| Structural highlights
Function
ENO_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 PubMed
Many 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 Also
References
- ↑ Py B, Higgins CF, Krisch HM, Carpousis AJ. A DEAD-box RNA helicase in the Escherichia coli RNA degradosome. Nature. 1996 May 9;381(6578):169-72. PMID:8610017 doi:http://dx.doi.org/10.1038/381169a0
- ↑ Bernstein JA, Lin PH, Cohen SN, Lin-Chao S. Global analysis of Escherichia coli RNA degradosome function using DNA microarrays. Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2758-63. Epub 2004 Feb 23. PMID:14981237 doi:http://dx.doi.org/10.1073/pnas.0308747101
- ↑ Morita T, Kawamoto H, Mizota T, Inada T, Aiba H. Enolase in the RNA degradosome plays a crucial role in the rapid decay of glucose transporter mRNA in the response to phosphosugar stress in Escherichia coli. Mol Microbiol. 2004 Nov;54(4):1063-75. PMID:15522087 doi:http://dx.doi.org/10.1111/j.1365-2958.2004.04329.x
- ↑ Krucinska J, Lombardo MN, Erlandsen H, Hazeen A, Duay SS, Pattis JG, Robinson VL, May ER, Wright DL. Functional and structural basis of E. coli enolase inhibition by SF2312: a mimic of the carbanion intermediate. Sci Rep. 2019 Nov 19;9(1):17106. doi: 10.1038/s41598-019-53301-3. PMID:31745118 doi:http://dx.doi.org/10.1038/s41598-019-53301-3
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