Mycobacterial OtsA Structures Unveil Substrate Preference Mechanism and Allosteric Regulation by 2-Oxoglutarate and 2-Phosphoglycerate.
American Society for Microbiology
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Mendes, V., Acebrón-García-de-Eulate, M., Verma, N., Blaszczyk, M., Dias, M. V., & Blundell, T. (2019). Mycobacterial OtsA Structures Unveil Substrate Preference Mechanism and Allosteric Regulation by 2-Oxoglutarate and 2-Phosphoglycerate.. mBio, 10 (6)https://doi.org/10.1128/mbio.02272-19
Trehalose is an essential disaccharide for mycobacteria and a key constituent of several cell wall glycolipids with fundamental roles in pathogenesis. Mycobacteria possess two pathways for trehalose biosynthesis. However, only the OtsAB pathway was found to be essential in M. tuberculosis, with marked growth and virulence defects of OtsA mutants and strict essentiality of OtsB2. Herein, we report the first mycobacterial OtsA structures from M. thermoresistibile in both apo and ligand-bound forms. Structural information reveals three key residues in the mechanism of substrate preference that were further confirmed by site-directed mutagenesis. Additionally, we identify 2-oxoglutarate and 2-phosphoglycerate as allosteric regulators of OtsA. The structural analysis in this work strongly contributed to define the mechanisms for feedback inhibition, show different conformational states of the enzyme and map a new allosteric site.
Mycobacteriaceae, Ketoglutaric Acids, Glyceric Acids, Glucosyltransferases, Trehalose, Bacterial Proteins, Gene Expression Regulation, Bacterial, Gene Expression Regulation, Enzymologic, Allosteric Regulation, Substrate Specificity
Bill and Melinda Gates Foundation (OPP1158806)
Bill & Melinda Gates Foundation (via Foundation for the National Institutes of Health (FNIH)) (BLUN17STB)
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External DOI: https://doi.org/10.1128/mbio.02272-19
This record's URL: https://www.repository.cam.ac.uk/handle/1810/298750
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