6bfy
Crystal structure of enolase from Escherichia coli with bound 2-phosphoglycerate substrateCrystal structure of enolase from Escherichia coli with bound 2-phosphoglycerate substrate
Structural highlights
FunctionENO_ECOLI Catalyzes the reversible conversion of 2-phosphoglycerate into phosphoenolpyruvate. It is essential for the degradation of carbohydrates via glycolysis. It is also a component of the RNA degradosome, a multi-enzyme complex involved in RNA processing and messenger RNA degradation. Its interaction with RNase E is important for the turnover of mRNA, in particular on transcripts encoding enzymes of energy-generating metabolic routes. Its presence in the degradosome is required for the response to excess phosphosugar. May play a regulatory role in the degradation of specific RNAs, such as ptsG mRNA, therefore linking cellular metabolic status with post-translational gene regulation.[1] [2] [3] Publication Abstract from PubMedEnolase is a glycolytic metalloenzyme involved in carbon metabolism. The advantage of targeting enolase lies in its essentiality in many biological processes such as cell wall formation and RNA turnover and as a plasminogen receptor. We initially used a DARTS assay to identify enolase as a target in Escherichia coli. The antibacterial activities of alpha-, beta-, and gamma-substituted seven-member ring tropolones were first evaluated against four strains representing a range of Gram-negative bacteria. We observed that the chemical properties and position of the substituents on the tropolone ring play an important role in the biological activity of the investigated compounds. Both alpha- and beta-substituted phenyl derivatives of tropolone were the most active with minimum inhibitory concentrations in the range of 11-14 mug/mL. The potential inhibitory activity of the synthetic tropolones was further evaluated using an enolase inhibition assay, X-ray crystallography, and molecular docking simulations. The catalytic activity of enolase was effectively inhibited by both the naturally occurring beta-thujaplicin and the alpha- and beta-substituted phenyl derivatives of tropolones with IC50 values in range of 8-11 muM. Ligand binding parameters were assessed by isothermal titration calorimetry and differential scanning calorimetry techniques and agreed with the in vitro data. Our studies validate the antibacterial potential of tropolones with careful consideration of the position and character of chelating moieties for stronger interaction with metal ions and residues in the enolase active site. Structural and Functional Studies of Bacterial Enolase, a Potential Target against Gram-Negative Pathogens.,Krucinska J, Falcone E, Erlandsen H, Hazeen A, Lombardo MN, Estrada A, Robinson VL, Anderson AC, Wright DL Biochemistry. 2019 Mar 5;58(9):1188-1197. doi: 10.1021/acs.biochem.8b01298. Epub , 2019 Feb 15. PMID:30714720[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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