Evolution, expression, and substrate specificities of aldehyde oxidase enzymes in eukaryotes

Abstract

Aldehyde oxidases (AOXs) are a small group of enzymes belonging to the larger family of molybdo-flavoenzymes, along with the well-characterized xanthine oxidoreductase. The two major types of reactions that are catalyzed by AOXs are the hydroxylation of heterocycles and the oxidation of aldehydes to their corresponding carboxylic acids. Different animal species have different complements of AOX genes. The two extremes are represented in humans and rodents; whereas the human genome contains a single active gene (AOX1), those of rodents, such as mice, are endowed with four genes (Aox1-4), clustering on the same chromosome, each encoding a functionally distinct AOX enzyme. It still remains enigmatic why some species have numerous AOX enzymes, whereas others harbor only one functional enzyme. At present, little is known about the physiological relevance of AOX enzymes in humans and their additional forms in other mammals. These enzymes are expressed in the liver and play an important role in the metabolisms of drugs and other xenobiotics. In this review, we discuss the expression, tissue-specific roles, and substrate specificities of the different mammalian AOX enzymes and highlight insights into their physiological roles.

Molybdenum Enzymes and How They Support Virulence in Pathogenic Bacteria

“…AOXs oxidize numerous aromatic and non-aromatic aldehydes to their respective carboxylic acids, and are responsible for metabolizing various xenobiotics and drugs in mammals (Romão et al, 2017;Terao et al, 2020), while the bacterial aldehyde oxidoreductases are likely involved in metabolizing aromatic aldehydes for detoxification (Correia et al, 2016).…”

“…The sulfido-group can be replaced by selenium or another oxo-group in some XO enzymes, and interestingly, there is no amino acid ligand to the Mo center (Boyington et al, 1997;Schräder et al, 1999;Hille et al, 2014;Nishino et al, 2017). All mammalian enzymes of this family contain Mo-PPT, while Mo-PCD is present in most bacterial enzymes (Gremer and Meyer, 1996;Leimkühler et al, 1998;Magalon et al, 2011;Hille et al, 2014;Leimkühler, 2020;Terao et al, 2020).…”

Aldehyde Oxidase Contributes to All-Trans-Retinoic Acid Biosynthesis in Human Liver

“…This is largely due to the lack of Aox knockout mouse models. The only available Aox4 -/mouse model did not show any major morphological abnormalities or lethal phenotype that would be expected if atRA biosynthesis was significantly impaired (Terao et al, 2009(Terao et al, , 2020. In addition, at present no quantitative characterization of AOX contribution to atRA biosynthesis in specific tissues has been published.…”

Nicotinamide N-Methyltransferase in Acquisition of Stem Cell Properties and Therapy Resistance in Cancer

“…As such, comprehensiveanalyses involve experiments performed on laboratory animals, and the differences in some aspects of NAD + metabolism between mice and humans should be carefully considered. In mice, a commonly used model animal in cancer research, four isoforms of AOX exist (mAOX1–4), of which only mAOX2 (highly restricted to the Bowman’s gland in the nasal cavity) and mAOX3 (expressed in liver) use MNAM as a substrate [ 132 ]. This, together with the difference in efficiency to biosynthesize NAD + from tryptophan, should be taken into account when using mice models in studying NAD + -dependent processes.…”