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

摘要

Hydroxypropyiphosphonic 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 (RHPP) 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 A resolution; R-HPP with active iron-containing enzyme (Fe(Ⅱ)-HppE) at 3.0 A resolution; and S-HPP-Fe(Ⅱ)-HppE in complex with dioxygen mimic NO at 2.9 A 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 enantdomers to catalyze two completely distinct reactions.