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Results for “Retinal Dehydrogenase”

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At least 19 recordsLinked to original sources

PubMed2003

Regulation of mouse retinol dehydrogenases and retinal dehydrogenases in hepatocyte differentiation.

Retinoic acid (RA) is produced via two sequential reactions of retinol dehydrogenases (RDHs) and retinal dehydrogenases (RALDHs). We found that primary cultured mouse hepatocytes on a single collagen gel gradually lost hepatocyte specific morphology, and that another collagen gel overlay remarkably recovered it. The levels of albumin and liver-dominant expressed RDHs expression in hepatocytes paralleled their morphological change, decreased during single collagen gel culture, and were up-regulated by sequential collagen overlay. Quite similar to the expression changes, albumin and those RDHs' mRNA expression levels increased along with liver differentiation during pre- and postnatal liver development. Our data supports that all-trans and 9-cis RA, catalyzed by the RDHs, indeed play an important role in liver differentiation and regeneration.

Aldehyde Oxidoreductases↗

PubMed2003

Enzymatic characterization of recombinant mouse retinal dehydrogenase type 1.

Retinal dehydrogenases (RALDHs) convert retinal into retinoic acids (RAs), which are important signaling molecules in embryogenesis and tissue differentiation. We expressed mouse RALDH type 1 (mRALDH1) in Escherichia coli and studied the kinetic properties of the recombinant enzyme for retinal substrates. Purified recombinant mRALDH1 catalyzed the oxidation of all-trans and 9-cis retinal but not 13-cis retinal, and exhibited two pH optimums, 7.8 and 9.4, for all-trans and 9-cis retinal substrates, respectively. The K(m) for all-trans retinal (11.6 micro M) was 3-fold higher than for 9-cis retinal (3.59 micro M). However, the conversion efficiencies of either all-trans or 9-cis retinal to the respective RAs were similar. MgCl(2) inhibited the oxidation of both all-trans and 9-cis retinal. Chloral hydrate and acetaldehyde competitively suppressed all-trans retinal oxidation with inhibition constants (K(i)) of 4.99 and 49.4 micro M, respectively. Retinol, on the other hand, blocked the reaction uncompetitively. These data extend the kinetic characterization of mRALDH1, provide insight into the possible role of this enzyme in the biogenesis of RAs, and should give useful information on the determination of amino acid residues that play crucial roles in the catalysis of all-trans and 9-cis retinal.

Aldehyde Oxidoreductases↗

PubMed1989

Increased hepatic retinal dehydrogenase activity after phenobarbital and ethanol administration.

Cytosolic retinal dehydrogenase (EC 1.2.1.36, retinal: NAD+ oxidoreductase) activity was measured by assessing the conversion of retinal to retinoic acid by HPLC. In vitro, acetaldehyde, chloral hydrate and disulfiram were found to be inhibitors, whereas 95% of the activity remained in the presence of cyanide or in the absence of oxygen. In rats, retinal dehydrogenase activity prevailed over that of retinal oxidase. By contrast, in deermice, 80% of retinal oxidation was due to the oxidase rather than the retinal dehydrogenase activity in a normal strain (ADH+) as well as in one lacking alcohol dehydrogenase (ADH-). In ADH- deermice, retinal oxidase activity was greater than in ADH+ animals. In vivo, in the rat, chronic ethanol administration resulted in a significant increase of the dehydrogenase activity in the liver, but not in other tissues. After phenobarbital administration, hepatic retinal dehydrogenase activity was increased 8-fold, but no extrahepatic induction was observed. Conversely, feeding rats with a diet devoid of the precursor for the substrate (retinal) by replacing retinyl acetate with an equivalent amount of retinoic acid resulted in decreased retinal dehydrogenase activity. Under conditions in which retinal dehydrogenase activity is rate-limiting for the metabolism of retinal to retinoic acid, its induction after phenobarbital or ethanol administration may contribute to hepatic vitamin A depletion.

Aldehyde Oxidoreductases↗

PubMed2002

Kinetic analysis of mouse retinal dehydrogenase type-2 (RALDH2) for retinal substrates.

Retinal dehydrogenase (RALDH) isozymes catalyze the terminal oxidation of retinol into retinoic acid (RA) that is essential for embryogenesis and tissue differentiation. To understand the role of mouse type 2 RALDH in synthesizing the ligands (all-trans and 9-cis RA) needed to bind and activate nuclear RA receptors, we determined the detailed kinetic properties of RALDH2 for various retinal substrates. Purified recombinant RALDH2 showed a pH optimum of 9.0 for all-trans retinal oxidation. The activity of the enzyme was lower at 37 degrees C compared to 25 degrees C. The efficiency of conversion of all-trans retinal to RA was 2- and 5-fold higher than 13-cis and 9-cis retinal, respectively. The K(m) for all-trans and 13-cis retinal were similar (0.66 and 0.62 microM, respectively). However, the K(m) of RALDH2 for 9-cis retinal substrate (2.25 microM) was 3-fold higher compared to all-trans and 13-cis retinal substrates. Among several reagents tested for their ability to either inhibit or activate RALDH2, citral and para-hydroxymercuribenzoic acid (p-HMB) inhibited and MgCl(2) activated the reaction. Comparison of the kinetic properties of RALDH2 for retinal substrates and its activity towards various reagents with those of previously reported rat kidney RALDH1 and human liver aldehyde dehydrogenase-1 showed distinct differences. Since RALDH2 has low K(m) and high catalytic efficiency for all-trans retinal, it may likely be involved in the production of all-trans RA in vivo.

Aldehyde Oxidoreductases↗

PubMed1999

The structure of retinal dehydrogenase type II at 2.7 A resolution: implications for retinal specificity.

Retinoic acid, a hormonally active form of vitamin A, is produced in vivo in a two step process: retinol is oxidized to retinal and retinal is oxidized to retinoic acid. Retinal dehydrogenase type II (RalDH2) catalyzes this last step in the production of retinoic acid in the early embryo, possibly producing this putative morphogen to initiate pattern formation. The enzyme is also found in the adult animal, where it is expressed in the testis, lung, and brain among other tissues. The crystal structure of retinal dehydrogenase type II cocrystallized with nicotinamide adenine dinucleotide (NAD) has been determined at 2.7 A resolution. The structure was solved by molecular replacement using the crystal structure of a mitochondrial aldehyde dehydrogenase (ALDH2) as a model. Unlike what has been described for the structures of two aldehyde dehydrogenases involved in the metabolism of acetaldehyde, the substrate access channel is not a preformed cavity into which acetaldehyde can readily diffuse. Retinal dehydrogenase appears to utilize a disordered loop in the substrate access channel to discriminate between retinaldehyde and short-chain aldehydes.

Aldehyde Oxidoreductases↗

PubMed1994

Rat liver cytosolic retinal dehydrogenase: comparison of 13-cis-, 9-cis-, and all-trans-retinal as substrates and effects of cellular retinoid-binding proteins and retinoic acid on activity.

A basic pI retinal dehydrogenase has been purified recently that accounts for approximately 90% of the all-trans-retinal dehydrogenase activity of rat liver cytosol. In this work, we show that this enzyme also accounts for approximately 90% of the 9-cis-retinal dehydrogenase activity of rat liver cytosol. The partially-purified enzyme displayed allosteric kinetics for 9-cis-retinal [K0.5 = 5.2 microM, Hill coefficient = 1.4, Vmax = 7.85 nmol min-1 (mg of protein)-1] with the ratio Vmax/K0.5 = 1.5. The latter is similar to that of 2.1 for all-trans-retinal [K0.5 = 1.6 microM, Hill coefficient = 1.4, Vmax = 3.4 nmol min-1 (mg of protein)-1]. Competition between all-trans- and 9-cis-retinal occurred only when micromolar concentrations of both were present, indicating that the dehydrogenase could catalyze both all-trans- and 9-cis-retinoic acid syntheses simultaneously at the nanomolar amounts of the retinals that are likely to occur physiologically. Although reactions of all-trans- and 9-cis-retinoids were catalyzed with similar efficiencies, 13-cis-retinal was not an efficient substrate. This retinal dehydrogenase was not feedback-inhibited by all-trans- or 9-cis-retinoic acid, nor by holocellular retinoic acid-binding protein, but was stimulated modestly by apocellular retinoic acid-binding protein, an effect not observed in the presence of cellular retinol-binding protein. These data indicate that products, via feedback inhibition, do not regulate retinoic acid synthesis by this dehydrogenase. This dehydrogenase may serve as a common enzyme in the conversion of all-trans- and 9-cis-retinal into their acids.

Aldehyde Oxidoreductases↗

PubMed1998

Changing patterns of renal retinal dehydrogenase expression parallel nephron development in the rat.

We have recently characterized a cytosolic aldehyde dehydrogenase from rat kidney that functions as a retinal dehydrogenase (RALDH) and have cloned the corresponding gene. RALDH catalyzes the oxidation of retinal to retinoic acid, which regulates cell growth and differentiation by activating retinoic acid receptors. In situ hybridization demonstrates that RALDH mRNA expression is prominent in kidney in 2-day-old rats, is detected in lung and in epithelia of several tissues, but is not found in liver tissue. Retinal dehydrogenase activity peaks in kidney at Day 2 after birth and decreases gradually until adulthood, correlating well with RALDH expression. Weaker activity is also detectable in lungs but not in liver. Notably, distribution patterns of RALDH in kidney tissues are dramatically altered during postnatal development (P). From P0 to P6, hybridization is essentially concentrated within the marginal nephrogenic zone of the cortex. Expression progresses to deeper cortical layers from P12 to P16 and is intense in the medulla at P42, and focal expression is still detectable in the cortex. Immunocytochemical localization of RALDH in neonatal kidney shows staining mostly in cortical zone convoluted tubules and in adult rat shows staining in segments of distal and proximal tubules. These data suggest an important role for RALDH in modulating retinoic acid levels in different cell types during rat kidney development. The changing patterns of RALDH expression mirror stages of nephron formation in the developing rat kidney, strongly suggesting a central role for RALDH and thus for retinoids in controlling kidney development.

Aging↗

PubMed2000

Localization of retinal dehydrogenase type 1 in the stomach and intestine.

Retinal dehydrogenase type 1 (RALDH1) is involved in the biosynthesis of retinoic acid (RA), a modulator of gene expression and cell differentiation. RALDH1 mRNA transcripts are present in the stomach and small intestine, and their expression is regulated by vitamin A status. In situ hybridization demonstrated RALDH1 mRNA expression in epithelial cells of the stomach, small intestine, and large intestine. Strong hybridization was also seen in the lamina propria of small intestinal mucosa and the smooth muscle layer of the small and large intestines. Immunocytochemical localization revealed RALDH1 staining in parietal cells of the stomach and prismatic cells of the small and large intestines. The presence of RALDH1 protein was also detectable within supportive glial cells around neuronal fibers throughout the muscular layers of the stomach as well as the small and large intestines. These data suggest an important role for RALDH1 in generating RA needed for the differentiation of specific epithelial cells in the stomach and intestines.

Aldehyde Oxidoreductases↗

PubMed1997

Cloning of a rat cDNA encoding retinal dehydrogenase isozyme type I and its expression in E. coli.

Peptides sequenced from the purified rat liver cytosolic retinal dehydrogenase P1 [Posch, K.C., Burns, R.D. and Napoli, J.L., 1992. Biosynthesis of all-trans-retinoic acid from retinal: recognition of retinal bound to cellular retinol-binding protein (type I) as substrate by a purified cytosolic dehydrogenase. J. Biol. Chem. 267, 19676-19682] were used to design oligonucleotides for cloning its cDNA. The deduced amino acid sequence of P1, now designated retinal dehydrogenase type I or RalDH(I), has close similarity with mouse AHD-2 and rat kidney aldehyde dehydrogenase, but is distinct from rat phenobarbital-inducible aldehyde dehydrogenase (PIADH), the presumed rat liver homolog of mouse AHD-2. Rat kidney (100%) and lung (88%) show relatively high mRNA levels of RalDH(I), liver (34%) and brain (22%) have moderate levels, and testis (8%) has low levels. Retinoid status affects RalDH(I) mRNA levels differently in different tissues. E. coli-expressed RalDH(I) exhibits allosteric kinetics for retinal with a Hill coefficient of 1.7, a K0.5 value of 1.4 microM and a Vmax of 52 nmol min(-1) mg(-1) protein. These data establish the cospecificity of P1 and RalDH(I), show that retinoid status affects expression of its mRNA in a tissue-dependent manner, and illustrate that aldehyde dehydrogenase isozymes with extensive homology can participate in different metabolic paths, e.g., RalDH vs. PIADH.

Aldehyde Dehydrogenase↗

PubMed1998

Retinal dehydrogenase gene expression in stomach and small intestine of rats during postnatal development and in vitamin A deficiency.

Retinal dehydrogenase (RALDH) catalyzes the oxidation of retinal to all-trans and 9-cis retinoic acid, which function as ligands controlling RAR and RXR nuclear receptor-signaling pathways. We have recently shown the expression of RALDH transcript in the stomach and small intestine by reverse transcription polymerase chain reaction [Bhat, P.V., Labrecque J., Dumas, F., Lacroix, A. and Yoshida, A. (1995) Gene 166, 303-306]. We have examined RALDH expression in the stomach and small intestine before and during postnatal development and in vitamin A deficiency by assaying for mRNA levels and protein as well as for enzyme activity. In -2 day fetuses, RALDH expression was high in the small intestine, whereas RALDH protein was not detectable in the stomach. However, expression of RALDH was seen in the stomach after birth, and gradually increased with age and reached the highest level at postnatal day 42. In the intestine, RALDH expression decreased postnatally. Vitamin A deficiency up-regulated RALDH expression in the stomach and small intestine, and administration of retinoids down-regulated the RALDH expression in these tissues. These results show the differential expression of RALDH in the stomach and small intestine during postnatal development, and that vitamin A status regulates the expression of RALDH gene in these tissues.

Age Factors↗

PubMed2001

Cellular expression of retinal dehydrogenase types 1 and 2: effects of vitamin A status on testis mRNA.

We examined expression of retinal dehydrogenase (RALDH) types 1 and 2 in liver and lung, and the effect of vitamin A status on testis expression by in situ hybridization. Liver expressed RALDH1 and RALDH2 only in stellate cells and hepatocytes, respectively. Lung expressed RALDH1 and RALDH2 throughout the epithelia of the airways, from the principal bronchi to the respiratory bronchiole. Vitamin A-sufficient rats expressed RALDH1 in spermatocytes, with less intense expression in spermatogonia and spermatids, and expressed RALDH2 in interstitial cells, spermatogonia, and spermatocytes. Neither Sertoli nor peritubular cells showed detectable RALDH1 or RALDH2 mRNA. Vitamin A deficiency produced a sevenfold increase in RALDH1 and a 70-fold decrease in RALDH2 mRNA in testis. In each case, the net change reflected extensive loss of germ cells, increased intensity of expression in residual germ cells, and expression in Sertoli and peritubular cells. Low-dose RA relatively early during vitamin A depletion supported spermatogenesis and affected expression of both RALDHs, but did not reinstate "vitamin A normal" expression patterns. These results show that: RALDH1 and RALDH2 have distinct mRNA expression patterns in multiple cell types in three vitamin A target tissues; RALDH expression occurs in cell types that express cellular retinol-binding protein and retinol dehydrogenase isozymes (except stellate cells, for which retinol dehydrogenase expression remains unknown); vitamin A deficiency and RA supplementation affects the loci and intensity of RALDH mRNAs in testis; and low-dose RA does not substitute completely for retinol. Overall, these data provide insight into the unique functions of RALDH1 and RALDH2 in retinoid metabolism.

Aldehyde Oxidoreductases↗

PubMed1998

Differentiation-dependent regulation of retinal dehydrogenase gene expression in the trachea.

Retinoic acid (RA), a metabolite of vitamin A, is known to be a key signaling molecule in regulating epithelial cell differentiation. We recently characterized and cloned a retinal dehydrogenase (RALDH) that catalyzes the oxidation of retinal to RA. In this study, we investigated the effects of retinoids on the level of RALDH mRNA and protein as well as RALDH activity in the trachea and cultured tracheal epithelial cells. Vitamin A deficiency induced squamous metaplasia in the tracheal epithelium and down-regulated RALDH expression. Supplementation of retinol and retinoic acid to vitamin A deficient rats restored the normal mucociliary epithelium and up-regulated the RALDH expression. In rat epithelial cells cultured in vitro, RAinhibited squamous differentiation and promoted mucociliary differentiation. Squamous differentiated cultures (RA-) expressed very low levels of RALDH mRNA, whereas mucociliary differentiated cultures (RA+) expressed high levels of RALDH mRNA. Retinal and retinol were poor inducers of mucociliary differentiation as well as RALDH expression. The RALDH expression paralleled the expression of the mucin-1 gene in mucociliary cultures. These results suggest that the expression of RALDH is dependent on the differentiation state of the airway epithelium.

Aldehyde Oxidoreductases↗

PubMed1998

Purification, crystallization and preliminary X-ray diffraction studies of retinal dehydrogenase type II.

One enzyme which catalyzes the last step of the formation of the hormone retinoic acid from vitamin A (retinol) is retinal dehydrogenase type II (Ra1DH2). Ra1DH2, expressed in the Escherichia coli BL21(DE3) strain, was purified and crystallized using ammonium sulfate as a precipitant. These crystals belong to the space group P212121 (a = 108, b = 150, c = 168 A, alpha = beta = gamma = 90 degrees).

Aldehyde Oxidoreductases↗

PubMed2006

Regulation of retinal dehydrogenases and retinoic acid synthesis by cholesterol metabolites.

Retinoic acid (RA) constitutes the major active ingredient of vitamin A and is required for various biological processes. The tissue RA level is maintained through a cascade of metabolic reactions where retinal dehydrogenases (RALDHs) catalyze the terminal reaction of RA biosynthesis from retinal, a rate-limiting step. We showed that dietary supplement of cholesterol enhanced the expression of RALDH1 and 2 genes and the cellular RA content in vital organs such as brain, kidney, liver and heart. Consistently, the cholesterol-lowering agent (pravastatin sodium) downregulated the expression of RALDH1 and 2 genes in several organs especially the liver and in cultured liver cells. Further, cholesterol metabolites, predominantly the oxysterols, the natural ligands for liver X receptor (LXR), induced these genes via upregulation of sterol regulatory element binding protein-1c (SREBP-1c) that bound to the regulatory regions of these genes. Knockdown of LXRalpha/beta or SREBP-1c downregulated the expression of RALDH genes, which could be rescued by re-expressing SREBP-1c, suggesting SREBP-1c as a direct positive regulator for these genes. This study uncovered a novel crosstalk between cholesterol and RA biosynthesis.

Aldehyde Oxidoreductases↗

PubMed2004

Postnatal changes in gene expression of retinal dehydrogenase and retinoid receptors in liver of rats.

Retinoic acid (RA) plays important roles in cellular differentiation and proliferation in various tissues including the liver. To explore a possible role of RA in the postnatal development of hepatic function, we analyzed RA-generation enzyme activity and the RA-related hepatic gene expressions in the suckling and weaning rats. At 5 days after birth, retinal dehydrogenase (RALDH) activity in the liver was relatively high. Its activity decreased by 70% until day 17, and then it gradually increased to a high level by the completion of weaning period. Northern blot analysis showed that RALDH2 mRNA levels decreased in the suckling period, whereas RALDH1 mRNA levels increased in the weaning period. Retinoid X receptor alpha (RXRalpha) mRNA levels increased in the suckling period and attained to a higher level at 17 days after birth. Retinoic acid receptor alpha (RARalpha) mRNA level showed only a slight and temporary increase on day 13. The mRNA levels of hepatocyte nuclear factors (HNF-4 and HNF-1alpha) exhibited parallel increases around suckling-weaning period, and the transcript levels of albumin, a typical target gene of the hepatocyte nuclear factors, increased during the suckling-weaning transition period. Electrophoretic mobility shift assay using a putative nuclear receptor-binding element on rat HNF-1 alpha gene revealed that HNF-4 homodimer, but not RXRalpha homodimer, bound to this element. These results suggest that postnatal expressions of hepatocyte-specific genes might be up-regulated by retinoid receptors, which may be related with the alterations of RALDH expression during postnatal development in the liver.

Aldehyde Oxidoreductases↗

PubMed2003

Retinal dehydrogenase-2 is inhibited by compounds that induce congenital diaphragmatic hernias in rodents.

Currently, the etiology of the serious developmental anomaly congenital diaphragmatic hernia (CDH) is unknown. We have used an animal model of CDH to address this issue. We characterized four separate teratogens that produced diaphragmatic defects in embryonic rats that are similar to those in infants with CDH. We then tested the hypothesis that all these agents share the common mechanism of perturbing the retinoid-signaling pathway. Specifically, inhibition of retinal dehydrogenase-2 (RALDH2), a key enzyme necessary for the production of retinoic acid and that is expressed in the developing diaphragm, was assayed by measuring retinoic acid production in cytosolic extracts from an oligodendrocyte cell line. The following compounds all induce posterolateral defects in the rat diaphragm; nitrofen, 4-biphenyl carboxylic acid, bisdiamine, and SB-210661. Importantly, we demonstrate that they all share the common mechanism of inhibiting RALDH2. These data provide an important component of mounting evidence suggesting that the retinoid system warrants consideration in future studies of the etiology of CDH.

Aldehyde Oxidoreductases↗

PubMed2000

Identification of endogenous retinoids, enzymes, binding proteins, and receptors during early postimplantation development in mouse: important role of retinal dehydrogenase type 2 in synthesis of all-trans-retinoic acid.

Specific combinations of nuclear retinoid receptors acting as ligand-inducible transcription factors mediate the essential role of retinoids in embryonic development. Whereas some data exist on the expression of these receptors during early postimplantation development in mouse, little is known about the enzymes controlling the production of active ligands for the retinoid receptors. Furthermore, at early stages of mouse development virtually no data are available on the presence of endogenous retinoids. In the present study we have used a recently developed high-performance liquid chromatographic (HPLC) technique to identify endogenous retinoids in mouse embryos down to the egg cylinder stage. All-trans-retinoic acid, a ligand for the retinoic acid receptors, was detected in embryos dissected as early as 7.5 dpc (i.e., a combination of midstreak until late allantoic bud stage embryos). At these stages, we detected mRNA coding for all the retinoid receptors, retinoid binding proteins, and two enzymes able to convert retinol to retinal (retinol dehydrogenase 5 (RDH5) and alcohol dehydrogenase 4 (ADH4)). We also detected retinal dehydrogenase type 2 (RALDH2), an enzyme capable of oxidising the final step in the all-trans-retinoic acid synthesis. In egg cylinder stage mouse embryos no all-trans-retinoic acid was detected. However, at this stage its precursor all-trans-retinal was present. In accordance with these HPLC observations, RDH5 and ADH4 were expressed, but no transcripts coding for enzymes that oxidise retinal to retinoic acid. Therefore, our results suggest that RALDH2 is a key regulator in initiating retinoic acid synthesis sometime between the mid-primitive streak stage and the late allantoic bud stage in mouse embryos.

Aldehyde Oxidoreductases↗

PubMed2004

Retinal dehydrogenase 12 (RDH12) mutations in leber congenital amaurosis.

Leber congenital amaurosis (LCA), the most early-onset and severe form of all inherited retinal dystrophies, is responsible for congenital blindness. Ten LCA genes have been mapped, and seven of these have been identified. Because some of these genes are involved in the visual cycle, we regarded the retinal pigment epithelium and photoreceptor-specific retinal dehydrogenase (RDH) genes as candidate genes in LCA. Studying a series of 110 unrelated patients with LCA, we found mutations in the photoreceptor-specific RDH12 gene in a significant subset of patients (4.1%). Interestingly, all patients harboring RDH12 mutations had a severe yet progressive rod-cone dystrophy with severe macular atrophy but no or mild hyperopia.

Alcohol Oxidoreductases↗