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
Function[ENO_ECO45] Catalyzes the reversible conversion of 2-phosphoglycerate into phosphoenolpyruvate. It is essential for the degradation of carbohydrates via glycolysis. 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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