Structural basis for the role of mammalian aldehyde oxidases in the metabolism of drugs and xenobiotics

[Display omitted] •Molybdenum is a trace element with an important contribution for human health.•Aldehyde oxidase (AOX) has a broad substrate specificity but the physiological substrates remain so far elusive.•Human AOX1 has been recognized as an enzyme with an emerging importance in phase I drug m...

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Published in:Current opinion in chemical biology 2017-04, Vol.37, p.39-47
Main Authors: Romão, Maria João, Coelho, Catarina, Santos-Silva, Teresa, Foti, Alessandro, Terao, Mineko, Garattini, Enrico, Leimkühler, Silke
Format: Article
Language:English
Subjects:
Aldehyde Oxidase - antagonists & inhibitors
Aldehyde Oxidase - chemistry
Aldehyde Oxidase - genetics
Aldehyde Oxidase - metabolism
Animals
Enzyme Inhibitors - metabolism
Enzyme Inhibitors - pharmacology
Humans
Mammals
Pharmaceutical Preparations - metabolism
Polymorphism, Single Nucleotide
Xenobiotics - metabolism
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Summary:[Display omitted] •Molybdenum is a trace element with an important contribution for human health.•Aldehyde oxidase (AOX) has a broad substrate specificity but the physiological substrates remain so far elusive.•Human AOX1 has been recognized as an enzyme with an emerging importance in phase I drug metabolism.•Single nucleotide polymorphisms result in altered AOX1 activities influencing drug metabolism.•The X-ray structure of AOX1 contributed significantly to reveal substrate and inhibitor binding. Aldehyde oxidases (AOXs) are molybdo-flavoenzymes characterized by broad substrate specificity, oxidizing aromatic/aliphatic aldehydes into the corresponding carboxylic acids and hydroxylating various heteroaromatic rings. Mammals are characterized by a complement of species-specific AOX isoenzymes, that varies from one in humans (AOX1) to four in rodents (AOX1, AOX2, AOX3 and AOX4). The physiological function of mammalian AOX isoenzymes is unknown, although human AOX1 is an emerging enzyme in phase-I drug metabolism. Indeed, the number of therapeutic molecules under development which act as AOX substrates is increasing. The recent crystallization and structure determination of human AOX1 as well as mouse AOX3 has brought new insights into the mechanisms underlying substrate/inhibitor binding as well as the catalytic activity of this class of enzymes.
ISSN:1367-5931
1879-0402
DOI:10.1016/j.cbpa.2017.01.005