discovery. parasite requires supply purines and pyrimidines growth proliferation unable to take up from the host. Direct (or indirect) inhibition pyrimidine biosynthesis via dihydroorotate dehydrogenase ( Pf DHODH), fourth enzyme pathway, has already been shown be lethal parasite. In second step plasmodial pyrimidine-synthesis aspartate carbamoyl phosphate are condensed N...
Malaria is a tropical disease that kills about half million people around the world annually. Enzymatic reactions within pyrimidine biosynthesis have been proven to be essential for Plasmodium proliferation. Here we report on essentiality of second enzymatic step pathway, catalyzed by aspartate transcarbamoylase (ATC). Crystallization experiments using double mutant ofPlasmodium falciparum ATC (PfATC) revealed importance mutated residues enzyme catalysis. Subsequently, this was employed in...
Pex4p is a peroxisomal E2 involved in ubiquitinating the conserved cysteine residue of cycling receptor protein Pex5p. Previously, we demonstrated that from yeast Saccharomyces cerevisiae binds directly to membrane Pex22p and this interaction vital for ubiquitination. In addition, binding allows specifically produce lysine 48 linked ubiquitin chains vitro through an unknown mechanism. This activity likely play role targeting proteins proteasomal degradation. Here present crystal structures...
The appearance of multi-drug resistant strains malaria poses a major challenge to human health and validated drug targets are urgently required. To define protein's function in vivo thereby validate it as target, highly specific tools required that modify protein with minimal cross-reactivity. While modern genetic approaches often offer the desired level target specificity, applying these techniques is frequently challenging-particularly most dangerous parasite, Plasmodium falciparum. Our...
Abstract Thiosulfate sulfurtransferase (TST, EC 2.8.1.1), also known as Rhodanese, was initially discovered a cyanide detoxification enzyme. However, it recently found to be genetic predictor of resistance obesity-related type 2 diabetes. Diabetes is characterized by progressive loss adequate β-cell insulin secretion and onset with increased demand, which contributes the development hyperglycemia. Diabetic complications have been replicated in adult hyperglycemic zebrafish, including...
Abstract Arginine metabolism mediated by arginases plays a critical role in cell and tissue function. The arginine hydrolysis is deeply involved the urea cycle, which helps kidney excrete ammonia from blood. Upregulation of affects microenvironment stability due to presence excess To regulate arginase activities properly, synthetic peptide based on structure human I was designed assessed. Preliminary data shows it inhibits II with an IC 50 2.4 ± 0.3 1.8 0.1 mmol, respectively. Our kinetic...
The expression, purification, crystallization and preliminary X-ray diffraction characterization of malate dehydrogenase (MDH) from the malarial parasite Plasmodium falciparum (PfMDH) are reported. In order to gain a deeper understanding function role PfMDH, protein was purified homogeneity. crystallized in space group P1, with unit-cell parameters = 72, b 157, c 159 Å, α 105, β 101, γ 95°. resulting crystals diffracted maximal resolution 2.24 Å structure has been solved by molecular...
Pyridoxal kinases (PdxK) catalyze the phosphorylation of vitamin B6 precursors. Thus, these enzymes are an essential part many metabolic processes in all organisms. The protozoan parasite Plasmodium falciparum (the main causative agent Malaria tropica) possesses a unique de novo B6-biosynthesis pathway addition to interconversion based on activity plasmodial PdxK (PfPdxK). role salvage has prompted previous authors suggest as promising target for structure-based antimalarial drug design....
Peroxisomes are a major cellular compartment of eukaryotic cells, and involved in variety metabolic functions pathways according to species, cell type environmental conditions. Their biogenesis relies on conserved genes known as PEX that encode peroxin proteins. Peroxisomal membrane proteins peroxisomal matrix generated the cytosol subsequently imported into peroxisome post-translationally. Matrix containing targeting signal 1 (PTS1) recognized by cycling receptor Pex5p transported lumen....
The majority of modern anticancer approaches target DNA/protein targets involved in tumour-cell proliferation. Such have a major drawback, as nonproliferating cancer cells remain unaffected and may cause relapse or remission. Human coatomer protein complex I (COPI) subunit ζ (Copζ), component the coat cell apoptosis intracellular trafficking, has recently been proposed potential drug target. Previous studies shown that two different isoforms Copζ exist mammalian cells. While normal express...