title: Structural basis of regiospecificity of a mononuclear iron enzyme in antibiotic fosfomycin biosynthesis.
abstract: 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.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Danny
authors.initials: D
authors.lastname: Yun
authors.forename: Mishtu
authors.initials: M
authors.lastname: Dey
authors.forename: Luke J
authors.initials: LJ
authors.lastname: Higgins
authors.forename: Feng
authors.initials: F
authors.lastname: Yan
authors.forename: Hung-wen
authors.initials: HW
authors.lastname: Liu
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Drennan
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001419:Bacteria / Q000737:chemistry / Q000201:enzymology*; D001665:Binding Sites; D003035:Cobalt / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D005578:Fosfomycin / Q000378:metabolism*; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D010088:Oxidoreductases / Q000737:chemistry* / Q000378:metabolism*; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D000900:Anti-Bacterial Agents; D005578:Fosfomycin; D003035:Cobalt; D007501:Iron; D010088:Oxidoreductases; C405402:2-hydroxypropylphosphonic acid epoxidase; D010100:Oxygen