Interactions of retinoid binding proteins and enzymes in retinoid metabolism

Napoli, Joseph L.

doi:10.1016/s1388-1981(99)00117-1

Cited by 358 publications

(298 citation statements)

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“…41). To determine whether Rdh12 deficiency affects retinoic acid synthesis in the retina, directly or indirectly, we assayed retinal homogenates from dark-adapted mice using HPLC-coupled tandem mass spectrometry.…”

Section: Rpe Lipofuscin Pigments In Eyes Of Rdh12-deficient Mice-mentioning

confidence: 99%

Rdh12 Activity and Effects on Retinoid Processing in the Murine Retina

Chrispell¹,

Feathers

Kane

et al. 2009

Journal of Biological Chemistry

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RDH12 mutations are responsible for early-onset autosomal recessive retinal dystrophy, which results in profound retinal pathology and severe visual handicap in patients. To investigate the function of RDH12 within the network of retinoid dehydrogenases/reductases (RDHs) present in retina, we studied the retinal phenotype of Rdh12-deficient mice. In vivo rates of alltrans-retinal reduction and 11-cis-retinal formation during recovery from bleaching were similar in Rdh12-deficient and wild-type mice matched for an Rpe65 polymorphism that impacts visual cycle efficiency. However, retinal homogenates from Rdh12-deficient mice exhibited markedly decreased capacity to reduce exogenous retinaldehydes in vitro. Furthermore, in vivo levels of the bisretinoid compound diretinoid-pyridinium-ethanolamine (A2E) were increased in Rdh12-deficient mice of various genetic backgrounds. Conversely, in vivo levels of retinoic acid and total retinol were significantly decreased. Rdh12 transcript levels in wild-type mice homozygous for the Rpe65-Leu 450 polymorphism were greater than in Rpe65-Met 450 mice and increased during postnatal development in wild-type mice and Nrl-deficient mice having an all-cone retina. Rdh12-deficient mice did not exhibit increased retinal degeneration relative to wild-type mice at advanced ages, when bred on the lightsensitive BALB/c background, or when heterozygous for a null allele of superoxide dismutase 2 (Sod2 ؉/؊ ). Our findings suggest that a critical function of RDH12 is the reduction of all-trans-retinal that exceeds the reductive capacity of the photoreceptor outer segments.RDH12 is a major disease gene for Leber congenital amaurosis, with RDH12 mutations responsible for approximately 2% of cases of childhood-onset severe autosomal recessive retinal dystrophy (1-4). Affected individuals experience poor vision in early life, which progressively declines with age as a result of both rod and cone degeneration (5). Analyses of retinal organization and visual function in patients with mutations in RDH12 or RPE65, another Leber congenital amaurosis gene involved in retinoid metabolism, show distinctly different pathologies associated with defects in each gene that will be important to consider when developing targeted forms of therapy (6).RDH12 encodes a member of the family of short chain dehydrogenases/reductases that catalyze oxidation and reduction reactions involved in various aspects of metabolism (reviewed in Refs. 7 and 8). In the photoreceptor cells and retinal pigment epithelium (RPE), 3 the interconversion of oxidized and reduced retinoids by RDH enzymes is an important feature of the visual cycle, the process responsible for the conversion of vitamin A (all-trans-retinol) to 11-cis-retinal, the chromophore of the visual pigments (reviewed in Ref. 9). On the basis of in vitro assays showing reactivity toward retinaldehyde substrates and expression in photoreceptor cells, RDH12 was initially proposed to function in the reduction of all-trans-retinal released by bleached visual pigments (10...

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Section: Rpe Lipofuscin Pigments In Eyes Of Rdh12-deficient Mice-mentioning

confidence: 99%

Rdh12 Activity and Effects on Retinoid Processing in the Murine Retina

Chrispell¹,

Feathers

Kane

et al. 2009

Journal of Biological Chemistry

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“…6 transfected Sf9 Cells, Respectively-RPE microsomes (1.3 ml, 5 mg/ml) were solubilized with 5 mM n-dodecyl-β-D-maltoside in the presence of 20 mM BTP, pH 7.4, 1 mM DTT, and 1 μM leupeptin (buffer A) with 20 μM NAD and NADP for 60 min on ice. The solubilized mixtures were centrifuged at 71,700 × g for 40 min, and the supernatant was loaded onto the monoclonal anti-RDH5 antibodies Sepharose 4B (∼0.6 ml of gel) equilibrated with buffer A.…”

Section: Assay For Rdh Activity-activitiesmentioning

confidence: 99%

“…The key enzymes involved in retinoid metabolisms are alcohol and aldehyde dehydrogenases that convert retinols to aldehydes and aldehydes to carboxylic acids, respectively. The first oxidation reaction is catalyzed by a large number of enzymes from the SDR superfamily (6,7) and by classic medium chain alcohol dehydrogenases (8). SDRs are weakly conserved in their primary sequences, with the exception of key residues involved in catalysis, nucleotide recognition, and members of closely related subfamilies.…”

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confidence: 99%

Dual-substrate Specificity Short Chain Retinol Dehydrogenases from the Vertebrate Retina

Haeseleer¹,

Jang²,

Imanishi³

et al. 2002

Journal of Biological Chemistry

188

227

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Retinoids are chromophores involved in vision, transcriptional regulation, and cellular differentiation. Members of the short chain alcohol dehydrogenase/reductase superfamily catalyze the transformation of retinol to retinal. Here, we describe the identification and properties of three enzymes from a novel subfamily of four retinol dehydrogenases (RDH11-14) that display dualsubstrate specificity, uniquely metabolizing all-trans-and cis-retinols with C 15 pro-R specificity. RDH11-14 could be involved in the first step of all-trans-and 9-cis-retinoic acid production in many tissues. RDH11-14 fill the gap in our understanding of 11-cis-retinal and all-trans-retinal transformations in photoreceptor (RDH12) and retinal pigment epithelial cells (RDH11). The dualsubstrate specificity of RDH11 explains the minor phenotype associated with mutations in 11-cisretinol dehydrogenase (RDH5) causing fundus albipunctatus in humans and engineered mice lacking RDH5. Furthermore, photoreceptor RDH12 could be involved in the production of 11-cis-retinal from 11-cis-retinol during regeneration of the cone visual pigments. These newly identified enzymes add new elements to important retinoid metabolic pathways that have not been explained by previous genetic and biochemical studies.Retinoids are indispensable light-sensitive elements of vision and also serve as essential modulators of cellular differentiation and proliferation in diverse cell types, including those comprising the epithelium and immune system. Retinoids modulate the growth of both normal and malignant cells through their binding to retinoid receptors. All-trans-retinoic acid signals through specific interactions with the nuclear retinoic acid receptors, whereas its isomer, 9-cis-retinoic acid, is a high affinity ligand of retinoic acid receptors and retinoid X receptors. In the retina, light-dependent photoisomerization of 11-cis-retinylidene to the all-transretinylidene moiety of rod and cone photoreceptors is a key reaction that triggers visual * This research was supported by National Institutes of Health Grants EY08061, CA75173, and DK59125, a grant from Research to Prevent Blindness, Inc. (to the Department of Ophthalmology, University of Washington), and by the E. K. Bishop Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. S The on-line version of this article (available at http://www.jbc.org) contains Supplemental Figs. 1 and 2 and Tables 1-3. § These authors contributed equally to this work. § § Recipient of a Research to Prevent Blindness Senior Investigator Award. To whom correspondence should be addressed: Dept. of Ophthalmology, University of Washington, Seattle,; E-mail: palczews@u.washington.edu. Transformations of retinoids occur mostly through enzymatic or photochemical reactions, although they readily isomerize non-enzymatically to thermodynamic equilibriu...

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“…Specific binding proteins, enzymes, and receptors control flux through the central pathways of retinoid homeostasis, ultimately to produce retinoic acid, an active form of vitamin A (Figure 1) (6)(7). RA effects a wide range of physiological processes, including development, nervous system function, immune response, cell proliferation, cell differentiation, and reproduction through activation of type II nuclear receptors (RAR, RXR, PPARβ/δ) (8)(9)(10)(11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

HPLC/UV quantitation of retinal, retinol, and retinyl esters in serum and tissues

Kane

Folias

Napoli

2008

Analytical Biochemistry

158

166

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We report robust HPLC/UV methods for quantifying retinyl esters (RE), retinol (ROL) and retinal (RAL) applicable to diverse biological samples, with lower limits of detection of 0.7 pmol, 0.2 pmol, and 0.2 pmol, respectively, and linear ranges >3 orders of magnitude. These assays function well with small, complex biological samples (10-20 mg tissue). Coefficients of variation range from: intra-day, 5.9-10.0%; inter-day, 5.9-11.0%. Quantification of endogenous RE, ROL, and RAL in mouse serum and tissues (liver, kidney, adipose, muscle, spleen, testis, skin, brain, and brain regions) reveals utility. Ability to discriminate spatial concentrations of ROL and RE is illustrated with C57BL/6 mouse brain loci (hippocampus, cortex, olfactory bulb, thalamus, cerebellum, and striatum.) We also developed a method to distinguish isomeric forms of ROL to investigate precursors of retinoic acid. The ROL isomer assay has limits of detection between 3.5-4.5 pmol and a similar linear range and % CV as the ROL/RE and RAL assays. The assays described here provide for sensitive and rigorous quantification of endogenous RE, ROL, and RAL to elucidate retinoid homeostasis in disease states, such as Alzheimer's disease, type 2 diabetes, obesity, and cancer.

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Interactions of retinoid binding proteins and enzymes in retinoid metabolism

Cited by 358 publications

References 175 publications

Rdh12 Activity and Effects on Retinoid Processing in the Murine Retina

Rdh12 Activity and Effects on Retinoid Processing in the Murine Retina

Dual-substrate Specificity Short Chain Retinol Dehydrogenases from the Vertebrate Retina

HPLC/UV quantitation of retinal, retinol, and retinyl esters in serum and tissues

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