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The first mammalian aldehyde oxidase crystal structure insights into substrate specificity

  • Aldehyde oxidases (AOXs) are homodimeric proteins belonging to the xanthine oxidase family of molybdenum-containing enzymes. Each 150-kDa monomer contains a FAD redox cofactor, two spectroscopically distinct [2Fe-2S] clusters, and a molybdenum cofactor located within the protein active site. AOXs are characterized by broad range substrate specificity, oxidizing different aldehydes and aromatic N-heterocycles. Despite increasing recognition of its role in the metabolism of drugs and xenobiotics, the physiological function of the protein is still largely unknown. We have crystallized and solved the crystal structure of mouse liver aldehyde oxidase 3 to 2.9 angstrom. This is the first mammalian AOX whose structure has been solved. The structure provides important insights into the protein active center and further evidence on the catalytic differences characterizing AOX and xanthine oxidoreductase. The mouse liver aldehyde oxidase 3 three-dimensional structure combined with kinetic, mutagenesis data, molecular docking, and molecularAldehyde oxidases (AOXs) are homodimeric proteins belonging to the xanthine oxidase family of molybdenum-containing enzymes. Each 150-kDa monomer contains a FAD redox cofactor, two spectroscopically distinct [2Fe-2S] clusters, and a molybdenum cofactor located within the protein active site. AOXs are characterized by broad range substrate specificity, oxidizing different aldehydes and aromatic N-heterocycles. Despite increasing recognition of its role in the metabolism of drugs and xenobiotics, the physiological function of the protein is still largely unknown. We have crystallized and solved the crystal structure of mouse liver aldehyde oxidase 3 to 2.9 angstrom. This is the first mammalian AOX whose structure has been solved. The structure provides important insights into the protein active center and further evidence on the catalytic differences characterizing AOX and xanthine oxidoreductase. The mouse liver aldehyde oxidase 3 three-dimensional structure combined with kinetic, mutagenesis data, molecular docking, and molecular dynamics studies make a decisive contribution to understand the molecular basis of its rather broad substrate specificity.show moreshow less

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Author:Catarina Coelho, Martin Mahro, Jose Trincao, Alexandra T. P. Carvalho, Maria Joao Ramos, Mineko Terao, Enrico Garattini, Silke Leimkühler, Maria Joao Romao
DOI:https://doi.org/10.1074/jbc.M112.390419
ISSN:0021-9258 (print)
Parent Title (English):The journal of biological chemistry
Publisher:American Society for Biochemistry and Molecular Biology
Place of publication:Bethesda
Document Type:Article
Language:English
Year of first Publication:2012
Year of Completion:2012
Release Date:2017/03/26
Volume:287
Issue:48
Pagenumber:13
First Page:40690
Last Page:40702
Funder:Portuguese Science and Technology Foundation (FCT-MCTES) [PTDC/BIA-PRO/118377/2010, SFRH/BD/37948/2007]; Deutsche Forschungsgemeinschaft; DAAD-GRICES; Associazione Italiana per la Ricerca controil Cancro(AIRC); Fondazione Italo Monzino; Negri-Weizmann Foundation
Organizational units:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie
Peer Review:Referiert