Retraction Note: Endoperoxide formation by an α-ketoglutarate-dependent mononuclear non-haem iron enzyme.

The X-ray crystal structures of FtmOx1, the first known α-ketoglutarate-dependent mononuclear non-haem iron enzyme that can catalyse an endoperoxide formation reaction, are presented, along with further biochemical analyses which reveal the catalytic versatility of mononuclear non-haem iron enzymes, and help to unravel the mechanisms of endoperoxide biosyntheses. Verruculogen, a non-ribosomal peptide produced by various Aspergillus and Penicillium strains, contains an unusual and highly reactive endoperoxide (R-O-O-R) functional group that is generated from fumitremorgin B by the mononuclear non-haem iron enzyme FtmOx1. Pinghua Liu and colleagues report the X-ray crystal structures of FtmOx1 alone and in the presence of fumitremorgen B or α-ketoglutarate. Together with further biochemical analyses, these structures reveal the catalytic versatility of mononuclear non-haem iron enzymes, and help to unravel the mechanisms of endoperoxide biosyntheses. Verruculogen, a non-ribosomal peptide produced by various Aspergillus and Penicillium strains, contains an unusual and highly reactive endoperoxide (R-O-O-R) functional group that is generated from fumitremorgin B by the mononuclear non-haem iron enzyme FtmOx1. Pinghua Liu and colleagues report the X-ray crystal structures of FtmOx1 alone and in the presence of fumitremorgen B or α-ketoglutarate. Together with further biochemical analyses, these structures reveal the catalytic versatility of mononuclear non-haem iron enzymes, and help to unravel the mechanisms of endoperoxide biosyntheses. Many peroxy-containing secondary metabolites1,2 have been isolated and shown to provide beneficial effects to human health3,4,5. Yet, the mechanisms of most endoperoxide biosyntheses are not well understood. Although endoperoxides have been suggested as key reaction intermediates in several cases6,7,8, the only well-characterized endoperoxide biosynthetic enzyme is prostaglandin H synthase, a haem-containing enzyme9. Fumitremorgin B endoperoxidase (FtmOx1) from Aspergillus fumigatus is the first reported α-ketoglutarate-dependent mononuclear non-haem iron enzyme that can catalyse an endoperoxide formation reaction10,11,12. To elucidate the mechanistic details for this unique chemical transformation, we report the X-ray crystal structures of FtmOx1 and the binary complexes it forms with either the co-substrate (α-ketoglutarate) or the substrate (fumitremorgin B). Uniquely, after α-ketoglutarate has bound to the mononuclear iron centre in a bidentate fashion, the remaining open site for oxygen binding and activation is shielded from the substrate or the solvent by a tyrosine residue (Y224). Upon replacing Y224 with alanine or phenylalanine, the FtmOx1 catalysis diverts from endoperoxide formation to the more commonly observed hydroxylation. Subsequent characterizations by a combination of stopped-flow optical absorption spectroscopy and freeze-quench electron paramagnetic resonance spectroscopy support the presence of transient radical species in FtmOx1 catalysis. Our results help to unravel the novel mechanism for this endoperoxide formation reaction.