scholarly journals Functional Characterization of a SUMO Deconjugating Protease of Plasmodium falciparum Using Newly Identified Small Molecule Inhibitors

2011 ◽  
Vol 18 (6) ◽  
pp. 711-721 ◽  
Author(s):  
Elizabeth L. Ponder ◽  
Victoria E. Albrow ◽  
Brittany A. Leader ◽  
Miklós Békés ◽  
Jowita Mikolajczyk ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Functional Characterization

scholarly journals Structural and functional characterization of Rv0792c from Mycobacterium tuberculosis: identifying small molecule inhibitors against GntR protein

2021 ◽  
Author(s):  
Neeraj Kumar Chauhan ◽  
Anjali Anand ◽  
Arun Sharma ◽  
Kanika Dhiman ◽  
Tannu Priya Gosain ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Small Molecule ◽  
Model Building ◽  
Small Molecule Inhibitors ◽  
Functional Characterization ◽  
Binding Activity ◽  
Microbial Pathogens ◽  
Saxs Data ◽  
Gntr Family

ABSTRACTIn order to adapt in host tissues, microbial pathogens regulate their gene expression through an array of transcription factors. Here, we have functionally characterized Rv0792c, a GntR homolog from M. tuberculosis. In comparison to the parental strain, ΔRv0792c mutant strain of M. tuberculosis was compromised for survival upon exposure to oxidative stress, cell wall agents and infection in guinea pigs. RNA-seq analysis revealed that Rv0792c regulates the expression of genes that are involved in stress adaptation and virulence of M. tuberculosis. Solution small angle X-ray scattering (SAXS) data steered model building confirmed that the C-terminal region plays a pivotal role in dimer formation. Systematic evolution of ligands by exponential enrichment resulted in identification of ssDNA aptamers that can be used as a tool to identify small molecule inhibitors targeting Rv0792c. Using SELEX and SAXS data based modelling, we identified residues essential for the DNA binding activity of Rv0792c and I-OMe-Tyrphostin as an inhibitor of Rv0792c aptamer binding activity. Taken together, we provide a detailed shape-function characterization of GntR family of transcription factors from M. tuberculosis. To the best of our knowledge, this is the first study that has resulted in the identification of small molecule inhibitors against GntR family of transcription factors from bacterial pathogens.

scholarly journals Discovery and mechanism of action of small molecule inhibitors of ceramidases

2021 ◽  
Author(s):  
Sebastien Granier ◽  
Robert D Healey ◽  
Essa Saied ◽  
Xiaojing Cong ◽  
Gergely Karsai ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Small Molecules ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Integral Membrane Proteins ◽  
Sphingolipid Metabolism ◽  
New Paradigm ◽  
Biophysical Characterization ◽  
Sphingosine 1 Phosphate

Sphingolipid metabolism is tightly controlled by enzymes to regulate essential processes such as energy utilisation and cell proliferation. The central metabolite is ceramide, a pro-apoptotic lipid catabolized by ceramidase enzymes to ultimately produce pro-proliferative sphingosine-1-phosphate. Human ceramidases can be soluble proteins (acid and neutral ceramidase) or integral membrane proteins (alkaline ceramidases). Increasing ceramide levels to increase apoptosis has shown efficacy as a cancer treatment using small molecules inhibiting a soluble ceramidase. Due to the transmembrane nature of alkaline ceramidases, no specific small molecule inhibitors have been reported. Here, we report novel fluorescent substrates (FRETceramides) of ceramidases that can be used to monitor enzyme activity in real-time. We use FRETceramides to discover the first drug-like inhibitors of alkaline ceramidase 3 (ACER3) which are active in cell-based assays. Biophysical characterization of enzyme:inhibitor interactions reveal a new paradigm for inhibition of lipid metabolising enzymes with non-lipidic small molecules.

Structural and Functional Characterization of Plasmodium falciparum Nicotinic Acid Mononucleotide Adenylyltransferase

2016 ◽  
Vol 428 (24) ◽  
pp. 4946-4961 ◽  
Author(s):  
Jochen Bathke ◽  
Karin Fritz-Wolf ◽  
Christina Brandstädter ◽  
Anja Burkhardt ◽  
Esther Jortzik ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Nicotinic Acid ◽  
Functional Characterization
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