Critical overview on the structure and metabolism of human aldehyde oxidase and its role in pharmacokinetics
- 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 comparisonAldehyde 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.…
Verfasserangaben: | Cristiano MotaORCiD, Catarina Coelho, Silke LeimkühlerORCiDGND, Enrico GarattiniORCiD, Mineko TeraoORCiD, Teresa Santos-SilvaORCiD, Maria Joao Romao |
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DOI: | https://doi.org/10.1016/j.ccr.2018.04.006 |
ISSN: | 0010-8545 |
ISSN: | 1873-3840 |
Titel des übergeordneten Werks (Englisch): | Coordination chemistry reviews |
Verlag: | Elsevier |
Verlagsort: | Lausanne |
Publikationstyp: | Rezension |
Sprache: | Englisch |
Jahr der Erstveröffentlichung: | 2018 |
Erscheinungsjahr: | 2018 |
Datum der Freischaltung: | 19.10.2021 |
Freies Schlagwort / Tag: | Aldehyde oxidase; Drug metabolism; Hepatic clearance; Molybdoenzymes; Non-CYP enzymes; Xenobiotics |
Band: | 368 |
Seitenanzahl: | 25 |
Erste Seite: | 35 |
Letzte Seite: | 59 |
Fördernde Institution: | Fundacao para a Ciencia e TecnologiaPortuguese Foundation for Science and Technology [PTDC/BBB-BEP/1185/2014, UID/Multi/04378/2013, SFRH/BPD/84581/2012]; ERDFEuropean Union (EU) [POCI-01-0145-FEDER-007728]; Associazione Italiana per la Ricerca contro it Cancro (AIRC)Associazione Italiana per la Ricerca sul Cancro (AIRC); Fondazione Italo Monzino; Deutsche Forschungsgemeinschaft (DFG)German Research Foundation (DFG) [LE1171/8-3] |
Organisationseinheiten: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Chemie |
DDC-Klassifikation: | 5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften |
Peer Review: | Referiert |