RDH12, a retinol dehydrogenase causing Leber's congenital amaurosis, is also involved in steroid metabolism

Keller, Brigitte; Adamski, Jerzy

doi:10.1016/j.jsbmb.2007.03.015

Cited by 20 publications

(15 citation statements)

References 13 publications

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“…Fluorescence imaging of single, isolated rod cells showed that, following exposure to light, outer segments appeared to leak all-trans -retinaldehyde to inner segments in rods lacking RDH12 ( 77 ). Human RDH12 was reported to have some activity as a steroid reductase, reducing dihydrotestosterone to androstanediol when expressed in living HEK 293 T cells, but this activity is not conserved in its murine ortholog and is absent in other members of this group characterized to date ( 78 ).…”

Section: Reduction Of Retinaldehyde Back To Retinolmentioning

confidence: 99%

Enzymology of retinoic acid biosynthesis and degradation

Kedishvili

2013

Journal of Lipid Research

165

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This article is available online at http://www.jlr.org ( 10 ), and regulation of energy homeostasis ( 11,12 ). atRA exerts its actions by serving as an activating ligand of nuclear atRA receptors [retinoid acid receptor (RAR) ␣ , RAR ␤ , and RAR ␥ ] and peroxisome proliferator-activated receptors (PPAR) ␤ / ␦ , which form heterodimers with retinoid X receptors ( 13,14 ). The actions of the RARs are described in more detail in this thematic series by RochetteEgly and colleagues. The concentration of atRA during embryonic development is tightly controlled in a spatial and temporal manner, and in adult tissues, it is maintained within a very narrow range that is specifi c for each given tissue. If the control mechanisms fail and the concentration of atRA exceeds or falls below the optimal range, tissues and cells undergo pathophysiological changes that in most severe cases can lead to disease. Thus, the maintenance of optimal atRA levels is essential for life. This review focusses on recent fi ndings regarding the mechanisms that control atRA homeostasis, with specifi c emphasis on the enzymes involved in atRA biosynthesis and degradation. All-trans -retinoic acid (atRA) is a highly potent derivative of vitamin A that is required for virtually all essential physiological processes and functions because of its involvement in transcriptional regulation of over 530 different genes ( 1, 2 ). For example, atRA is necessary for differentiation and development of fetal and adult tissues, stem cell differentiation, and apoptosis ( 3-7 ), and for support of reproductive functions ( 8, 9 ), immune response

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Section: Reduction Of Retinaldehyde Back To Retinolmentioning

confidence: 99%

Enzymology of retinoic acid biosynthesis and degradation

Kedishvili

2013

Journal of Lipid Research

165

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“…Unlike other RDHs, it is a mitochondrial enzyme (Keller and Adamski 2007;Lois et al 2002). This observation was confirmed by a proteomic approach on mitochondria from human skeletal muscle (Lefort et al 2009).…”

Section: Subcellular Localization and Membrane Binding Of Retinol Dehmentioning

confidence: 59%

“…It can be seen that all RDHs, but not RDH5, RDH11, and RDH12, show a catalytic efficiency only towards retinoids. Indeed, RDH5 and RDH12 can also use steroid substrates (Keller and Adamski 2007;Wang et al 1999), whereas RDH11 and RDH12 accordingly both show an additional reductive activity towards aldehydes (Belyaeva et al 2005; Kasus-Jacobi et al…”

Section: Structural Organization and Activity Of Retinol Dehydrogenasesmentioning

confidence: 99%

Retinol dehydrogenases: Membrane-bound enzymes for the visual function

Lhor

Salesse

2014

Biochem. Cell Biol.

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Retinoid metabolism is important for many physiological functions, such as differenciation, growth, and vision. In the visual context, after the absorption of light in rod photoreceptors by the visual pigment rhodopsin, 11-cis retinal is isomerized to all-trans retinal. This retinoid subsequently undergoes a series of modifications during the visual cycle through a cascade of reactions occurring in photoreceptors and in the retinal pigment epithelium. Retinol dehydrogenases (RDHs) are enzymes responsible for crucial steps of this visual cycle. They belong to a large family of proteins designated as short-chain dehydrogenases/reductases. The structure of these RDHs has been predicted using modern bioinformatics tools, which allowed to propose models with similar structures including a common Rossman fold. These enzymes undergo oxidoreduction reactions, whose direction is dictated by the preference and concentration of their individual cofactor (NAD(H)/NADP(H)). This review presents the current state of knowledge on functional and structural features of RDHs involved in the visual cycle as well as knockout models. RDHs are described as integral or peripheral enzymes. A topology model of the membrane binding of these RDHs via their N- and (or) C-terminal domain has been proposed on the basis of their individual properties. Membrane binding is a crucial issue for these enzymes because of the high hydrophobicity of their retinoid substrates.

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“…RDH12 is highly expressed in the retina and involved in retinoid metabolism as well as protection against lipid peroxidation products (Lee et al 2008). RDH12 is shown to localize to the ER and microsomal fraction in microscopic analysis (Keller and Adamski 2007) and subcellular fractionation (Lee et al 2007), respectively. While its specific cellular substrate remains unknown, RDH12 displays enzymatic activity on both retinoid and sterol substrates in vitro (Keller and Adamski 2007).…”

Section: Introductionmentioning

confidence: 99%

“…RDH12 is shown to localize to the ER and microsomal fraction in microscopic analysis (Keller and Adamski 2007) and subcellular fractionation (Lee et al 2007), respectively. While its specific cellular substrate remains unknown, RDH12 displays enzymatic activity on both retinoid and sterol substrates in vitro (Keller and Adamski 2007). Mutations in RDH12 have been genetically linked to several different forms of retinal dystrophies including Stargardt disease (Zolnikova et al 2016), cone–rod dystrophy (Huang et al 2016), retinitis pigmentosa (Gong et al 2015), and Leber congenital amaurosis (LCA), which is the most severe form of childhood retinal dystrophy characterized by early visual loss (Janecke et al 2004; Thompson et al 2005; Mackay et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Yeast ENV9 encodes a conserved lipid droplet (LD) short-chain dehydrogenase involved in LD morphology

et al. 2017

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Lipid droplets (LDs) have emerged as dynamic and interactive organelles with important roles in lipid metabolism and membrane biogenesis. Here, we report that Saccharomyces cerevisiae Env9 is a novel conserved oxidoreductase involved in LD morphology. Microscopic and biochemical studies confirm localization of tagged Env9 to LDs and implicate its C-terminal hydrophobic domain (aa241–265) in its membrane association and stability. Confocal studies reveal a role for Env9 in LD morphology. Env9 positively affects both formation of large LDs upon overexpression and LD proliferation under poor carbon source. In silico bioinformatic and modeling approaches establish that ENV9 is a widely conserved member of the short-chain dehydrogenase (SDR) superfamily. Bayesian phylogenetic studies strongly support ENV9 as an ortholog of human SDR retinol dehydrogenase 12 (RDH12). Dehydrogenase activity of Env9 was confirmed by in vitro oxidoreductase assays. RDH12 mutations have been linked to Leber Congenital Amaurosis. Similar site-directed point mutations in the predicted Env9 oxidoreductase active site (N146L) or cofactor-binding site (G23–24A) abolished its reductase activity in vitro, consistent with those reported in other retinol dehydrogenases. The same residues were essential for affecting LD size and number in vivo. Taken together, our results implicate oxidoreductase activity of Env9 in its cellular role in LD morphology.

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RDH12, a retinol dehydrogenase causing Leber's congenital amaurosis, is also involved in steroid metabolism

Cited by 20 publications

References 13 publications

Enzymology of retinoic acid biosynthesis and degradation

Enzymology of retinoic acid biosynthesis and degradation

Retinol dehydrogenases: Membrane-bound enzymes for the visual function

Yeast ENV9 encodes a conserved lipid droplet (LD) short-chain dehydrogenase involved in LD morphology

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