Evidence that the Fosfomycin-Producing Epoxidase, HppE, Is a Non–Heme-Iron Peroxidase

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Science  22 Nov 2013:
Vol. 342, Issue 6161, pp. 991-995
DOI: 10.1126/science.1240373

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The HppE enzyme uses iron to catalyze oxidation of an alcohol to an epoxide ring in the biosynthesis of the antibiotic fosfomycin. Because this process is a two-electron oxidation, it has been unclear how the enzyme reduces its presumed oxidative partner O2 all the way to water. Where do the two extra electrons come from? Wang et al. (p. 991, published 10 October; see the Perspective by Raushel) now show that HppE is actually a peroxidase, and thus reduces H2O2, for which just two electrons are sufficient. The result expands the structural scope of iron-bearing peroxidase enzymes beyond heme motifs.


The iron-dependent epoxidase HppE converts (S)-2-hydroxypropyl-1-phosphonate (S-HPP) to the antibiotic fosfomycin [(1R,2S)-epoxypropylphosphonate] in an unusual 1,3-dehydrogenation of a secondary alcohol to an epoxide. HppE has been classified as an oxidase, with proposed mechanisms differing primarily in the identity of the O2-derived iron complex that abstracts hydrogen (H•) from C1 of S-HPP to initiate epoxide ring closure. We show here that the preferred cosubstrate is actually H2O2 and that HppE therefore almost certainly uses an iron(IV)-oxo complex as the H• abstractor. Reaction with H2O2 is accelerated by bound substrate and produces fosfomycin catalytically with a stoichiometry of unity. The ability of catalase to suppress the HppE activity previously attributed to its direct utilization of O2 implies that reduction of O2 and utilization of the resultant H2O2 were actually operant.

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