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PubMed2006

Characterization of retinaldehyde dehydrogenase 3.

RALDH3 (retinal dehydrogenase 3) was characterized by kinetic and binding studies, protein engineering, homology modelling, ligand docking and electrostatic-potential calculations. The major recognition determinant of an RALDH3 substrate was shown to be an eight-carbon chain bonded to the aldehyde group whose kinetic influence (kcat/Km at pH 8.5) decreases when shortened or lengthened. Surprisingly, the b-ionone ring of all-trans-retinal is not a major recognition site. The dissociation constants (Kd) of the complexes of RALDH3 with octanal, NAD+ and NADH were determined by intrinsic tryptophan fluorescence. The similarity of the Kd values for the complexes with NAD+ and with octanal suggests a random kinetic mechanism for RALDH3, in contrast with the ordered sequential mechanism often associated with aldehyde dehydrogenase enzymes. Inhibition of RALDH3 by tri-iodothyronine binding in competition with NAD+, predicted by the modelling, was established kinetically and by immunoprecipitation. Mechanistic implications of the kinetically influential ionizations with macroscopic pKa values of 5.0 and 7.5 revealed by the pH-dependence of kcat are discussed. Analogies with data for non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase from Streptococcus mutans, together with the present modelled structure of the thioacyl RALDH3, suggest (a) that kcat characterizes deacylation of this intermediate for specific substrates and (b) the assignment of the pKa of the major ionization (approximating to 7.5) to the perturbed carboxy group of Glu280 whose conjugate base is envisaged as supplying general base catalysis to attack of a water molecule. The macroscopic pKa of the minor ionization (5.0) is considered to approximate to that of the carboxy group of Glu488.

Aldehyde Oxidoreductases↗
PubMed2000

Feedback inhibition of the retinaldehyde dehydrogenase gene ALDH1 by retinoic acid through retinoic acid receptor alpha and CCAAT/enhancer-binding protein beta.

Aldehyde dehydrogenase 1 (ALDH1) plays a major role in the biosynthesis of retinoic acid (RA), a hormone required for several essential life processes. Recent evidence, using the aryl hydrocarbon receptor-null mouse, suggests that elevated hepatic RA down-regulates ALDH1 in a unique feedback pathway to control RA biosynthesis. To determine the mechanism of suppression of the ALDH1 gene by RA, transactivation studies were carried out in Hepa-1 mouse hepatoma cells. RA decreased expression of an ALDH1-CAT construct containing -2536 base pairs of DNA upstream of the transcription start site. Retinoic acid receptor alpha (RARalpha) transactivates the ALDH1 gene promoter through a complex with an RA response-like element (RARE) located at -91/-75 bp, which bound to the RARalpha/retinoid X receptor beta heterodimer. CCAAT/enhancer-binding protein (C/EBPbeta) also transactivates the ALDH1 gene promoter through a CCAAT box located 3' and directly adjacent to the RARE, and the ALDH1 gene is down-regulated in C/EBPbeta-null mouse liver. Exposure of Hepa-1 cells to RA results in a decrease in C/EBPbeta mRNA levels; however, there was no difference in mRNA and protein levels between wild-type and AHR-null mouse liver. These data support a model in which the RARalpha and C/EBPbeta activate the ALDH1 gene promoter through the RARE and C/EBP response elements, and in Hepa-1 cells, high levels of RA inhibit this activation by decreasing cellular levels of C/EBPbeta.

Aldehyde Dehydrogenase↗
PubMed1994

Retinoid specificity of interphotoreceptor retinoid-binding protein.

Interphotoreceptor retinoid-binding protein (IRBP), the predominant protein in the interphotoreceptor matrix of retina, has been implicated in transfer of retinoids between retinal pigment epithelium and photoreceptor cells. In this work, the interactions of several retinoids with IRBP were studied in order to clarify whether the protein displays specificity toward particular forms of these ligands. The equilibrium dissociation constants of complexes of 11-cis- and all-trans-retinols and retinaldehydes with IRBP were measured. It was found that IRBP contains two binding sites for 11-cis-retinaldehyde and for all-trans-retinaldehyde and retinol. Binding affinities followed the order: 11-cis-retinaldehyde > all-trans-retinol > all-trans-retinaldehyde > 11-cis-retinol. The kinetic parameters of the dissociation of these retinoids from binding sites on IRBP were measured by monitoring the rate of transfer of the retinoids from IRBP to synthetic unilamellar vesicles. 11-cis-Retinaldehyde and all-trans-retinol were found to dissociate from the strong binding site of IRBP 3-4-fold slower than all-trans-retinaldehyde and 11-cis-retinol. The higher binding affinities and the slower rates of dissociation from IRBP displayed by 11-cis-retinaldehyde and by all-trans-retinol correspond to the physiological need to shuttle these particular retinoids between pigment epithelium and photoreceptor cells across the interphotoreceptor matrix as part of the visual cycle.

Animals↗
PubMed1994

Control of substrate flow at a branch in the visual cycle.

Photoisomerization of rhodopsin's chromophore, 11-cis-retinaldehyde, and subsequent regeneration of the 11-cis configuration are accomplished in vertebrates by a series of reactions known as the visual cycle. At one point in the cycle, 11-cis-retinol can either be enzymatically oxidized to 11-cis-retinaldehyde and exported for visual pigment regeneration or be enzymatically esterified and stored. Partition of substrate at this branch was examined in this study and found to be influenced by cellular retinaldehyde-binding protein (CRALBP), a retinoid-binding protein found in retina. Esterification was reduced to about 10% and oxidation stimulated 2-3-fold in the presence of this protein. Other experiments confirmed that "free" 11-cis-retinol was esterified more rapidly than 11-cis-retinol complexed with CRALBP and that CRALBP.11-cis-retinol was not an inhibitor of the esterification. Following oxidation of CRALBP.11-cis-retinol, the reaction product, 11-cis-retinaldehyde, was found associated with the binding protein. 11-cis-Retinaldehyde is not available for reaction with carbonyl reagents when the retinoid is bound to CRALBP. However, enzymatic oxidation of CRALBP.11-cis-retinol in the presence of O-ethylhydroxylamine produced ca. 30% retinaldehyde O-ethyloxime and 70% free 11-cis-retinaldehyde, suggesting that about one-third of the retinol oxidized had dissociated from the binding protein. Neither oxidation nor esterification of CRALBP.11-cis-retinol was inhibited by including CRALBP.11-cis-retinaldehyde in the reaction mixture.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Xanthine oxidase catalyzes the synthesis of retinoic acid.

Milk xanthine oxidase (xanthine: oxygen oxidoreductase; XO; EC 1.1.3.22) was found to catalyze the conversion of retinaldehyde to retinoic acid. The ability of XO to synthesize all trans-retinoic acid efficiently was assessed by its turnover number of 31.56 min-1, determined at pH 7.0 with 1 nM XO and all trans-retinaldehyde varying between 0.05 to 2 microM. The determination of both retinoid and purine content in milk was also considered in order to correlate their concentrations with kinetic parameters of retinaldehyde oxidase activity. The velocity of the reaction was dependent on the isomeric form of the substrate, the all trans- and 9-cis-forms being the preferred substrates rather than 13-cis-retinaldehyde. The enzyme was able to oxidize retinaldehyde in the presence of oxygen with NAD or without NAD addition. In this latter condition the catalytic efficiency of the enzyme was higher. The synthesis of retinoic acid was inhibited 87% and 54% by 4 microM and 2 microM allopurinol respectively and inhibited 48% by 10 microM xanthine in enzyme assays performed at 2 microM all trans-retinaldehyde. The Ki value determined for xanthine as an inhibitor of retinaldehyde oxidase activity was 4 microM.

Animals↗
PubMed1996

Light-mediated retinoic acid production.

Retinoids serve two main functions in biology: retinaldehyde forms the chromophore bound to opsins, and retinoic acid (RA) is the activating ligand of transcription factors. These two functions are linked in the vertebrate eye: we describe here that illumination of the retina results in an increase in RA synthesis, as detected with a RA bioassay and by HPLC. The synthesis is mediated by retinaldehyde dehydrogenases which convert some of the chromophore all-trans retinaldehyde, released from bleached rhodopsin, into RA. As the eye contains high levels of retinaldehyde dehydrogenases, and as the oxidation of retinaldehyde is an irreversible reaction, RA production has to be considered an unavoidable by-product of light. Through RA synthesis, light can thus directly influence gene transcription in the eye, which provides a plausible mechanism for light effects that cannot be explained by electric activity. Whereas the function of retinaldehyde as chromophore is conserved from bacteria to mammals, RA-mediated transcription is fully evolved only in vertebrates. Invertebrates differ from vertebrates in the mechanism of chromophore regeneration: while in the invertebrate visual cycle the chromophore remains bound, it is released as free all-trans retinaldehyde from illuminated vertebrate rhodopsin. RA synthesis occurring as corollary of dark regeneration in the vertebrate visual cycle may have given rise to the expansion of RA-mediated transcriptional regulation.

Animals↗
PubMed1990

Synthesis of retinoids by human retinal epithelium and transfer to rod outer segments.

The synthesis and release of 11-cis-retinoids by primary cultures of human retinal pigment epithelium (RPE) and the transfer of these retinoids to co-incubated human rod outer segments (ROS) were studied. Monolayers of 2-3-week-old cultured RPE incorporate tritiated all-trans-retinol, esterify it to the corresponding retinyl palmitate, form 11-cis-retinol and 11-cis-retinaldehyde and release retinaldehyde into the culture medium. The ratio of 11-cis to all-trans isomers of retinol, retinyl palmitate and retinaldehyde formed in the cells along with retinaldehyde released and incorporated into the ROS progressively increases, indicating a progressive increase in the concentration of 11-cis isomer from the time it is formed in RPE cells until its transfer to ROS. Incorporation of 11-cis-retinaldehyde into the ROS is directly related to the amount of albumin present in the media, suggesting the transfer of retinoids from RPE to photoreceptor to be a protein-mediated process. Events leading to isomerization, esterification, oxidation and release of retinoids by human RPE and incorporation of retinoids into ROS can therefore be examined in vitro.

Adult↗
PubMed1987

Binding specificities of cellular retinol-binding protein and cellular retinol-binding protein, type II.

Cellular retinol-binding protein (CRBP) and cellular retinol-binding protein, type ii (CRBP(II] are cytoplasmic proteins that bind trans-retinol as an endogenous ligand. These proteins are structurally similar having greater than 50% sequence homology. Employing fluorescence, absorbance, and competition studies, the ability of pure preparations of CRBP(II) and CRBP to bind various members of the vitamin A family has been examined. In addition to trans-retinol, CRBP(II) was able to form high affinity complexes (K'd less than 5 X 10(-8) M) with 13-cis-retinol, 3-dehydroretinol, and all-trans-retinaldehyde. CRBP bound those retinol isomers with similar affinities, but did not bind trans-retinaldehyde. Neither protein bound retinoic acid nor 9-cis- and 11-cis-retinol. The spectra of 13-cis-retinol and 3-dehydroretinol, when bound, were shifted and displayed fine structure compared to their spectra in organic solution. However, the lambda max and fluorescent yield of a particular ligand were different when bound to CRBP(II) versus CRBP. It appears that CRBP(II) and CRBP bind trans-retinol, 13-cis-retinol, and 3-dehydroretinol in a planar configuration. However, the binding sites of CRBP(II) and CRBP are clearly distinct based on the observed spectral differences of the bound ligands and the observations that only CRBP(II) could bind trans-retinaldehyde. The ability of CRBP(II) to bind trans-retinaldehyde suggests a physiological role for the protein in accepting retinaldehyde generated from the cleavage of beta-carotene in the absorptive cell.

Animals↗
PubMed1982

Identification of the endogenous retinoids associated with three cellular retinoid-binding proteins from bovine retina and retinal pigment epithelium.

The endogenous retinoids associated with three cellular retinoid-binding proteins from bovine retina and retinal pigment epithelium have been identified by their spectral characteristics and their co-migration with authentic retinoids on high performance liquid chromatography. All-trans-retinol is the only retinoid associated with the cellular retinol-binding protein from retina and retinal pigment epithelium. The saturation of the binding site with native ligand is 0.95 +/- 0.05 mol of retinoid/mol of protein for cellular retinol-binding protein purified from frozen and fresh retina and retinal pigment epithelium. All-trans-retinoic acid has been identified as the endogenous ligand associated with the cellular retinoic acid-binding protein of cattle retina. The saturation of the binding site of cellular retinoic acid-binding protein from frozen and fresh retina (the protein is absent in extracts of retinal pigment epithelium) is about 0.2 mol of retinoid/mol of protein, probably a minimum value due to losses of the ligand. Retinoic acid has not been detected previously in retina. Cellular retinaldehyde-binding protein from retina purifies with two endogenous ligands which cochromatograph on high performance liquid chromatography with 11-cis-retinaldehyde and 11-cis-retinol and occur in a ratio of approximately 3:1, respectively. The binding site of cellular retinaldehyde-binding protein from frozen retina is nearly fully occupied with these two ligands (saturation greater than 0.9 mol of retinoids/mol of protein). In contrast, purified cellular retinaldehyde-binding protein from retinal pigment epithelium carries only 11-cis-retinaldehyde as an endogenous ligand. The saturation of the binding site with this ligand is greater than 0.95.

Animals↗
PubMed2005

Retinoid metabolism during development of liver cirrhosis.

The changes in retinoid metabolism have been documented in liver cirrhosis. However, the dynamic alterations in levels of this vitamin between circulation and liver during development of the liver cirrhosis are not well understood. The aim of this study was to measure retinoids in the liver and circulation in parallel, during and after development of cirrhosis induced by carbon tetrachloride and thioacetamide. Retinoid levels were measured by HPLC. A decrease in retinaldehyde and total retinol, together with an increase in retinoic acid was evident in liver from both carbon tetrachloride or thioacetamide treated rats within a month after initiation of treatment. Activity of enzymes involved in retinoid metabolism such as retinaldehyde oxidase, retinaldehyde dehydrogenase, and retinaldehyde reductase were decreased in the liver. In parallel, levels of retinol and retinaldehyde in the serum were increased while retinoic acid was decreased. This study indicates that during development of cirrhosis, there is reciprocal transfer of retinoid metabolites between the circulation and the liver.

Aging↗