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Title: Structural and Chemical Aspects of Resistance to the Antibiotic Fosfomycin Conferred by FosB from Bacillus cereus

Authors:
; ; ; ; ; ;  [1];  [2]
  1. Vanderbilt
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1104569
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemistry; Journal Volume: 52; Journal Issue: (41) ; 10, 2013
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Thompson, Matthew K., Keithly, Mary E., Harp, Joel, Cook, Paul D., Jagessar, Kevin L., Sulikowski, Gary A., Armstrong, Richard N., and Grand Valley). Structural and Chemical Aspects of Resistance to the Antibiotic Fosfomycin Conferred by FosB from Bacillus cereus. United States: N. p., 2014. Web. doi:10.1021/bi4009648.
Thompson, Matthew K., Keithly, Mary E., Harp, Joel, Cook, Paul D., Jagessar, Kevin L., Sulikowski, Gary A., Armstrong, Richard N., & Grand Valley). Structural and Chemical Aspects of Resistance to the Antibiotic Fosfomycin Conferred by FosB from Bacillus cereus. United States. doi:10.1021/bi4009648.
Thompson, Matthew K., Keithly, Mary E., Harp, Joel, Cook, Paul D., Jagessar, Kevin L., Sulikowski, Gary A., Armstrong, Richard N., and Grand Valley). Wed . "Structural and Chemical Aspects of Resistance to the Antibiotic Fosfomycin Conferred by FosB from Bacillus cereus". United States. doi:10.1021/bi4009648.
@article{osti_1104569,
title = {Structural and Chemical Aspects of Resistance to the Antibiotic Fosfomycin Conferred by FosB from Bacillus cereus},
author = {Thompson, Matthew K. and Keithly, Mary E. and Harp, Joel and Cook, Paul D. and Jagessar, Kevin L. and Sulikowski, Gary A. and Armstrong, Richard N. and Grand Valley)},
abstractNote = {},
doi = {10.1021/bi4009648},
journal = {Biochemistry},
number = (41) ; 10, 2013,
volume = 52,
place = {United States},
year = {Wed Aug 20 00:00:00 EDT 2014},
month = {Wed Aug 20 00:00:00 EDT 2014}
}
  • The biosynthetic pathway of the clinically important antibiotic fosfomycin uses enzymes that catalyse reactions without precedent in biology. Among these is hydroxypropylphosphonic acid epoxidase, which represents a new subfamily of non-haem mononuclear iron enzymes. Here we present six X-ray structures of this enzyme: the apoenzyme at 2.0 Angstrom resolution; a native Fe(ii)-bound form at 2.4 Angstrom resolution; a tris(hydroxymethyl)aminomethane-Co(ii)-enzyme complex structure at 1.8 Angstrom resolution; a substrate-Co(ii)-enzyme complex structure at 2.5 Angstrom resolution; and two substrate-Fe(ii)-enzyme complexes at 2.1 and 2.3 Angstrom resolution. These structural data lead us to suggest how this enzyme is able to recognize and respond tomore » its substrate with a conformational change that protects the radical-based intermediates formed during catalysis. Comparisons with other family members suggest why substrate binding is able to prime iron for dioxygen binding in the absence of {alpha}-ketoglutarate (a co-substrate required by many mononuclear iron enzymes), and how the unique epoxidation reaction of hydroxypropylphosphonic acid epoxidase may occur.« less
  • Hydroxypropylphosphonic acid epoxidase (HppE) is an unusual mononuclear iron enzyme that uses dioxygen to catalyze the oxidative epoxidation of (S)-2-hydroxypropylphosphonic acid (S-HPP) in the biosynthesis of the antibiotic fosfomycin. Additionally, the enzyme converts the R-enantiomer of the substrate (R-HPP) to 2-oxo-propylphosphonic acid. To probe the mechanism of HppE regiospecificity, we determined three X-ray structures: R-HPP with inert cobalt-containing enzyme (Co(II)-HppE) at 2.1 {angstrom} resolution; R-HPP with active iron-containing enzyme (Fe(II)-HppE) at 3.0 {angstrom} resolution; and S-HPP-Fe(II)-HppE in complex with dioxygen mimic NO at 2.9 {angstrom} resolution. These structures, along with previously determined structures of S-HPP-HppE, identify the dioxygen binding sitemore » on iron and elegantly illustrate how HppE is able to recognize both substrate enantiomers to catalyze two completely distinct reactions.« less
  • No abstract prepared.
  • No abstract prepared.