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 - TY - JOUR A1 - Marelja, Zvonimir A1 - Dambowsky, Miriam A1 - Bolis, Marco A1 - Georgiou, Marina L. A1 - Garattini, Enrico A1 - Missirlis, Fanis A1 - Leimkühler, Silke T1 - The four aldehyde oxidases of Drosophila melanogaster have different gene expression patterns and enzyme substrate specificities JF - The journal of experimental biology N2 - In the genome of Drosophila melanogaster, four genes coding for aldehyde oxidases (AOX1-4) were identified on chromosome 3. Phylogenetic analysis showed that the AOX gene cluster evolved via independent duplication events in the vertebrate and invertebrate lineages. The functional role and the substrate specificity of the distinct Drosophila AOX enzymes is unknown. Two loss-of-function mutant alleles in this gene region, low pyridoxal oxidase (Po-lpo) and aldehyde oxidase-1 (Aldox-1(n1)) are associated with a phenotype characterized by undetectable AOX enzymatic activity. However, the genes involved and the corresponding mutations have not yet been identified. In this study we characterized the activities, substrate specificities and expression profiles of the four AOX enzymes in D. melanogaster. We show that the Po-lpo-associated phenotype is the consequence of a structural alteration of the AOX1 gene. We identified an 11-bp deletion in the Po-lpo allele, resulting in a frame-shift event, which removes the molybdenum cofactor domain of the encoded enzyme. Furthermore, we show that AOX2 activity is detectable only during metamorphosis and characterize a Minos-AOX2 insertion in this developmental gene that disrupts its activity. We demonstrate that the Aldox-1(n1) phenotype maps to the AOX3 gene and AOX4 activity is not detectable in our assays. KW - Aldehyde oxidase KW - Molybdoenzymes KW - Drosophila melanogaster KW - Gene duplication KW - Substrate specificities Y1 - 2014 U6 - https://doi.org/10.1242/jeb.102129 SN - 0022-0949 SN - 1477-9145 VL - 217 IS - 12 SP - 2201 EP - 2211 PB - Company of Biologists Limited CY - Cambridge ER - TY - JOUR A1 - Badalyan, Artavazd A1 - Yoga, Etienne Galemou A1 - Schwuchow, Viola A1 - Pöller, Sascha A1 - Schuhmann, Wolfgang A1 - Leimkühler, Silke A1 - Wollenberger, Ursula T1 - Analysis of the interaction of the molybdenum hydroxylase PaoABC from Escherichia coli with positively and negatively charged metal complexes JF - Electrochemistry communications : an international journal dedicated to rapid publications in electrochemistry N2 - An unusual behavior of the periplasmic aldehyde oxidoreductase (PaoABC) from Escherichia coil has been observed from electrochemical investigations of the enzyme catalyzed oxidation of aromatic aldehydes with different mediators under different conditions of ionic strength. The enzyme has similarity to other molybdoenzymes of the xanthine oxidase family, but the catalytic behavior turned out to be very different. Under steady state conditions the turnover of PaoABC is maximal at pH 4 for the negatively charged ferricyanide and at pH 9 for a positively charged osmium complex. Stopped-flow kinetic measurements of the catalytic half reaction showed that oxidation of benzaldehyde proceeds also above pH 7. Thus, benzaldehyde oxidation can proceed under acidic and basic conditions using this enzyme, a property which has not been described before for molybdenum hydroxylases. It is also suggested that the electron transfer with artificial electron acceptors and PaoABC can proceed at different protein sites and depends on the nature of the electron acceptor in addition to the ionic strength. (C) 2013 Elsevier B.V. All rights reserved. KW - Electron transfer KW - Multi-cofactor enzymes KW - Molybdoenzymes KW - Aldehyde oxidoreductase Y1 - 2013 U6 - https://doi.org/10.1016/j.elecom.2013.09.017 SN - 1388-2481 SN - 1873-1902 VL - 37 SP - 5 EP - 7 PB - Elsevier CY - New York ER -