Structural Basis of Regiospecificity of a Mononuclear Iron Enzyme in Antibiotic Fosfomycin Biosynthesis

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 subst...

Full description

Saved in:
Bibliographic Details
Published in:Journal of the American Chemical Society 2011-07, Vol.133 (29), p.11262-11269
Main Authors: Yun, Danny, Dey, Mishtu, Higgins, Luke J, Yan, Feng, Liu, Hung-wen, Drennan, Catherine L
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Anti-Bacterial Agents - metabolism
ANTIBIOTICS
Bacteria - chemistry
Bacteria - enzymology
Binding Sites
BIOSYNTHESIS
Cobalt - chemistry
Cobalt - metabolism
Crystallography, X-Ray
ENZYMES
Fosfomycin - metabolism
IRON
Iron - chemistry
Iron - metabolism
Models, Molecular
Oxidoreductases - chemistry
Oxidoreductases - metabolism
Oxygen - chemistry
Oxygen - metabolism
Protein Conformation
RESOLUTION
Stereoisomerism
Substrate Specificity
SUBSTRATES
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 Å resolution; R-HPP with active iron-containing enzyme (Fe(II)–HppE) at 3.0 Å resolution; and S-HPP–Fe(II)–HppE in complex with dioxygen mimic NO at 2.9 Å resolution. These structures, along with previously determined structures of S-HPP–HppE, identify the dioxygen binding site on iron and elegantly illustrate how HppE is able to recognize both substrate enantiomers to catalyze two completely distinct reactions.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja2025728