6npf
Structure of E.coli enolase in complex with an analog of the natural product SF-2312 metabolite.Structure of E.coli enolase in complex with an analog of the natural product SF-2312 metabolite.
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 PubMedMany years ago, the natural secondary metabolite SF2312, produced by the actinomycete Micromonospora, was reported to display broad spectrum antibacterial properties against both Gram-positive and Gram-negative bacteria. Recent studies have revealed that SF2312, a natural phosphonic acid, functions as a potent inhibitor of human enolase. The mechanism of SF2312 inhibition of bacterial enolase and its role in bacterial growth and reproduction, however, have remained elusive. In this work, we detail a structural analysis of E. coli enolase bound to both SF2312 and its oxidized imide-form. Our studies support a model in which SF2312 acts as an analog of a high energy intermediate formed during the catalytic process. Biochemical, biophysical, computational and kinetic characterization of these compounds confirm that altering features characteristic of a putative carbanion (enolate) intermediate significantly reduces the potency of enzyme inhibition. When SF2312 is combined with fosfomycin in the presence of glucose-6 phosphate, significant synergy is observed. This suggests the two agents could be used as a potent combination, targeting distinct cellular mechanism for the treatment of bacterial infections. Together, our studies rationalize the structure-activity relationships for these phosphonates and validate enolase as a promising target for antibiotic discovery. Functional and structural basis of E. coli enolase inhibition by SF2312: a mimic of the carbanion intermediate.,Krucinska J, Lombardo MN, Erlandsen H, Hazeen A, Duay SS, Pattis JG, Robinson VL, May ER, Wright DL Sci Rep. 2019 Nov 19;9(1):17106. doi: 10.1038/s41598-019-53301-3. PMID:31745118[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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