RETRACTED ARTICLE: Endoperoxide formation by an α-ketoglutarate-dependent mononuclear non-haem iron enzyme
Authors: Nathchar Naowarojna
Yi Pu
Yisong Guo
Lixin Zhang
Yan Jessie Zhang
Pinghua Liu
Andrew Weitz
Fuhang Song
Shu Wang
Ampon Sae Her
Cheng-Hsuan Wu
Heng Song
Catherine E Costello
Wupeng Yan
Michael P Hendrich
Journal: Nature (2015)
Discipline: Multidisciplinary
Keywords: peroxy-containing secondary metabolites; endoperoxide biosyntheses; prostaglandin H synthase; Fumitremorgin B endoperoxidase; α-ketoglutarate-dependent
Affiliations: Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas 78712, USA., Department of Chemistry, Boston University, Boston, Massachusetts 02215, USA., CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China., Department of Chemistry, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA., Center for Biomedical Mass Spectrometry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.

Abstract:  Many peroxy-containing secondary metabolites have been isolated and shown to provide beneficial effects to human health. Yet, the mechanisms of most endoperoxide biosyntheses are not well understood. Although endoperoxides have been suggested as key reaction intermediates in several cases, the only well-characterized endoperoxide biosynthetic enzyme is prostaglandin H synthase, a haem-containing enzyme. 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 reaction. 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. 

Retracted: Yes

PubPeer comments:
 2021 retraction. https: www.nature.com articles s41586-021-03527-x Retraction to: Nature https: doi.org 10.1038 nature15519 Published online 02 November 2015 Nature is retracting this Article because after extensive consultation with peer reviewers, it has come to our attention that the data contained within do not support its central conclusions about the mechanism of fumitremorgin B endoperoxidase (FtmOx1) and the central role of Tyr224 in catalysis. Further expert review of the crystal structure 4ZON, which was alleged to show fumitremorgin B bound to FtmOx1 (Fig. 2f of the original Article), noted that the substrate density can also be assigned to bound MES buffer and a cluster of water molecules. We have notified the Protein Data Bank about entry 4ZON. The catalytically competent binding mode of fumitremorgin B therefore remains undefined. Biochemical data on Tyr224 mutants do not conclusively support either the assignment of the observed transient radical to Tyr224 or its mechanistic role in catalysis. Author Yan Jessie Zhang has agreed with the Retraction of this Article, whereas the other authors stand by their data and disagree with this Retraction. ,