Species differences in enantioselective 2-oxidations of RS-8359, a selective and reversible MAO-A inhibitor, and cinchona alkaloids by aldehyde oxidase

Itoh, Kunio; Yamamura, Manabu; Takasaki, Wataru; Sasaki, Takuma; Masubuchi, Akiko; Tanaka, Yorihisa

doi:10.1002/bdd.494

Cited by 30 publications

(30 citation statements)

References 22 publications

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“…In contrast, roughly 1 order of magnitude higher AOX1-catalyzed zonisamide reduction activity was observed in monkey compared with that of rabbit (Kitamura et al, 2001). Monkey had more than several times greater (S)-RS-8359 2-oxidation activity than did rabbit (Itoh et al, 2006). Thus, the two species show remarkably different catalytic properties from each other depending on the substrate structures used as already documented by Beedham (2002), Kitamura et al (2006), andGarattini et al (2008).…”

Section: And (؉)-4-(4-cyanoanilino)-56-dihydro-7-hydroxy-7h-cyclopenmentioning

confidence: 76%

“…Approximately 2 orders of magnitude higher methotrexate 7-hydroxylase activity was shown in rabbit compared with that of monkey (Kitamura et al, 1999). Likewise, rabbit exhibited 2 to 3 orders of magnitude higher activity toward cinchonidine 2Ј-oxidation than did that of monkey (Itoh et al, 2006). In contrast, roughly 1 order of magnitude higher AOX1-catalyzed zonisamide reduction activity was observed in monkey compared with that of rabbit (Kitamura et al, 2001).…”

Section: And (؉)-4-(4-cyanoanilino)-56-dihydro-7-hydroxy-7h-cyclopenmentioning

confidence: 91%

“…The oxidation activities of cinchonidine and (S)-RS-8359 were measured according to our previous methods (Itoh et al, 2006). In brief, (S)-RS-8359 (2.5-400 M) or cinchonidine (2.0 -200 M) was incubated at 37°C for 30 min with enzyme solution (0.10 ml) in a reaction mixture (0.25 ml) consisting of 80 mM phosphate buffer, pH 7.4.…”

Section: Methodsmentioning

confidence: 99%

“…All the other reagents were of reagent grade. The cinchonidine 2Ј-oxide derivative was prepared according to the method previously reported (Itoh et al, 2006). The chemical structures of (S)-RS-8359 and cinchonidine are shown in Fig.…”

Section: Chemicals and Reagents (S)-rs-8359mentioning

confidence: 99%

“…The enzyme catalyzes the nucleophilic, but not electrophilic, oxidation of a wide range of endogenous and exogenous aldehydes and N-heterocyclic aromatic compounds. In addition, the enzyme can also catalyze the reductive-ring cleavage metabolism of the atypical antipsychotic drug ziprasidone in humans (Prakash et al, 1997;Beedham et al, 2003).Being fundamentally different from XOR, AOX1-catalyzed drug metabolism results in marked species differences, which have been well documented for methotrexate (Jordan et al, 1999;Kitamura et al, 1999), famciclovir (Rashidi et al, 1997), cinchona alkaloids (Beedham et al, 1992;Itoh et al, 2006), zonisamide (Kitamura et al, 2001), and a monoamine oxidase A inhibitor RS-8359 (Takasaki et al, 1999(Takasaki et al, , 2005Itoh et al, 2005Itoh et al, , 2006. As a rule, AOX1 activity is high in monkeys and humans, moderate to low in rabbits, rats, and mice, and deficient in dogs.…”

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confidence: 99%

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

Fukiya

Itoh²,

Yamaguchi³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Aldehyde oxidase 1 (AOX1) is a major member of the xanthine oxidase family belonging to the class of complex molybdo-flavoenzymes and plays an important role in the nucleophilic oxidation of N-heterocyclic aromatic compounds and various aldehydes. The enzyme has been well known to show remarkable species differences. Comparing the rabbit and monkey enzymes, the former showed extremely high activity toward cinchonidine and methotrexate, but the latter exhibited only marginal activities. In contrast, monkey had several times greater activity than did rabbit toward zonisamide and (؉)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]-pyrimidine [(S)-RS-8359]. In this report, we tried to confer high cinchonidine oxidation activity comparable with that of rabbit AOX1 to monkey AOX1. The chimera proteins prepared by restriction enzyme digestion and recombination methods between monkey and rabbit AOX1s indicated that the sequences from Asn993 to Ala1088 of rabbit AOX1 are essential for the activity. The kinetic parameters were then measured using monkey AOX1 mutants prepared by site-directed mutagenesis. The monkey V1085A mutant acquired the high cinchonidine oxidation activity. Inversely, the reciprocal rabbit A1081V mutant lost the activity entirely: amino acid 1081 of rabbit AOX1 corresponding to amino acid 1085 of monkey AOX1. Thus, cinchonidine oxidation activity was drastically changed by mutation of a single residue in AOX1. 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. 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. MO(IV) is reoxidized via rapid one-electron transfer to the Fe-S cluster and further intramolecular electron transfer to FAD. FADH 2 is finally reoxidized by molecular oxygen to produce a superoxide anion and hydrogen peroxide via either a one-electron or a two-electron transfer. The enzyme catalyzes the nucleophilic, but not electrophilic, oxidation of a wide range of endogenous and e...

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Section: And (؉)-4-(4-cyanoanilino)-56-dihydro-7-hydroxy-7h-cyclopenmentioning

confidence: 76%

Section: And (؉)-4-(4-cyanoanilino)-56-dihydro-7-hydroxy-7h-cyclopenmentioning

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Chemicals and Reagents (S)-rs-8359mentioning

confidence: 99%

mentioning

confidence: 99%

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

Fukiya

Itoh²,

Yamaguchi³

et al. 2009

Drug Metab Dispos

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Molybdenum‐Containing Hydroxylases

Zientek¹,

Kang²,

Hutzler³

et al. 2012

Encyclopedia of Drug Metabolism and Interactions

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This chapter contains a comprehensive summary about molybdenum‐containing hydroxylases and what role these enzymes play in drug metabolism. The molybdenum‐containing hydroxylases of interest to drug discovery consist of mainly two enzymes: aldehyde oxidase (AO) EC 1.2.3.1 and xanthine oxidoreductase (XOR) EC 1.2.3.2. These two enzymes will be compared and contrasted. Topics covered for both of these enzymes are structure, function, genetics, biotransformation, known inhibitors, tissue distribution, species and ethnic differences, enzyme activity variation and possible clinical implications.

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Rat strain differences in stereospecific 2‐oxidation of RS‐8359, a reversible and selective MAO‐A inhibitor, by aldehyde oxidase

Sasaki

Masubuchi

Yamamura

et al. 2006

Biopharm & Drug Disp

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Aldehyde oxidase catalysed 2-oxidation activity of the (S)-enantiomer of RS-8359, a selective and reversible monoamine oxidase A (MAO-A) inhibitor, was investigated in liver cytosolic fractions from ten rat strains. Remarkably large strain differences were observed with approximately a 230 variation between the highest activity in the Wistar-Imamichi strain and the lowest activity in the Slc:Wistar strain. The activities of Crj:SD and Slc:SD strain rats were considerably low, and that of the F344/DuCrj strain was very low. Among six Wistar strains, Crj:Wistar, Slc:Wistar, WKY/Izm, WKAH/Hkm, Jcl:Wistar and Wistar-Imamichi, the Slc:Wistar strain rats showed exceptionally low 2-oxidation activity that was comparable to that of the F344/DuCrj strain. The rat strain differences in the catalytic activity of aldehyde oxidase could correlate in part with the expressed levels of protein based on the mRNA of aldehyde oxidase. However, no small discrepancy existed in the almost negligible catalytic activity and the fairly high expression levels of protein and mRNA in the F344/DuCrj and Slc:Wistar strain rats. Some genetic factors might possibly be one of reasons for the discrepancy.

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Species differences in enantioselective 2-oxidations of RS-8359, a selective and reversible MAO-A inhibitor, and cinchona alkaloids by aldehyde oxidase

Cited by 30 publications

References 22 publications

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

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

Molybdenum‐Containing Hydroxylases

Rat strain differences in stereospecific 2‐oxidation of RS‐8359, a reversible and selective MAO‐A inhibitor, by aldehyde oxidase

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