1. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
2. Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, USA

Correspondence to: Catherine L. Drennan¹ Correspondence and requests for materials should be addressed to C.L.D. (Email: cdrennan@mit.edu). Atomic coordinates for the following structures have been deposited in the Protein Data Bank: apo-HppE (1ZZ6), Fe(II)-HppE (1ZZ9), form-1 S-HPP–Fe(II)-HppE (1ZZ7), form-2 S-HPP–Fe(II)-HppE (1ZZ8), Tris–Co(II)-HppE (1ZZC) and S-HPP–Co(II)-HppE (1ZZB).

Abstract

The biosynthetic pathway of the clinically important antibiotic fosfomycin uses enzymes that catalyse reactions without precedent in biology. Among these is hydroxypropylphosphonic acid epoxidase, which represents a new subfamily of non-haem mononuclear iron enzymes. Here we present six X-ray structures of this enzyme: the apoenzyme at 2.0 Å resolution; a native Fe(ii)-bound form at 2.4 Å resolution; a tris(hydroxymethyl)aminomethane–Co(ii)-enzyme complex structure at 1.8 Å resolution; a substrate–Co(ii)-enzyme complex structure at 2.5 Å resolution; and two substrate–Fe(ii)-enzyme complexes at 2.1 and 2.3 Å resolution. These structural data lead us to suggest how this enzyme is able to recognize and respond to its substrate with a conformational change that protects the radical-based intermediates formed during catalysis. Comparisons with other family members suggest why substrate binding is able to prime iron for dioxygen binding in the absence of -ketoglutarate (a co-substrate required by many mononuclear iron enzymes), and how the unique epoxidation reaction of hydroxypropylphosphonic acid epoxidase may occur.

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