title: Structure and function of mammalian aldehyde oxidases.
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.
authors.affiliation: Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156, Milan, Italy.
authors.forename: Mineko
authors.initials: M
authors.lastname: Terao
authors.affiliation: UCIBIO, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 32829-516, Caparica, Lisbon, Portugal.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Romão
authors.affiliation: Department of Molecular Enzymology, Institute of Biochemistry and Biology, University of Potsdam, Karl-Liebknecht-Str. 24-25, 14476, Potsdam, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Leimkühler
authors.affiliation: Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bolis
authors.affiliation: Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156, Milan, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Fratelli
authors.affiliation: UCIBIO, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 32829-516, Caparica, Lisbon, Portugal.
authors.forename: Catarina
authors.initials: C
authors.lastname: Coelho
authors.affiliation: UCIBIO, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 32829-516, Caparica, Lisbon, Portugal.
authors.forename: Teresa
authors.initials: T
authors.lastname: Santos-Silva
authors.affiliation: Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156, Milan, Italy. enrico.garattini@marionegri.it.
authors.forename: Enrico
authors.initials: E
authors.lastname: Garattini
mesh_terms: D042931:Aldehyde Oxidase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000445:Aldehyde Oxidoreductases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002384:Catalysis; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics; D019143:Evolution, Molecular; D006801:Humans; D008658:Inactivation, Metabolic; D008322:Mammals; D020641:Polymorphism, Single Nucleotide; D015262:Xenobiotics / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D015262:Xenobiotics; D000445:Aldehyde Oxidoreductases; C443116:Aox3 protein, mouse; C526436:AOX1 protein, human; D042931:Aldehyde Oxidase
keywords: Aldehyde oxidase; Drug metabolism; Molybdo-flavoenzymes; Xanthine oxidoreductase