TY - JOUR A1 - Terao, Mineko A1 - Romao, Maria Joao A1 - Leimkühler, Silke A1 - Bolis, Marco A1 - Fratelli, Maddalena A1 - Coelho, Catarina A1 - Santos-Silva, Teresa A1 - Garattini, Enrico T1 - Structure and function of mammalian aldehyde oxidases JF - Archives of toxicology : official journal of EUROTOX N2 - 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. KW - Aldehyde oxidase KW - Molybdo-flavoenzymes KW - Xanthine oxidoreductase KW - Drug metabolism Y1 - 2016 U6 - https://doi.org/10.1007/s00204-016-1683-1 SN - 0340-5761 SN - 1432-0738 VL - 90 SP - 753 EP - 780 PB - Springer CY - Heidelberg ER - TY - JOUR A1 - Mota, Cristiano A1 - Coelho, Catarina A1 - Leimkühler, Silke A1 - Garattini, Enrico A1 - Terao, Mineko A1 - Santos-Silva, Teresa A1 - Romao, Maria Joao T1 - Critical overview on the structure and metabolism of human aldehyde oxidase and its role in pharmacokinetics JF - Coordination chemistry reviews N2 - Aldehyde oxidases are molybdenum and flavin dependent enzymes characterized by a very wide substrate specificity and performing diverse reactions that include oxidations (e.g., aldehydes and azaheterocycles), hydrolysis of amide bonds, and reductions (e.g., nitro, S-oxides and N-oxides). Oxidation reactions and amide hydrolysis occur at the molybdenum site while the reductions are proposed to occur at the flavin site. AOX activity affects the metabolism of different drugs and xenobiotics, some of which designed to resist other liver metabolizing enzymes (e.g., cytochrome P450 monooxygenase isoenzymes), raising its importance in drug development. This work consists of a comprehensive overview on aldehyde oxidases, concerning the genetic evolution of AOX, its diversity among the human population, the crystal structures available, the known catalytic reactions and the consequences in pre-clinical pharmacokinetic and pharmacodynamic studies. Analysis of the different animal models generally used for pre-clinical trials and comparison between the human (hAOX1), mouse homologs as well as the related xanthine oxidase (XOR) are extensively considered. The data reviewed also include a systematic analysis of representative classes of molecules that are hAOX1 substrates as well as of typical and well characterized hAOX1 inhibitors. The considerations made on the basis of a structural and functional analysis are correlated with reported kinetic and metabolic data for typical classes of drugs, searching for potential structural determinants that may dictate substrate and/or inhibitor specificities. KW - Drug metabolism KW - Aldehyde oxidase KW - Xenobiotics KW - Molybdoenzymes KW - Non-CYP enzymes KW - Hepatic clearance Y1 - 2018 U6 - https://doi.org/10.1016/j.ccr.2018.04.006 SN - 0010-8545 SN - 1873-3840 VL - 368 SP - 35 EP - 59 PB - Elsevier CY - Lausanne ER -