Distinct Retinoid Metabolic Functions for Alcohol Dehydrogenase Genes Adh1 and Adh4 in Protection against Vitamin A Toxicity or Deficiency Revealed in Double Null Mutant Mice

Molotkov, Andrei; Deltour, Louise; Foglio, Mario; Cuenca, Arnold E.; Duester, Gregg

doi:10.1074/jbc.m112039200

Cited by 86 publications

(89 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1). Mutants RD (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) or RD(1-30), which lack the first 18 and 30 amino acid residues of Rdh1, respectively, did not localize to the ER. Surprisingly both distributed in the mitochondria fraction with cytochrome c and localized in mitochondria in intact cells (Figs.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover alcohol dehydrogenase access to physiological amounts of unbound retinol in intact cells may be limited because retinol has very low solubility in aqueous media when not sequestered tightly with CRBP. Notably gene knock-out experiments did not provide evidence for an alcohol dehydrogenase contribution to retinol metabolism under normal circumstances, because Adh1 Ϫ/Ϫ , Adh3 Ϫ/Ϫ , Adh4 Ϫ/Ϫ , and dual Adh1/Adh4 Ϫ/Ϫ null mice showed no retinoic acid deficiency phenotype nor any disturbance of retinoid metabolism or compensatory response (12,13).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Elements in the N-terminal Signaling Sequence That Determine Cytosolic Topology of Short-chain Dehydrogenases/Reductases

Zhang

Napoli

2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

High affinity, retinoid-specific binding proteins chaperone retinoids to manage their transport and metabolism. Proposing mechanisms of retinoid transfer between these binding proteins and membrane-associated retinoid-metabolizing enzymes requires insight into enzyme topology. We therefore determined the topology of mouse retinol dehydrogenase type 1 (Rdh1) and cis-retinoid androgen dehydrogenase type 1 (Crad1) in the endoplasmic reticulum of intact mammalian cells. The properties of Rdh1 were compared with a chimera with a luminal signaling sequence (11␤-hydroxysteroid dehydrogenase (11␤-HSD1)(1-41)/Rdh1(23-317); the green fluorescent protein (GFP) fusion proteins Rdh1(1-22)/ GFP, Crad1(1-22)/GFP, and 11␤-HSD1(1-41)/GFP; and signaling sequence charge difference mutants using confocal immunofluorescence, antibody access, proteinase K sensitivity, and deglycosylation assays. An N-terminal signaling sequence of 22 residues, consisting of a hydrophobic helix ending in a net positive charge, anchors Rdh1 and Crad1 in the endoplasmic reticulum facing the cytoplasm. Mutating arginine to glutamine in the signaling sequence did not affect topology. Inserting one or two arginine residues near the N terminus of the signaling sequence caused 28-95% inversion from cytoplasmic to luminal, depending on the net positive charge remaining at the C terminus of the signaling sequence; e.g. the mutant L3R,L5R,R16Q,R19Q,R21Q faced the lumen. Experiments with N-and C-terminal epitope-tagged Rdh1 and molecular modeling indicated that a hydrophobic helix-turn-helix near the C terminus of Rdh1 (residues 289 -311) projects into the cytoplasm. These data provide insight into the features necessary to orient type III (reverse signal-anchor) proteins and demonstrate that Rdh1, Crad1, and other short-chain dehydrogenases/reductases, which share similar N-terminal signaling sequences such as human Rdh5 and mouse Rdh4, orient with their catalytic domains facing the cytoplasm.Retinol requires conversion into all-trans-retinoic acid to fulfill the vitamin A function of regulating gene expression that begins shortly after conception and continues throughout vertebrate life (1, 2). Retinoid-active SDRs 1 recognize the major physiological form of retinol, retinol bound with CRBP, to generate retinal for irreversible conversion into all-trans-retinoic acid (3). The most active of the retinol dehydrogenases include mouse Rdh1 and its orthologs, rat Rodh1 and -2 and human RDH-E/RoDH4 (4 -8). rRodh2 e.g. has lower apparent K m values with holo-CRBP than with unbound retinol and catalyzes retinal synthesis in the presence of excess apoCRBP. Dehydrogenation of retinol in the presence of excess CRBP with concentrations of both ligand and binding protein in the micromolar range indicates that the reaction proceeds through the SDR accessing CRBP-bound retinol because the CRBP-retinol complex has a K d value ϳ0

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Elements in the N-terminal Signaling Sequence That Determine Cytosolic Topology of Short-chain Dehydrogenases/Reductases

Zhang

Napoli

2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The cytosolic activity has been linked to the members of the alcohol dehydrogenase (ADH) (42)(43)(44) and aldoketo reductase (AKR) superfamilies (45). The microsomal activity has been linked to the members of the SDR superfamily (46)(47)(48)(49)(50).…”

Section: Discussionmentioning

confidence: 99%

Biochemical Properties of Purified Human Retinol Dehydrogenase 12 (RDH12): Catalytic Efficiency toward Retinoids and C₉ Aldehydes and Effects of Cellular Retinol-Binding Protein Type I (CRBPI) and Cellular Retinaldehyde-Binding Protein (CRALBP) on the Oxidation and Reduction of Retinoids

et al. 2005

View full text Add to dashboard Cite

Retinol dehydrogenase 12 (RDH12) is a novel member of the short-chain dehydrogenase/reductase superfamily of proteins that was recently linked to Leber's congenital amaurosis 3 (LCA). We report the first biochemical characterization of purified human RDH12 and analysis of its expression in human tissues. RDH12 exhibits ~2000-fold lower K m values for NADP + and NADPH than for NAD + and NADH and recognizes both retinoids and lipid peroxidation products (C 9 aldehydes) as substrates. The k cat values of RDH12 for retinaldehydes and C 9 aldehydes are similar, but the K m values are, in general, lower for retinoids. The enzyme exhibits the highest catalytic efficiency for all-trans-retinal (k cat /K m ~900 min −1 μM −1 ), followed by 11-cis-retinal (450 min −1 mM −1 ) and 9-cis-retinal (100 min −1 mM −1 ). Analysis of RDH12 activity toward retinoids in the presence of cellular retinol-binding protein (CRBP) type I or cellular retinaldehyde-binding protein (CRALBP) suggests that RDH12 utilizes the unbound forms of all-trans-and 11-cis-retinoids. As a result, the widely expressed CRBPI, which binds all-trans-retinol with much higher affinity than all-transretinaldehyde, restricts the oxidation of all-trans-retinol by RDH12, but has little effect on the reduction of all-trans-retinaldehyde, and CRALBP inhibits the reduction of 11-cis-retinal stronger than the oxidation of 11-cis-retinol, in accord with its higher affinity for 11-cis-retinal. Together, the tissue distribution of RDH12 and its catalytic properties suggest that, in most tissues, RDH12 primarily contributes to the reduction of all-trans-retinaldehyde; however, at saturating concentrations of peroxidic aldehydes in the cells undergoing oxidative stress, for example, photoreceptors, RDH12 might also play a role in detoxification of lipid peroxidation products.

show abstract

“…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).…”

mentioning

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.

Self Cite

208

View full text Add to dashboard Cite

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.

show abstract

Distinct Retinoid Metabolic Functions for Alcohol Dehydrogenase Genes Adh1 and Adh4 in Protection against Vitamin A Toxicity or Deficiency Revealed in Double Null Mutant Mice

Cited by 86 publications

References 37 publications

Elements in the N-terminal Signaling Sequence That Determine Cytosolic Topology of Short-chain Dehydrogenases/Reductases

Elements in the N-terminal Signaling Sequence That Determine Cytosolic Topology of Short-chain Dehydrogenases/Reductases

Biochemical Properties of Purified Human Retinol Dehydrogenase 12 (RDH12): Catalytic Efficiency toward Retinoids and C₉ Aldehydes and Effects of Cellular Retinol-Binding Protein Type I (CRBPI) and Cellular Retinaldehyde-Binding Protein (CRALBP) on the Oxidation and Reduction of Retinoids

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

Contact Info

Product

Resources

About

Distinct Retinoid Metabolic Functions for Alcohol Dehydrogenase Genes Adh1 and Adh4 in Protection against Vitamin A Toxicity or Deficiency Revealed in Double Null Mutant Mice

Cited by 86 publications

References 37 publications

Elements in the N-terminal Signaling Sequence That Determine Cytosolic Topology of Short-chain Dehydrogenases/Reductases

Elements in the N-terminal Signaling Sequence That Determine Cytosolic Topology of Short-chain Dehydrogenases/Reductases

Biochemical Properties of Purified Human Retinol Dehydrogenase 12 (RDH12): Catalytic Efficiency toward Retinoids and C9 Aldehydes and Effects of Cellular Retinol-Binding Protein Type I (CRBPI) and Cellular Retinaldehyde-Binding Protein (CRALBP) on the Oxidation and Reduction of Retinoids

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

Contact Info

Product

Resources

About

Biochemical Properties of Purified Human Retinol Dehydrogenase 12 (RDH12): Catalytic Efficiency toward Retinoids and C₉ Aldehydes and Effects of Cellular Retinol-Binding Protein Type I (CRBPI) and Cellular Retinaldehyde-Binding Protein (CRALBP) on the Oxidation and Reduction of Retinoids