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Structure and evolution of vertebrate aldehyde oxidases: from gene duplication to gene suppression

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Abstract

Aldehyde oxidases (AOXs) and xanthine dehydrogenases (XDHs) belong to the family of molybdo-flavoenzymes. Although AOXs are not identifiable in fungi, these enzymes are represented in certain protists and the majority of plants and vertebrates. The physiological functions and substrates of AOXs are unknown. Nevertheless, AOXs are major drug metabolizing enzymes, oxidizing a wide range of aromatic aldehydes and heterocyclic compounds of medical/toxicological importance. Using genome sequencing data, we predict the structures of AOX genes and pseudogenes, reconstructing their evolution. Fishes are the most primitive organisms with an AOX gene (AOXα), originating from the duplication of an ancestral XDH. Further evolution of fishes resulted in the duplication of AOXα into AOXβ and successive pseudogenization of AOXα. AOXβ is maintained in amphibians and it is the likely precursors of reptilian, avian, and mammalian AOX1. Amphibian AOXγ is a duplication of AOXβ and the likely ancestor of reptilian and avian AOX2, which, in turn, gave rise to mammalian AOX3L1. Subsequent gene duplications generated the two mammalian genes, AOX3 and AOX4. The evolution of mammalian AOX genes is dominated by pseudogenization and deletion events. Our analysis is relevant from a structural point of view, as it provides information on the residues characterizing the three domains of each mammalian AOX isoenzyme. We cloned the cDNAs encoding the AOX proteins of guinea pig and cynomolgus monkeys, two unique species as to the evolution of this enzyme family. We identify chimeric RNAs from the human AOX3 and AOX3L1 pseudogenes with potential to encode a novel microRNA.

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Acknowledgments

Grants from the Telethon-Italy Foundation, the Fondazione Cariplo, the Fondazione Italo Monzino, and the Negri-Weizmann Foundation were fundamental for the completion of this work. The work was also partially supported with grants from the Associazione Italiana per la Ricerca contro il Cancro (AIRC). We would like to thank the talented student, Valentina Novelli for sequence analysis. We acknowledge the help of Felice Deceglie with the artwork.

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Authors and Affiliations

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

    Mami Kurosaki, Marco Bolis, Maddalena Fratelli, Maria Monica Barzago, Mineko Terao & Enrico Garattini

  2. Department of Bioengineering, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133, Milan, Italy

    Linda Pattini

  3. Istututo di Biologia Cellulare e Neurobiologia, Consiglio Nazionale delle Ricerche, via Anguillarese 301, 00123, Rome, Italy

    Gemma Perretta

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  1. Mami Kurosaki
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Correspondence to Enrico Garattini.

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M. Kurosaki and M. Bolis contributed equally to this work.

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Kurosaki, M., Bolis, M., Fratelli, M. et al. Structure and evolution of vertebrate aldehyde oxidases: from gene duplication to gene suppression. Cell. Mol. Life Sci. 70, 1807–1830 (2013). https://doi.org/10.1007/s00018-012-1229-5

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