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Structure and function of mammalian aldehyde oxidases

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Abstract

Mammalian aldehyde oxidases (AOXs; EC1.2.3.1) are a group of conserved proteins belonging to the family of molybdo-flavoenzymes along with the structurally related xanthine dehydrogenase enzyme. AOXs are characterized by broad substrate specificity, oxidizing not only aromatic and aliphatic aldehydes into the corresponding carboxylic acids, but also hydroxylating a series of heteroaromatic rings. The number of AOX isoenzymes expressed in different vertebrate species is variable. The two extremes are represented by humans, which express a single enzyme (AOX1) in many organs and mice or rats which are characterized by tissue-specific expression of four isoforms (AOX1, AOX2, AOX3, and AOX4). In vertebrates each AOX isoenzyme is the product of a distinct gene consisting of 35 highly conserved exons. The extant species-specific complement of AOX isoenzymes is the result of a complex evolutionary process consisting of a first phase characterized by a series of asynchronous gene duplications and a second phase where the pseudogenization and gene deletion events prevail. In the last few years remarkable advances in the elucidation of the structural characteristics and the catalytic mechanisms of mammalian AOXs have been made thanks to the successful crystallization of human AOX1 and mouse AOX3. Much less is known about the physiological function and physiological substrates of human AOX1 and other mammalian AOX isoenzymes, although the importance of these proteins in xenobiotic metabolism is fairly well established and their relevance in drug development is increasing. This review article provides an overview and a discussion of the current knowledge on mammalian AOX.

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Acknowledgments

The financial support granted by the Fondazione Italo Monzino and the Associazione Italiana per la Ricerca contro il Cancro (AIRC) to Enrico Garattini was fundamental for the extension of this review article. This work was also financially supported by the Deutsche Forschungsgemeinschaft (DFG) grant LE1171/8-1 to Silke Leimkühler and by. Fundação para a Ciência e Tecnologia through projects UID/Multi/04378/2013, PTDC/BBB-BEP/1185/2014, EXCL/QEQ-COM/0394/2012, PTDC/BIA-PRO/118377/2010 (M.J.R., T.S.-S., C.C.), SFRH/BPD/84581/2012 (C.C.) and DAAD-441.00 (M.J.R., T.S.-S., S.L.). We also thank the I02 staff of the Diamond Light Source (DLS), the X06DA-PXIII staff from the Swiss Light Source (SLS) and the staff from ID14-1, ID29-1, and ID23-1 from the European Synchrotron Radiation Facility (ESRF). We would also like to acknowledge the help of Mr. Felice Deceglie and Mr. Alessandro Soave for the artwork.

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Authors and Affiliations

  1. Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, via La Masa 19, 20156, Milan, Italy

    Mineko Terao, Marco Bolis, Maddalena Fratelli & Enrico Garattini

  2. UCIBIO, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 32829-516, Caparica, Lisbon, Portugal

    Maria João Romão, Catarina Coelho & Teresa Santos-Silva

  3. Department of Molecular Enzymology, Institute of Biochemistry and Biology, University of Potsdam, Karl-Liebknecht-Str. 24-25, 14476, Potsdam, Germany

    Silke Leimkühler

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  1. Mineko Terao
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Correspondence to Enrico Garattini.

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Terao, M., Romão, M.J., Leimkühler, S. et al. Structure and function of mammalian aldehyde oxidases. Arch Toxicol 90, 753–780 (2016). https://doi.org/10.1007/s00204-016-1683-1

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