Structural insight into antibiotic fosfomycin biosynthesis by a mononuclear iron enzyme.
Publication Type:Journal Article
Source:Nature, Volume 437, Issue 7060, p.838-44 (2005)
Keywords:Apoenzymes, Binding Sites, Catalysis, Cobalt, Crystallography, X-Ray, Fosfomycin, Iron, Models, Molecular, Molecular Structure, Organophosphonates, Oxidoreductases, Propane, Protein Binding, Streptomyces, Structure-Activity Relationship, Tromethamine, Water
<p>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 A resolution; a native Fe(II)-bound form at 2.4 A resolution; a tris(hydroxymethyl)aminomethane-Co(II)-enzyme complex structure at 1.8 A resolution; a substrate-Co(II)-enzyme complex structure at 2.5 A resolution; and two substrate-Fe(II)-enzyme complexes at 2.1 and 2.3 A 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 alpha-ketoglutarate (a co-substrate required by many mononuclear iron enzymes), and how the unique epoxidation reaction of hydroxypropylphosphonic acid epoxidase may occur.</p>