The O2-activating, non-heme iron enzymes catalyze a wide range of oxidation reactions with important biological implications, such as DNA repair, hypoxic response, collagen biosynthesis, and histone demethylation. Most of these enzymes possess a single iron center coordinated by two His and one Asp/Glu residues in a tridentate binding motif referred to as the '2-His-1-carboxylate facial triad'. Understanding the mechanism of O2-activation by these enzymes may provide key insights into the source of their diverse substrate specificities despite similarly coordinated active site metal centers.  HppE is a unique member of this class of enzymes and functions as an iron-dependent epoxidase to convert (S)-2-hydroxypropyl-1-phosphonate (S-HPP) to the antibiotic fosfomycin. The reaction catalyzed by HppE is unusual, because it involves the 1,3-dehydrogenation of a secondary alcohol to an epoxide. Several mechanisms have been proposed for HppE catalysis, and these are differentiated primarily in terms of the identity of the O2-activated iron complex that abstracts a hydrogen atom from C1 of S-HPP to initiate epoxide ring closure.  The recent results have shown that the preferred cosubstrate is H2O2 and that HppE uses an iron(IV)-oxo complex as the hydrogen atom abstractor. These results along with recent studies using radical probes to gain insight into the mechanism of this enzyme will be presented.

Mechanistic studies of an unusual C-O bond formation in fosfomycin biosynthesis

248th National Meeting (2014)

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