Stimulation of retinoic acid production and growth by ubiquitously expressed alcohol dehydrogenase
            <i>Adh3</i>

Molotkov, Andrei; Fan, Xiaohong; Deltour, Louise; Foglio, Mario; Martras, Sílvia; Farrés, Jaume; Parés, Xavier; Duester, Gregg

doi:10.1073/pnas.082093299

Cited by 129 publications

(135 citation statements)

References 52 publications

(80 reference statements)

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“…In particular, acetaldehyde is the oxidation product of ethanol and is involved in the liver damage observed in individuals chronically exposed to alcohol (35,36). Butyraldehyde is a catabolite of butyryl-CoA (www.expasy.org/cgi-bin/search-biochem-index), and retinaldehyde is the direct precursor of the vitamin A active metabolite retinoic acid (37,38). As shown in Table IV, upon incubation with purified AOH1 and AOX1, benzaldehyde and retinaldehyde are rapidly oxidized and reduce the electron acceptor potassium ferricyanide.…”

Section: The Structure Of the Promoter Region Of The Aoh1 Gene In Dbamentioning

confidence: 99%

Regulation and Biochemistry of Mouse Molybdo-flavoenzymes

Vila¹,

Kurosaki²,

Barzago³

et al. 2004

Journal of Biological Chemistry

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Mouse molybdo-flavoenzymes consist of xanthine oxidoreductase, aldehyde oxidase (AOX1), and two recently identified proteins, AOH1 and AOH2 (aldehyde oxidase homologues 1 and 2). Here we demonstrate that CD-1, C57BL/6, 129/Sv, and other mouse strains synthesize high levels of AOH1 in the liver and AOH2 in the skin. By contrast, the DBA/2 and CBA strains are unique, having a selective deficit in the expression of the AOH1 and AOH2 genes. DBA/2 animals synthesize trace amounts of a catalytically active AOH1 protein. However, relative to CD-1 animals, an over 2 log reduction in the steady-state levels of liver AOH1 mRNA, protein, and enzymatic activity is observed in basal conditions and following administration of testosterone. The DBA/2 mouse represents a unique opportunity to purify AOX1 and compare its enzymatic characteristics to those of the AOH1 protein. The spectroscopy and biochemistry of AOX1 are very similar to those of AOH1 except for a differential sensitivity to the non-competitive inhibitory effect of norharmane. AOX1 and AOH1 oxidize an overlapping set of aldehydes and heterocycles. For most compounds, the substrate efficiency (V max /K m ) of AOX1 is superior to that of AOH1. Alkylic alcohols and acetaldehyde, the toxic metabolite of ethanol, are poor substrates of both enzymes. Consistent with this, the levels of acetaldehyde in the livers of ethanol administered CD-1 and DBA/2 mice are similar, indicating that neither enzyme is involved in the in vivo biotransformation of acetaldehyde.

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Section: The Structure Of the Promoter Region Of The Aoh1 Gene In Dbamentioning

confidence: 99%

Regulation and Biochemistry of Mouse Molybdo-flavoenzymes

Vila¹,

Kurosaki²,

Barzago³

et al. 2004

Journal of Biological Chemistry

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“…Biochemical studies indicate that both isomers of RA can be generated in vitro from vitamin A (retinol) by cytosolic alcohol dehydrogenases (21) and microsomal short-chain dehydrogenases (22,23), which each catalyze oxidation of all-trans-retinol and 9-cis-retinol to the corresponding retinaldehyde derivatives, followed by cytosolic retinaldehyde dehydrogenase (Raldh), which catalyzes further oxidation of both all-trans-retinaldehyde and 9-cis-retinaldehyde to produce all-trans-RA or 9-cis-RA (24,25). Mouse genetic studies support a role in RA synthesis for alcohol dehydrogenase genes Adh1, Adh3, and Adh4 (26,27) as well as Raldh genes Raldh2 (Aldh1a2) (28,29) and Raldh1 (Aldh1a1) (30). Thus, 9-cis-RA can potentially be synthesized by presently known enzymes, or it can be derived from isomerization of all-trans-RA (8).…”

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confidence: 99%

Retinoid activation of retinoic acid receptor but not retinoid X receptor is sufficient to rescue lethal defect in retinoic acid synthesis

Mic

Molotkov

Benbrook

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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208

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Two isomers of retinoic acid (RA) may be necessary as ligands for retinoid signaling: all-trans-RA for RA receptors (RARs) and 9-cis-RA for retinoid X receptors (RXRs). This was explored by using retinaldehyde dehydrogenase (Raldh)2 ؊/؊ mouse embryos lacking mesodermal RA synthesis that display early growth arrest unless rescued by all-trans-RA administration. Because isomerization of all-trans-RA to 9-cis-RA can occur, it is unclear whether both ligands are needed for rescue. We show here that an RAR-specific ligand can rescue Raldh2 ؊/؊ embryos as efficiently as all-trans-RA, whereas an RXR-specific ligand has no effect. Further, whereas all-trans-RA was detected in embryos, 9-cis-RA was undetectable unless a supraphysiological dose of all-trans-RA was administered, revealing that 9-cis-RA is of pharmacological but not physiological significance. Because 9-cis-RA is undetectable and unnecessary for Raldh2 ؊/؊ rescue, and others have shown that 4-oxo-RA is unnecessary for mouse development, all-trans-RA emerges as the only ligand clearly necessary for retinoid receptor signaling.

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“…Genetic studies in mice have demonstrated that oxidation of retinol to retinaldehyde is ubiquitous during development as it is controlled by ubiquitously expressed alcohol dehydrogenase Adh3 and several additional overlapping tissue-specific enzymes (21). As for the second step, mouse genetic studies have shown that oxidation of retinaldehyde to RA is controlled by tissue-specific retinaldehyde dehydrogenase genes including Raldh1 (Aldh1a1) (22), Raldh2 (Aldh1a2) (19,23), and Raldh3 (Aldh1a3) (24).…”

mentioning

confidence: 99%

Retinoic Acid Synthesis Controlled by Raldh2 Is Required Early for Limb Bud Initiation and Then Later as a Proximodistal Signal during Apical Ectodermal Ridge Formation

Mic

Sîrbu

Duester

2004

Journal of Biological Chemistry

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103

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We present evidence for the existence of two phases of retinoic acid (RA) signaling required for vertebrate limb development. Limb RA synthesis is under the control of retinaldehyde dehydrogenase-2 (Raldh2) expressed in the lateral plate mesoderm, which generates a proximodistal RA signal during limb outgrowth. We report that Raldh2 ؊/؊ embryos lack trunk mesodermal RA activity and fail to initiate forelimb development. This is associated with deficient expression of important limb determinants Tbx5, Meis2, and dHand needed to establish forelimb bud initiation, proximal identity, and the zone of polarizing activity (ZPA), respectively. Limb expression of these genes can be rescued by maternal RA treatment limited to embryonic day 8 (E8) during limb field establishment, but the mutant forelimbs obtained at E10 display a significant growth defect associated with a smaller apical ectodermal ridge (AER), referred to here as an apical ectodermal mound (AEM). In these RA-deficient forelimbs, a ZPA expressing Shh forms, but it is located distally adjacent to the Fgf8 expression domain in the AEM rather than posteriorly as is normal. AER formation in Raldh2 ؊/؊ forelimbs is rescued by continuous RA treatment through E10, which restores RA to distal ectoderm fated to become the AER. Our findings indicate the existence of an early phase of RA signaling acting upstream of Tbx5, Meis2, and dHand, followed by a late phase of RA signaling needed to expand AER structure fully along the distal ectoderm. During ZPA formation, RA acts early to activate expression of dHand, but it is not required later for Shh activation.

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Stimulation of retinoic acid production and growth by ubiquitously expressed alcohol dehydrogenase Adh3

Cited by 129 publications

References 52 publications

Regulation and Biochemistry of Mouse Molybdo-flavoenzymes

Regulation and Biochemistry of Mouse Molybdo-flavoenzymes

Retinoid activation of retinoic acid receptor but not retinoid X receptor is sufficient to rescue lethal defect in retinoic acid synthesis

Retinoic Acid Synthesis Controlled by Raldh2 Is Required Early for Limb Bud Initiation and Then Later as a Proximodistal Signal during Apical Ectodermal Ridge Formation

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