Understanding RetinolMetabolism: Structure andFunction of RetinolDehydrogenases*Published, JBC Papers in Press, January 20, 2006, DOI 10.1074/jbc.R500027200

Martin Liden and Ulf Eriksson1

From the Ludwig Institute for Cancer Research, Stockholm Branch,Box 240, S-171 77 Stockholm, Sweden

Retinoids (vitamin A derivatives) have dual functions in physiology. 11-cis-Retinal serves as the universal chromophore of the visual pigments in the eye,and the hormonal retinoids, mainly all-trans- and 9-cis-retinoic acid (RA),2regulate the expression of target genes via activation of two classes of nuclearretinoid receptors, the retinoic acid receptors (RARs), and the retinoid Xreceptors (RXRs) (1). The dietary sources of retinoids are the proforms of thevitamin, mainly esterified retinol, or the ultimate precursors for retinoids, var-ious carotenoids. Thus, the biosynthesis of active forms of retinoids is of cru-cial importance for many physiological processes, including embryonic devel-opment, reproduction, postnatal growth, differentiation and maintenance ofvarious epithelia, immune responses, and vision (2–4).During fasting conditions the common precursor of the active retinoids,

all-trans-retinol (vitamin A), is transported in plasma in a 1:1 complex withretinol-binding protein (RBP) (5). Retinol, in the form of retinyl esters, can alsobe transported to target cells using the common lipoproteins in plasma (6).Following uptake by target cells, retinol is converted, through several enzy-matic steps, into its active derivatives (Fig. 1). Retinol is oxidized once togenerate retinal and twice to generate RA. For the generation of the 9-cis- or11-cis-retinoids, an isomerization reaction takes place prior to the first oxida-tion (7). The enzymes for most of these activities have been identified. To datesome 20 different enzymes displaying all-trans- or -cis-retinol dehydrogenase(RDH) activities have been isolated and partially characterized by standardbiochemical methods (Table 1). However, whether all of these enzymes trulyfunction as retinol dehydrogenases in vivo remains to be determined. To thisend it will be of great importance to analyze the enzymatic characteristics ofthe identified RDHs in intact cells, isolated organs, and in animal models. Herewe discuss current knowledge regarding the biological roles, and structure-function relationships of RDHs, focusing on the microsomal members of theshort chain dehydrogenase/reductase (SDR) family.

Two Families of Mammalian Retinol Dehydrogenases

Two different classes of retinol dehydrogenases have been proposed to carryout the oxidative conversion of retinol into retinal, namely the classical cyto-solic alcohol dehydrogenases (ADHs), belonging to the medium chain dehy-drogenases/reductases family, and some microsomal members of the SDRsuperfamily (RDHs) (Table 1) (8).ADHs are well known to catalyze the oxidation of a wide range of substrates

in vitro (or reduction of the corresponding aldehyde forms), including ethanol,retinol, other aliphatic alcohols, steroids, and lipid peroxidation products (9).At present it is unclear whether members of the ADH family contribute toretinol oxidation under normal physiological conditions.Mice lackingAdh1 orAdh4 are viable and fertile and show no abnormalities unless challenged withexcess doses of retinol (10). Targeted deletion ofAdh3 indicates a potential rolefor this ubiquitously expressed enzyme in retinoid metabolism (11). However,evidence supporting a direct role of this enzyme in RA biosynthesis is lacking.

In conclusion, data accumulated until now do not provide strong support for arole of the ADHs in physiological RA biosynthesis.The microsomal RDHs of the SDR family generally display higher substrate

specificity as compared with the ADHs, catalyzing the oxidation of differentisomers of retinol as well as some steroids (12, 13). Genetic evidence, mainlyfrom different eye diseases and studies of zebra fish development, providestrong support for a key role of these enzymes in physiological oxidation ofretinol. The biological roles of this class of RDHs are discussed in more detailbelow.

Biological Roles of Retinol Dehydrogenases of the SDR Family

The prototypic microsomal retinol dehydrogenase, RDH5 (11-cis-retinoldehydrogenase), was identified in the retinal pigment epithelium (RPE) of theeye andwas shown to catalyze the oxidation of 11-cis-retinol into 11-cis-retinalin the visual cycle (14).Missensemutations in rdh5 are associatedwith the rarerecessive eye disease known as fundus albipunctatus, characterized by station-ary night blindness, accumulation of white spots in the retina, and develop-ment of cone dystrophy among elderly (15). This observation provided the firstgenetic evidence for the involvement of microsomal RDHs in retinoid metab-olism in vivo. Interestingly, targeted deletion of murine rdh5 generates a muchmilder phenotype, suggesting a higher degree of redundancy in mice (16).Indeed, other retinol dehydrogenases have recently been implicated in thegeneration of visual chromophore inmice (RDH11–14) (17, 18).Most notably,mutations in rdh12 have been shown to cause a retinal disease known asLeber’s congenital amaurosis, demonstrating that this enzyme is responsiblefor the reduction of all-trans-retinal into retinol in the photoreceptor cells (19).The proposed role of RDH11 in the visual cycle has, however, been questioned(20), and others (21) have suggested that this enzyme (also referred to as RalR1or PSDR1) serves as a retinal reductase rather than an oxidizing enzyme,although purely based on in vitro data. This same enzyme has also been impli-cated in retinoid homeostasis in normal and neoplastic prostate, and itsexpression seems to be regulated by androgens (22).Recent data also show that RDHs play important roles in RA signaling dur-

ing gut development and differentiation andmaybe in pathological conditions.Thus, RDH5 and RDHL (also known as hRoDH-E2) are down-regulated incolon adenomas and carcinomas, leading to reduced synthesis of RA (23).Moreover, the same report demonstrates that adenomatous polyposis coli(APC) and the colon-specific transcription factor CDX2 can control the pro-duction of RA via regulated expression of RDHL. Further investigations haveidentified two zebrafish RDHs, rdh1/zRDHB and rdh1l/zRDHA, that are nec-essary for proper development of the intestine, as well as other organs, anddemonstrate a genetic link between RDH-mediated RA synthesis and theupstream regulator APC (24, 25).Taken together, several RDHs have been ascribed functional roles in the

generation of 11-cis-retinal and RA. Further genetic dissection is clearlyneeded to pinpoint the exact roles of the different enzymes.However, given thepossible redundancy among the RDHs, it is likely that different combinationsof RDHs need to be inactivated to generate clear morphological and/or func-tional phenotypes in mice.

Domain Organization and Topology of RetinolDehydrogenases

The RDHs of the SDR family have an overall amino acid sequence similarityof at least 30%. Among the conserved features is the cofactor binding site(amino acid residuesG-X-X-X-G-X-G,X representing any amino acid residue)and the catalytic site (amino acid residues Y-X-X-X-K) (8). In addition,many ofthem display a similar domain organization and most likely share a commonfolding and membrane topology. Particularly, the catalytic core SDR domainseems very conserved within the SDR superfamily, with an almost identicaldomain fold in most of the crystallized enzymes. Nevertheless, researchersexploring themembrane topology of the RDHs have come to different conclu-sions regarding the topology of these enzymes and the number of transmem-brane domains (TMDs) that anchor these enzymes in the ER membrane(Fig. 2).Initial studies conducted in 1999 demonstrated that the prototypic RDH5 is

anchored to the ER membrane by two TMDs, which flank the conserved SDRcore domain (27). It was shownby proteinaseKprotection experiments, aswellas endoglycosidase H treatment of an RDH5 mutant carrying an ectopic gly-

* This minireview will be reprinted in the 2006 Minireview Compendium, which will beavailable in January, 2007.

1 To whom correspondence should be addressed. Tel.: 46-8-52487109; Fax: 46-8-332812;E-mail: ulf.eriksson@licr.ki.se.

2 The abbreviations used are: RA, retinoic acid; ADH, alcohol dehydrogenase; RAR, reti-noic acid receptor; RBP, retinol-binding protein; RDH, retinol dehydrogenase; RPE,retinal pigment epithelium; RXR, retinoid X receptor; SDR, short chain dehydrogen-ase/reductase; TMD, transmembrane domain; APC, adenomatous polyposis coli; ER,endoplasmic reticulum; CRBPI, cellular retinol-binding protein I; CRALBP, cellular reti-naldehyde-binding protein.

THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 281, NO. 19, pp. 13001–13004, May 12, 2006© 2006 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in the U.S.A.

MAY 12, 2006 • VOLUME 281 • NUMBER 19 JOURNAL OF BIOLOGICAL CHEMISTRY 13001

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cosylation site, that the catalytic ectodomain is facing the lumen of the ER andthat only a shortC-terminal tail of seven amino acids protrudes into the cytosol(Fig. 2B, model a). Studies on the related SDR member CRAD1 have con-firmed, by independent techniques, that this enzyme has a lumenal topology ofthe catalytic domain (28, 29). Moreover, genetic and biochemical data, as wellas computer-based modeling, suggest that these enzymes occur as functionalhomodimers (29, 30).Other groups have presented different results regarding the topology of

related enzymes, based on computer predictions and biochemical analyses oftruncated variants of RoDH1 and RoDh4 (Fig. 2B,model b (31, 32) andmodelc (33)) and also by searching for topological signals in the various domains ofmRDH1 by fusing them to the fluorescent reporter protein GFP (model c (34)).As shown in Fig. 2, the models differ not only in general membrane topologybut also with regard to the number of TMDs. In model b, hydrophobic seg-ments within the conserved core SDR domain has been proposed to serve asTMDs. However, the three-dimensional structure of the crystallizedmembersof the SDR family would argue against this model as these hydrophobicstretches of amino acid residues in all cases are confined to the central coreregion of the SDR domain. Inmodel c, the SDR domain has a cytosolic orien-tation and the C-terminal hydrophobic segment has not been included as aTMD. This model has also been supported by studies on the topology ofRDH11/RalR1 (35). However, recent data show that the corresponding C-ter-minal region in CRAD1 can serve as a bona fide TMD in CD4 fusion proteins,retaining the proteins in the ER membrane and orienting with the C terminusfacing the cytosol (29). Yet another report demonstrates that RDH12 carriesendoglycosidase H-sensitive glycans (19), which is consistent only with thelumenal topology represented bymodel a.

Unfortunately, the data summarized here do not allow a simple consensusinterpretation, a fact that has hampered the progress of the field during recentyears. It appears unlikely, but not possible to fully exclude, that these relatedenzymes display different membrane topologies. Instead, the experimentaldesign may influence the outcome. It is notable that the analyses of the wild-type proteins, at least concerning the prototypic RDH5 andCRAD1, give iden-tical results using several different techniques. Considering that membranetranslocation, topology, and domain folding are highly context-dependentprocesses, the use of fusion proteins containing distinct peptide segments mayintroduce artifacts (36–38) and are in the absence of careful analyses of theintact proteins only indicative.The topology of this class of enzymes has several important cell biological

implications with regard to substrate and cofactor delivery, interplay withother components of the retinoid signaling pathway, as well as possible regu-latory events taking place to control the enzymatic activity. Such issues arediscussed below.

Cell Biological Perspectives on Retinol Dehydrogenases

Although the number of identified RDHs belonging to the SDR family hasincreased considerably during the passed few years, most of them have onlybeen characterized bymeans of traditional biochemical approaches and not incells. Consequently, detailed knowledge of the molecular function of theseenzymes is limited. The development of cellular assays should provide the toolsnecessary for functional studies of these enzymes in vivo. While fundamentalbiochemical work has given important data, e.g. on the substrate specificitiesand cofactor preferences of the different enzymes (Table 1), in vitro studiesmight not accurately reflect their relevance in vivo, as exemplified below.

FIGURE 1. Schematic overview of the retinoid activating pathways. A, chemical structure of all-trans-retinol, and its active derivatives, all-trans-retinoic acid, 9-cis-retinoic acid, and11-cis-retinal. B, outline of the retinoid activation pathways. Target cells take up all-trans-retinol from retinol-binding protein (holo-RBP) or from retinyl esters transported in eitherchylomicrons (CM) or lipoproteins (LP). A putative receptor activity has been reported for RBP-mediated uptake. Intracellularly retinol may be isomerized into 9-cis- or 11-cis-retinol,of which the former activity is yet to be identified, followed by sequential oxidation into retinal and RA. RDHs and retinal dehydrogenases (RalDH) catalyze the first and secondoxidations, respectively. The two isoforms of RA activate the nuclear retinoid receptors, RARs and RXRs, to control target gene transcription. 11-cis-Retinal is regenerated in the eyeby a process referred to as the visual cycle (shaded).

TABLE 1Retinol dehydrogenases of the SDR family and their substrate and cofactor preferences

Speciesa Enzyme name(s) Substrate(s) (retinoid isomers) Cofactor preferencem CRAD1/rdh6 9-cis/11-cis NAD�m CRAD2/rdh7 11-cis (all-trans) NAD�m CRAD3/rdh9 9-cis/11-cis NAD�/NADP�m mRDH1/rdh1 All-trans/9-cis NAD�(NADP�)b/h/m 11-cis-RDH/RDH5/RDH4 9-cis/11-cis NAD�b/h/m RDH10 All-trans NADP�h/m RDH11/RalR1/PSDR1 All-trans/9-cis/11-cis NADP�h/m RDH12 All-trans/9-cis/11-cis NADP�h/m RDH13 Dual trans/cis NAh/m RDH14 All-trans/9-cis/11-cis NADP�m/r ERolDHb All-trans NAb/h hRoDH-E2/RDHLb All-trans NADP�r RoDH1 All-trans NADP�r RoDH2 All-trans NADP�r RoDH3 NAc NAh RoDH4/hRoDH-E All-trans NAD�b/h/m retSDR1 All-trans NADP�b/h/m prRDH/rdh8 All-trans NADP�z rdh1l/zRDHA All-trans NAz rdh1/zRDHB All-trans NA

a b, bovine; h, human; m, mouse; r, rat; z, zebrafish.b eRolDH and hRoDH-E2/RDHL are orthologs.c NA, not available.

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The use of reporter assays for studies of retinoid receptor activation andtarget genes, established in the 1990s, has inspired the development of coupledenzyme/reporter assays. These assays enable reconstitution of the biochemicalretinoid pathways generating RA in vivo. Using this approach, it was shownthat deletion of the cytosolic tail (see Fig. 2B, model a) in RDH5 and CRAD1resulted in abolished enzymatic activity in vivo but not in a traditional in vitroassay (28). Further studies have demonstrated that the cytosolic tail is neces-sary for the functional activity of these enzymes, which might reflect that thisregion is involved in interaction(s) with some type of effector molecule(s) (29).Several possible functions of such interactions can be envisaged, including arole in substrate and/or co-factor delivery, coupling with other functionalevents upstream or downstream in the pathway, or it may represent a controlpoint in the pathway, ultimately regulating the generation of RA. These resultsunderscore the necessity of analyzing RDH function in a cellular context toclarify their roles in physiological retinol oxidation.

Regulation of RDHActivity—Thepossible regulation of the enzymatic activ-ities of the RDHs is still largely unexplored. As the concentration of all-trans-retinol in plasma is �2–3 �M, whereas the concentration of RA ligandsrequired for receptor activation is a 1000-fold lower (i.e. in the nanomolarrange), target cells should require some means to control the generation ofthese highly potent receptor ligands. Apart from possible regulation at theprotein level, as implied by the data summarized above, recentwork shows thatsome RDHs are regulated at the transcriptional level. As mentioned above,RDHL is under the control of APC and CDX2 (24), and the expression ofRDH11/RalR1/PSDR1 seems to be regulated by androgens (22). Yet, otherenzymes of the family, such as the visual cycle enzymes RDH5 and RDH12, arelikely to be constitutively active and may not be subject to such regulation.

Subcellular Localization of RDHs—Despite the controversy regarding themembrane topology of RDHs, it is well established that these enzymes localizeto the smooth ER. Although the molecular mechanism underlying ER local-ization remains to be explained, recent work on CRAD1 demonstrates that itsputative C-terminal TMDmediates ER retention of the enzyme (29). Possiblereasons for this include lateral interaction(s) with other ER resident compo-nents within the membrane or exclusion from the lipid bilayer of forwardtransporting vesicles of the secretory pathway. The visual cycle enzyme RDH5is also known to localize in the smooth ER of RPE cells or in transfected cells(14, 27). In light of this, the isolation of RDH5 in a protein complex localized tothe apical membranes of RPE cells is intriguing. This is described furtherbelow.One of the RDHs expressed in photoreceptors, prRDH/rdh8, differs from

other RDHs, bothwith regard to the domains flanking the SDRdomain and themode of membrane interaction and localization. Thus, prRDH localizes to therod and cone outer segments by means of a C-terminal localization signal andis peripherally associated to the membranes via fatty acylation of one or moreconserved cysteine residues (39). However, any functional implications thisdistinct localization mechanism might have are yet to be resolved.

Interactions of RDHs with Other Proteins—It is widely believed that retinolbound to cellular retinol-binding protein I (CRBPI) is the physiological sub-strate for all-trans-specific RDHs, as evidenced by cross-linking experiments

and in vitro kinetics (reviewed in Ref 40). It follows that this view also requiresa cytosolic orientation of the catalytic domain of these RHDs (Fig. 2B,model c).However, at present no functional data exist to support this role for CRBPI ina cellular context. On the contrary, studies onmice deficient in CRBPI indicatethat this carrier protein is mainly involved in retinyl ester storage, rather thanplaying a vital role in RA biosynthesis (41, 42). More profound effects havebeen seen upon deletion of cellular retinaldehyde-binding protein (CRALBP),which operates in the visual cycle, in the regeneration of 11-cis-retinal(reviewed in Ref 43). CRALBPhas been suggested to facilitate the generation of11-cis-retinal by mediating the transfer of 11-cis-retinol from the retinoidisomerase to RDH5, which catalyzes oxidation of 11-cis-retinol into 11-cis-retinal. The mechanism of substrate delivery, whether it involves retinoid-binding proteins directly or not, needs to be determined at the molecular levelin the context of living cells.A few additional reports also demonstrate protein interactions involving

RDH5. For instance, RDH5 was first discovered through its association withRPE65 (14), a protein that has been implicated in retinol uptake (44, 45) andrecently was shown to be the retinoid isomerase in the visual cycle (46). How-ever, any functional roles of this interaction are yet unknown. Furthermore,RDH5 has been shown to interact with retinal G protein-coupled receptor(47). This RPE protein is an opsin, which mediates photoisomerization of itsbound all-trans-retinal into 11-cis-retinal. RDH5 has been proposed to reducethe product into 11-cis-retinol, although the functional significance of such areaction remains unknown. Recent studies also suggest that RDH5 occurs in alarger retinoid processing complex present in the apical processes of RPE cells(48, 49). This complex includes CRALBP, which binds to the PDZ domainprotein EBP50/NHERF1, which in turn interacts with ezrin. Ezrin binds tovarious plasma membrane components and links them physically to the actincytoskeleton. It was suggested that this retinoid processing complex mightfacilitate localized synthesis and release of an 11-cis-retinoid in the apical areaof the RPE.

Concluding Remarks

The RDHs are well characterized with regard to their enzymatic prop-erties in vitro. However, to learn more about their roles in physiologicalretinol oxidation, functional aspects need to be explored at the cellular andorganism levels. Tomorrow’s challenges are thus to investigate the cellbiological architecture of the retinoid metabolic pathways and to under-stand possible regulatory mechanisms that control the spatially and tem-porally restricted generation of active retinoids in vivo. Such analyses arelikely to involve different kinds of in vivo reporter strategies to monitorenzyme function, either established in cell lines, organ cultures, or in trans-genic animals carrying reporter constructs.

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Martin Lidén and Ulf ErikssonDehydrogenases

Understanding Retinol Metabolism: Structure and Function of Retinol

doi: 10.1074/jbc.R500027200 originally published online January 20, 20062006, 281:13001-13004.J. Biol. Chem. 

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