Understanding Retinol Metabolism: Structure and Function of Retinol Dehydrogenases

Lidén, Martin; Eriksson, Ulf

doi:10.1074/jbc.r500027200

Cited by 90 publications

(78 citation statements)

References 48 publications

(41 reference statements)

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“…Knockout studies have provided evidence for ADH1, ADH3, and ADH4 functions in retinol metabolism, although none of these knockouts-even in combination-lead to developmental abnormalities. Today, more than 20 different enzymes displaying all-trans and/or cis-RDH activities have been isolated, but no loss-of-function data are available (8). We suggest that before the onset of Rdh10 expression, RALDHs may use Ral produced by ubiquitously expressed ADHs and possibly RDHs.…”

Section: Discussionmentioning

confidence: 99%

“…In placental species, Rol is the main retinoid transferred from maternal to embryonic circulation via retinol-binding protein (RBP) (6). Oxidation of Rol to Ral can be catalyzed by several enzymes from the alcohol dehydrogenase (ADH) and short-chain dehydrogenase/ reductase (SDR) families (7,8). It was first assumed that this reaction was achieved in an essentially redundant manner, as targeted mutations of Adh or Rdh genes led to viable mice with no congenital abnormalities (7,9,10).…”

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confidence: 99%

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Involvement of retinol dehydrogenase 10 in embryonic patterning and rescue of its loss of function by maternal retinaldehyde treatment

Rhinn

Schuhbaur

Niederreither³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

130

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Retinoic acid (RA), an active vitamin A metabolite, is a key signaling molecule in vertebrate embryos. Morphogenetic RA gradients are thought to be set up by tissue-specific actions of retinaldehyde dehydrogenases (RALDHs) and catabolizing enzymes. According to the species, two enzymatic pathways (β-carotene cleavage and retinol oxidation) generate retinaldehyde, the substrate of RALDHs. Placental species depend on maternal retinol transferred to the embryo. The retinol-to-retinaldehyde conversion was thought to be achieved by several redundant enzymes; however, a random mutagenesis screen identified retinol dehydrogenase 10 [Rdh10 Trex allele; Sandell LL, et al. (2007) Genes Dev 21:1113-1124] as responsible for a homozygous lethal phenotype with features of RA deficiency. We report here the production and characterization of unique murine Rdh10 loss-of-function alleles generated by gene targeting. We show that although Rdh10 −/− mutants die at an earlier stage than Rdh10Trex mutants, their molecular patterning defects do not reflect a complete state of RA deficiency. Furthermore, we were able to correct most developmental abnormalities by administering retinaldehyde to pregnant mothers, thereby obtaining viable Rdh10 −/− mutants. This demonstrates the rescue of an embryonic lethal phenotype by simple maternal administration of the missing retinoid compound. These results underscore the importance of maternal retinoids in preventing congenital birth defects, and lead to a revised model of the importance of RDH10 and RALDHs in controlling embryonic RA distribution.branchial arches | hindbrain | phenotypic rescue | heart | organogenesis

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Involvement of retinol dehydrogenase 10 in embryonic patterning and rescue of its loss of function by maternal retinaldehyde treatment

Rhinn

Schuhbaur

Niederreither³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

130

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“…A multitude of cytosolic alcohol dehydrogenases and microsomal short-chain dehydrogenases/reductases (SDRs) (Duester et al, 2003;Lidén and Eriksson, 2006), as well as the recently identified CYP1B1 mono-oxygenase (Chambers et al, 2007), can mediate the first step of RA synthesis from vitamin A. Retinol dehydrogenase 10 (RDH10) is a member of the SDR family that oxidizes retinol into retinal (Wu et al, 2002;Wu et al, 2004) in an NAD + -dependent manner (Belyaeva et al, 2008), and exhibits tissue-specific expression at embryonic and foetal mouse stages (Sandell et al, 2007;Cammas et al, 2007;Romand et al, 2008). Analysis of an N-ethyl-N-nitrosourea-generated mutant called trex suggested an essential function of murine RDH10 for RA biosynthesis during limb, craniofacial and organ development (Sandell et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Retinol dehydrogenase 10 is a feedback regulator of retinoic acid signalling during axis formation and patterning of the central nervous system

et al. 2009

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Retinoic acid (RA) is an important morphogen that regulates many biological processes, including the development of the central nervous system (CNS). Its synthesis from vitamin A (retinol) occurs in two steps, with the second reaction -catalyzed by retinal dehydrogenases (RALDHs) -long considered to be crucial for tissue-specific RA production in the embryo. We have recently identified the Xenopus homologue of retinol dehydrogenase 10 (XRDH10) that mediates the first step in RA synthesis from retinol to retinal. XRDH10 is specifically expressed in the dorsal blastopore lip and in other domains of the early embryo that partially overlap with XRALDH2 expression. We show that endogenous RA suppresses XRDH10 gene expression, suggesting negativefeedback regulation. In mRNA-injected Xenopus embryos, XRDH10 mimicked RA responses, influenced the gene expression of organizer markers, and synergized with XRALDH2 in posteriorizing the developing brain. Knockdown of XRDH10 and XRALDH2 by specific antisense morpholino oligonucleotides had the opposite effects on organizer gene expression, and caused a ventralized phenotype and anteriorization of the brain. These data indicate that the conversion of retinol into retinal is a developmentally controlled step involved in specification of the dorsoventral and anteroposterior body axes, as well as in pattern formation of the CNS. We suggest that the combinatorial gene expression and concerted action of XRDH10 and XRALDH2 constitute a 'biosynthetic enzyme code' for the establishment of a morphogen gradient in the embryo.

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“…The first step is the reversible oxidation of retinol (ROH) into retinal by retinol dehydrogenases (RDH). 16,18 The second step, the oxidation of retinal into the biologically active RA, is carried out by retinal dehydrogenases (RalDH). RA activates 2 families of nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which are ligand-inducible transcription factors.…”

mentioning

confidence: 99%

CYP26 Inhibitor R115866 Increases Retinoid Signaling in Intimal Smooth Muscle Cells

Ocaya

Gidlöf²,

Olofsson³

et al. 2007

ATVB

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Objective-Intimal smooth muscle cells (SMCs) are dedifferentiated SMCs that have a powerful ability to proliferate and migrate. This cell-type is responsible for the development of intimal hyperplasia after vascular angioplasty. Retinoids, especially all-trans retinoid acid, are known to regulate many processes activated at sites of vascular injury, including modulation of SMC phenotype and inhibition of SMC proliferation. Intracellular levels of active retinoids are under firm control. A key enzyme is the all-trans retinoic acid-degrading enzyme cytochrome p450 isoform 26 (CYP26 10 Retinoids inhibit intimal hyperplasia after vascular injury 6,9 by reducing SMC proliferation. 11 They are known to influence differentiation of various cell types, and previous studies indicate that retinoids can alter the phenotype of vascular SMCs. 9,12 To date, a number of genes have been identified as markers of intimal SMCs including tropomyosin 4, 13 cytokeratins, 14 and cellular retinol binding protein-1 (CRBP-1). 15 Interestingly, CRBP-1 is involved in retinoid metabolism, 16 suggesting an altered retinoid metabolism in the intima. Indeed, we previously demonstrated that intimal SMCs have higher capacity to metabolize retinol into the active metabolite, all-trans retinoic acid (atRA), than medial SMCs. 17 The inhibition of DNA synthesis in intimal SMCs, in contrast to increased DNA synthesis in medial SMCs on retinol stimulation, 17 further supports the concept of differential retinoid metabolism in these subsets of cells.The metabolism of retinoids is complex and involves multiple binding proteins and metabolizing enzymes. The synthesis of retinoic acid (RA) is a 2-step reaction involving substrate-specific enzymes and cellular retinol binding proteins. The first step is the reversible oxidation of retinol (ROH) into retinal by retinol dehydrogenases (RDH). 16,18 The second step, the oxidation of retinal into the biologically active RA, is carried out by retinal dehydrogenases (RalDH). RA activates 2 families of nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which are ligand-inducible transcription factors. Retinoids exert their effects on gene transcription mainly through 2 active stereoisomers, atRA and 9-cis retinoic acid (9-cisRA). 19

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Understanding Retinol Metabolism: Structure and Function of Retinol Dehydrogenases

Cited by 90 publications

References 48 publications

Involvement of retinol dehydrogenase 10 in embryonic patterning and rescue of its loss of function by maternal retinaldehyde treatment

Involvement of retinol dehydrogenase 10 in embryonic patterning and rescue of its loss of function by maternal retinaldehyde treatment

Retinol dehydrogenase 10 is a feedback regulator of retinoic acid signalling during axis formation and patterning of the central nervous system

CYP26 Inhibitor R115866 Increases Retinoid Signaling in Intimal Smooth Muscle Cells

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