title: Structural insight into antibiotic fosfomycin biosynthesis by a mononuclear iron enzyme.
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 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.
authors: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors: Luke J
authors: LJ
authors: Higgins
authors: Feng
authors: F
authors: Yan
authors: Pinghua
authors: P
authors: Liu
authors: Hung-wen
authors: HW
authors: Liu
authors: Catherine L
authors: CL
authors: Drennan
mesh_terms: D001051:Apoenzymes / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002384:Catalysis; D003035:Cobalt / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D005578:Fosfomycin / Q000096:biosynthesis* / Q000737:chemistry; D007501:Iron / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry / Q000378:metabolism; D010088:Oxidoreductases / Q000737:chemistry* / Q000378:metabolism*; D011407:Propane / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D013302:Streptomyces / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014325:Tromethamine / Q000737:chemistry / Q000378:metabolism; D014867:Water / Q000737:chemistry / Q000378:metabolism
chemical_list: C504690:5-hydroxypropylphosphonic acid; D001051:Apoenzymes; D063065:Organophosphonates; D014325:Tromethamine; D014867:Water; D005578:Fosfomycin; D003035:Cobalt; D007501:Iron; D010088:Oxidoreductases; C405402:2-hydroxypropylphosphonic acid epoxidase; D011407:Propane