Mammalian aldehyde oxidases: genetics, evolution and biochemistry

Abstract

Mammalian aldehyde oxidases are a small group of proteins belonging to the larger family of molybdo-flavoenzymes along with xanthine oxidoreductase and other bacterial enzymes. The two general types of reactions catalyzed by aldehyde oxidases are the hydroxylation of heterocycles and the oxidation of aldehydes into the corresponding carboxylic acids. Different animal species are characterized by a different complement of aldehyde oxidase genes. Humans contain a single active gene, while marsupials and rodents are characterized by four such genes clustering at a short distance on the same chromosome. At present, little is known about the physiological relevance of aldehyde oxidases in humans and other mammals, although these enzymes are known to play a role in the metabolism of drugs and compounds of toxicological importance in the liver. The present article provides an overview of the current knowledge of genetics, evolution, structure, enzymology, tissue distribution and regulation of mammalian aldehyde oxidases.

Aldehyde oxidase 1 gene is regulated by Nrf2 pathway

“…Although its physiological substrates have not been identified, AOX is implicated in the oxidation of indol, pyridoxal, nicotinamide and retinaldehyde (Kitamura et al, 2006;Krenitsky et al, 1972). This enzyme is considered to be an important xenobiotic metabolizing enzymes (Garattini et al, 2008). There is also great interest in AOX since it has the ability to metabolize anti-cancer drugs (e.g., methotrexate), immunosupessive agent (e.g., 6-mercaptpurine) and anti-viral drugs (Garattini et al, 2008;Kitamura et al, 2006).…”

“…This enzyme is considered to be an important xenobiotic metabolizing enzymes (Garattini et al, 2008). There is also great interest in AOX since it has the ability to metabolize anti-cancer drugs (e.g., methotrexate), immunosupessive agent (e.g., 6-mercaptpurine) and anti-viral drugs (Garattini et al, 2008;Kitamura et al, 2006). Currently, much attention has been focused on this enzyme as the target of drug development, especially for anti-obesity and anti-cancer drugs (Pryde et al, 2010;Garattini and Terao, 2011).…”

Nitrite reduction by xanthine oxidase family enzymes: a new class of nitrite reductases

“…The subsequent XO-catalysed reduction of nitrite to nitric oxide radical (NO) has also been reported over the last decade [20,[22][23][24][25][26][27][28], but it is not yet generally recognised. Interestingly, the mammalian aldehyde oxidase [29], another member of the XO family, was also recently shown to catalyse the nitrite reduction to NO [28,30]. This XOcatalysed and aldehyde oxidase catalysed nitrite reduction assumes particular importance owing to the amount of experimental evidence that points towards the participation of these two enzymes in the human in vivo formation of NO from nitrite (as was extensively and recently reviewed in [31][32][33][34][35]).…”

A Single Amino Acid Substitution Confers High Cinchonidine Oxidation Activity Comparable with That of Rabbit to Monkey Aldehyde Oxidase 1

“…Aldehyde oxidase 1 (AOX1) consists of a homodimer with a subunit molecular mass of approximately 150 kDa. Each subunit is made up of a 20-kDa N-terminal domain containing two different 2Fe-2S clusters in which reducing equivalents necessary for catalysis are stored, a 40-kDa central domain containing a flavin adenine dinucleotide (FAD), and an 85-kDa C-terminal domain containing a molybdenum cofactor (MoCo) in which a substrate binding site is located (Garattini et al, 2008). Substrates are oxidized via Mo-OH by base-assisted hydroxylation at the MoCo center, the Mo being reduced from Mo(VI) to the MO(IV) state.…”

“…However, this might be true for bulky substrates such as cinchonidine but not for small substrates. The mechanism of substrate-dependent species differences in AOX1 activity toward bulky substrates is discussed.Aldehyde oxidase (AO, EC 1.2.3.1) is a major member of the xanthine oxidase family belonging to the molybdo-flavoenzymes (MFEs) together with xanthine oxidoreductase (XOR; xanthine dehydrogenase form, EC 1.1.1.204; xanthine oxidase form, EC 1.1.3.22) (Beedham, 1985(Beedham, , 1987(Beedham, , 1998(Beedham, , 2002Kitamura et al, 2006;Garattini et al, 2008;Schumann et al, 2009). Aldehyde oxidase 1 (AOX1) consists of a homodimer with a subunit molecular mass of approximately 150 kDa.…”