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Information on EC 1.1.1.300 - NADP-retinol dehydrogenase and Organism(s) Mus musculus and UniProt Accession Q9QYF1
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1.1.1.300 NADP-retinol dehydrogenaseIUBMB Comments
Greater catalytic efficiency in the reductive direction. This observation, and the enzyme's localization at the entrance to the mitochondrial matrix, suggest that it may function to protect mitochondria against oxidative stress associated with the highly reactive retinal produced from dietary beta-carotene by EC 1.13.11.63 (beta-carotene 15,15'-dioxygenase) . Km-values for NADP+ and NADPH are at least 800-fold lower than those for NAD+ and NADH [1,4]. This enzyme differs from EC 1.1.1.105, retinol dehydrogenase, which prefers NAD+ and NADH.
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Word Map
- 1.1.1.300
-
retinoids
- photoreceptors
-
cone
- rhodopsin
- 11-cis-retinal
-
all-trans-retinoic
-
leber
-
retinyl
- amaurosis
- retinylamine
- opsin
- medicine
- pharmacology
The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Synonyms
prrdh, retinol dehydrogenase 11, retinol dehydrogenase 8, ralr1, nrdrb1, mrdh11, nadp(h)-dependent retinol dehydrogenase/reductase, photoreceptor retinol dehydrogenase, rdh14, retinol dehydrogenase-10, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
RDH10
RDH12
RDH8
retinol dehydrogenase 10
retinol dehydrogenase 8
retinol dehydrogenase-10
PATHWAY SOURCE
PATHWAYS
-
-, -
SYSTEMATIC NAME
IUBMB Comments
retinol:NADP+ oxidoreductase
Greater catalytic efficiency in the reductive direction. This observation, and the enzyme's localization at the entrance to the mitochondrial matrix, suggest that it may function to protect mitochondria against oxidative stress associated with the highly reactive retinal produced from dietary beta-carotene by EC 1.13.11.63 (beta-carotene 15,15'-dioxygenase) [2]. Km-values for NADP+ and NADPH are at least 800-fold lower than those for NAD+ and NADH [1,4]. This enzyme differs from EC 1.1.1.105, retinol dehydrogenase, which prefers NAD+ and NADH.
CAS REGISTRY NUMBER
COMMENTARY
90033-53-8
cf. EC 1.1.1.105
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
(E)-4-hydroxy-2-nonenal + NADPH + H+
(E)-4-hydroxy-2-nonenol + NADP+
-
-
-
?
11-cis-retinal + NADPH + H+
11-cis-retinol + NADP+
The reverse reaction, oxidation of all-trans-retinol, is not catalyzed by mRDH11
-
-
ir
all-trans-retinal + NADPH + H+
all-tans-retinol + NADP+
The reverse reaction, oxidation of all-trans-retinol, is not catalyzed by mRDH11
-
-
ir
(E)-4-hydroxy-2-nonenal + NADPH + H+
(E)-4-hydroxy-2-nonenol + NADP+
Rdh12 is able to efficiently detoxify 4-hydroxynonenal in cells, most probably through its ability to reduce it to a nontoxic alcohol
-
-
?
13-cis-retinal + NADPH + H+
13-cis-retinol + NADP+
-
4fold lower activity than with all-trans-retinal
-
-
?
9-cis-retinal + NADPH + H+
9-cis-retinol + NADP+
-
60fold lower activity than with all-trans-retinal
-
-
?
retinal + NADPH + H+
retinol + NADP+
reaction of the retinoid oxidoreductive complex (ROC) composed of RDH10 (SDR16C4)and DHRS3 (EC 1.2.1.36)
-
-
ir
all-trans-retinal + NADPH + H+
all-trans-retinol + NADP+
RDH12 is dispensable in support of the visual cycle but appears to be a key component in clearance of free all-trans-retinal, thereby preventing accumulation of N-retinylidene-N-retinylethanolamine (a toxic substance known to contribute to retinal degeneration) and photoreceptor cell death
-
-
?
additional information
?
-
-
the low and constant expression of RDH11 suggests a housekeeping function for this enzyme in retina
-
-
?
additional information
?
-
the low and constant expression of RDH11 suggests a housekeeping function for this enzyme in retina
-
-
?
additional information
?
-
the low and constant expression of RDH11 suggests a housekeeping function for this enzyme in retina
-
-
?
additional information
?
-
-
dihydrotestosterone is not a substrate for mouse isoform RDH12
-
-
?
additional information
?
-
-
the onset of RDH12 expression during the maturation of photoreceptor cells suggests a function related to the visual process. The light-induced rapid decrease of RDH12 protein, preceding the decrease of the mRNA, suggested a specific degradation of the protein rather than a regulation of gene expression
-
-
?
additional information
?
-
the onset of RDH12 expression during the maturation of photoreceptor cells suggests a function related to the visual process. The light-induced rapid decrease of RDH12 protein, preceding the decrease of the mRNA, suggested a specific degradation of the protein rather than a regulation of gene expression
-
-
?
additional information
?
-
the onset of RDH12 expression during the maturation of photoreceptor cells suggests a function related to the visual process. The light-induced rapid decrease of RDH12 protein, preceding the decrease of the mRNA, suggested a specific degradation of the protein rather than a regulation of gene expression
-
-
?
additional information
?
-
-
recombinant RRD functions with both unbound and CRBP(I) (cellular retinol-binding protein)-bound retinal
-
-
?
additional information
?
-
the rod outer segment enzyme retinol dehydrogenase RDH8 uses NADPH as a cofactor. 11-cis retinal is not a substrate of RDH8. Narrow substrate specificity of RDH8
-
-
-
additional information
?
-
-
the rod outer segment enzyme retinol dehydrogenase RDH8 uses NADPH as a cofactor. 11-cis retinal is not a substrate of RDH8. Narrow substrate specificity of RDH8
-
-
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
all-trans-retinal + NADPH + H+
all-trans-retinol + NADP+
RDH12 is dispensable in support of the visual cycle but appears to be a key component in clearance of free all-trans-retinal, thereby preventing accumulation of N-retinylidene-N-retinylethanolamine (a toxic substance known to contribute to retinal degeneration) and photoreceptor cell death
-
-
?
additional information
?
-
-
the low and constant expression of RDH11 suggests a housekeeping function for this enzyme in retina
-
-
?
additional information
?
-
the low and constant expression of RDH11 suggests a housekeeping function for this enzyme in retina
-
-
?
additional information
?
-
the low and constant expression of RDH11 suggests a housekeeping function for this enzyme in retina
-
-
?
additional information
?
-
-
the onset of RDH12 expression during the maturation of photoreceptor cells suggests a function related to the visual process. The light-induced rapid decrease of RDH12 protein, preceding the decrease of the mRNA, suggested a specific degradation of the protein rather than a regulation of gene expression
-
-
?
additional information
?
-
the onset of RDH12 expression during the maturation of photoreceptor cells suggests a function related to the visual process. The light-induced rapid decrease of RDH12 protein, preceding the decrease of the mRNA, suggested a specific degradation of the protein rather than a regulation of gene expression
-
-
?
additional information
?
-
the onset of RDH12 expression during the maturation of photoreceptor cells suggests a function related to the visual process. The light-induced rapid decrease of RDH12 protein, preceding the decrease of the mRNA, suggested a specific degradation of the protein rather than a regulation of gene expression
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
recombinant RRD reduces free retinal (not bound with cellular retinol binding protein) with a K0.5 value of 0.0023 mM and a Hill constant of 1.7, and reduces CRBP(I)-bound retinal (2fold molar excess of cellular retinol binding protein(I) at each retinal concentration) with a K0.5 value of 0.0086 mM and a Hill constant of 2.1
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
mouse monoclonal anti-GRK1 (G-proteinassociated rhodopsin kinase-1)
SwissProt
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
RDH11 protein is most abundant in testis microsomes, with lower levels detectable in microsomes from liver, lung, and intestine. The rate of retinaldehyde reduction to retinol by the microsomes isolated from RDH11-null testis is 3fold lower compared with wild-type testis microsomes. Similarly to testis microsomes, liver microsomes lacking RDH11 show a lower rate (1.7fold) of retinaldehyde reduction. No differences are observed in the microsomal retinaldehyde reductase activities from livers of male versus female mice
low level expression. No differences are observed in the microsomal retinaldehyde reductase activities from livers of male versus female mice
the RDH11 level is low and remarkably constant during development and oxidative stress
level of isoform Rdh11 is low and remarkably constant during development and oxidative stress. Rdh12 expression starts at postnatal day 7 and increases until postnatal day 30 to approximately sevenfold higher than Rdh11. Oxidative stress induced by exposure to constant bright light leads to a rapid and significant decrease of Rdh12 protein
RDH12 expression starts at postnatal day and increases until postnatal day 30. Oxidative stress induced by exposure to constant bright light leads to a rapid and significant decrease of RDH12 protein
expression in inner segments, cell bodies and synaptic termini of photoreceptors
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
retinaldehyde can be produced in the cells by the oxidation of retinol or by the cleavage of beta-carotene at its central double bond (15,15') catalyzed by cytosolic BCO1. In rodents, cleavage of beta-carotene to retinaldehyde with subsequent conversion of retinaldehyde to retinol occurs mainly in the small intestine. RDH11 is essential for the maintenance of retinol levels in testis of mice on beta-carotene diet
physiological function
evolution
malfunction
metabolism
the enzyme is involved in retinoic acid biosynthesis, overview. Retinoic acid (RA)-mediated transcriptional feedback loops upregulate the expression of the reductive enzyme DHRS3 and downregulate the expression of the oxidative enzyme RDHE2 in response to an increase in retinoic acid levels. Members of two families of SDRs are involved in the regulation of RA homeostasis, SDR16C and SDR7C. Regulation of the flux from retinol to retinaldehyde
physiological function
evolution
retinol dehydrogenase 11 (RDH11) is a member of the short-chain dehydrogenase/reductase (SDR) superfamily of proteins. A mild reduction in retinoic acid signaling is observed in RDH11-null testis
evolution
RDH11 is co-expressed with BCO1 in several mouse tissues, and the retinaldehyde reductase activity of RDH11 is conserved in the mouse enzyme
malfunction
microsomes isolated from the testes and livers of Rdh11-/- mice fed a regular diet exhibit a 3 and 1.7fold lower rate of all-trans-retinaldehyde conversion to all-trans-retinol, respectively, than the microsomes of wild-type littermates. Testes and livers of Rdh11-/- mice fed a vitamin A-deficient diet have about 35% lower levels of all-trans-retinol than those of wild-type mice. Oxidative NAD+-dependent retinol dehydrogenase activity is not affected by inactivation of the rdh11 gene, while similarly to testis microsomes, liver microsomes lacking RDH11 show a lower rate (1.7fold) of retinaldehyde reduction. In lungs and intestines, the microsomal retinaldehyde reductase activities are comparable between RDH11-null mice and their wild-type littermates
malfunction
microsomes isolated from the testes and livers of Rdh11-/- mice fed a regular diet exhibited a 3 and 1.7fold lower rate of all-trans-retinaldehyde conversion to all-trans-retinol, respectively, than the microsomes of wild-type littermates. Testes and livers of Rdh11-/- mice fed a vitamin A-deficient diet have about 35% lower levels of all-trans-retinol than those of wild-type mice the conversion of beta-carotene to retinol via retinaldehyde as an intermediate appeared to be impaired in the testes of Rdh11-/-/retinol-binding protein 4-/- (Rbp4-/-) mice, which lack circulating holo RBP4 and rely on dietary supplementation with beta-carotene for maintenance of their retinoid stores. Overnight starvation results in a decrease in the amount of RDH11 in livers of fasted mice. Gene expression pattern indicates a mild reduction in retinoic acid signaling in RDH11-null testis. The oxidative NAD+-dependent retinol dehydrogenase activity is not affected by inactivation of the Rdh11 gene. The conversion of retinaldehyde to retinol in whole mouse embryonic fibroblasts (MEFs) lacking RDH11 occurs at a slower rate than in wild-type MEFs
physiological function
Rdh11 is able to efficiently detoxify 4-hydroxynonenal in cells. Rdh11 protects against 4-hydroxynonenal modification of proteins and 4-hydroxynonenal-induced apoptosis in HEK-293 cells
physiological function
retinol dehydrogenase 11 (RDH11) is a microsomal short-chain dehydrogenase/reductase that recognizes all-trans- and cis-retinoids as substrates and prefers NADPH as a cofactor. RDH11 contributes to the oxidation of 11-cis-retinol to 11-cis-retinaldehyde during the visual cycle in the eye's retinal pigment epithelium. The intestinal microsomes produce two products within the short 15-min incubations with retinaldehyde: retinol and retinyl esters. This suggests that, in the intestinal microsomes, the retinaldehyde reductase activity is coordinated with the retinol esterifying activity, possibly to ensure a highly efficient processing of retinaldehyde into retinyl esters for packaging into chylomicrons. RDH11 is essential for the maintenance of retinol levels in testis of mice on beta-carotene diet, and RDH11 is essential for the maintenance of retinol levels in liver and testis of mice during dietary vitamin A deficiency
physiological function
RDH11 contributes to the oxidation of 11-cis-retinol to 11-cis-retinaldehyde during the visual cycle in the eye's retinal pigment epithelium. In mouse testis and liver, RDH11 functions as an all-trans-retinaldehyde reductase essential for the maintenance of physiological levels of all-trans-retinol under reduced vitamin A availability. RDH11 is essential for the maintenance of retinol levels in testis of mice on beta-carotene diet
evolution
-
RDHs that catalyze the interconversion of retinal and retinol involved in rhodopsin turnover are members of the family of short chain dehydrogenase/reductases
evolution
enzyme RDH10 belongs to the 16C family of the short-chain dehydrogenase/reductase (SDR) superfamily. Most members of the SDR16C family (except for DHRS3) exhibit higher binding affinities for NAD(H) as cofactor, whereas members of the SDR7C family prefer NADP(H). The NAD(H)-dependent oxidoreductases usually function in the oxidative direction in intact cells, whereas the NADP(H)-dependent enzymes function in the reductive direction
malfunction
-
generation of Rdh13 knockout mice. No obvious difference in phenotype or function between Rdh13 knockout and wild-type mice. But in Rdh13-/- mice subjected to intense light exposure, the photoreceptor outer-plus-inner-segment and outer nuclear layer are dramatically shorter, and the amplitudes of a- and b-waves under scotopic conditions are significantly attenuated. Increased expression levels of CytC, CytC-responsive apoptosis proteinase activating factor-1 and caspases 3, and other mitochondria apoptosis-related genes, e.g. nuclear factor-kappa B P65 and B-cell lymphoma 2-associated X protein, are observed in Rdh13-/- mice
malfunction
-
loss-of-function mutations of RDH12 cause retinal degeneration in some forms of Leber congenital amaurosis. Outer segments of rods deficient in Rdh12 show no altered phenotype. Following exposure to light, a leak of retinoids from outer to inner segments is detected in rods from both wild-type and knock-out mice. In cells lacking Rdh8, EC 1.1.1.105, or Rdh12, this leak is mainly all-trans-retinal, overview. Retinal reductase activity is lost in RDH8-deficient mutants
malfunction
-
Rdh10 null mutant mouse embryos exhibit dorsal pancreas agenesis and a hypoplastic ventral pancreas with retarded tubulogenesis and branching. Rdh10 null mutant mouse embryos exhibit dorsal pancreas agenesis and a hypoplastic ventral pancreas with retarded tubulogenesis and branching
malfunction
cyclic-light-reared Rdh8-/- knockout mice show elevated levels of all-trans retinal, contributing to RPE lipofuscin formation and accumulation. Lipofuscin accumulates in the retinal pigment epithelium (RPE) of Rdh8-/- mice
malfunction
fetal mouth movement defects are correlated with cleft palate, cleft palate in retinoid deficiency results from a lack of fetal mouth movement. Mouse embryos deficient in retinoic acid (RA) have mispatterned pharyngeal nerves and skeletal elements that block spontaneous fetal mouth movement in utero. Embryos with deficient retinoid signaling are generated by stagespecific inactivation of retinol dehydrogenase 10 (Rdh10), a gene crucial for the production of RA during embryogenesis. Rdh10+ denotes the wild-type allele, Rdh10delta denotes a targeted knockout null allele with exon 2 deleted, and Rdh10flox is a floxed allele in which exon 2 is excised upon exposure to Cre recombinase thereby converting to Rdh10delta. Disruption of RA production at different embryonic stages can produce a variety of phenotypes, analysis of palate morphology in Rdh10flox/+ control and Rdh10delta/flox mutant embryos, overview
malfunction
mice lacking RDH10 either in cone photoreceptors, Müller cells, or the entire retina show normal cone photoresponses in all RDH10-deficient mouse lines. Their cone-driven dark adaptation both in vivo and in isolated retina is unaffected, indicating that RDH10 is not required for the function of the retina visual cycle. In transgenic mice overexpressing RDH10 ectopically in rod cells, rod dark adaptation is unaffected and transgenic rods are unable to use cis-retinol for pigment regeneration
malfunction
mutagenesis and targeted gene knockout studies in mice confirm that a functional RDH10 is critical for survival until embryonic day 11.5 (E11.5), as Rdh10-/- embryos can be rescued by maternal supplementation of retinaldehyde from E7.5 to E11.5. Genetic disruption of murine Rdh10 gene results in a marked reduction in retinoic acid (RA) synthesis that leads to numerous developmental abnormalities. RDH10-deficient embryos display defects in axial extension and embryonic turning, abnormal hindbrain and craniofacial patterning, agenesis of posterior pharyngeal arches, perturbed somitogenesis, hypoplastic forelimb buds, and abnormal organogenesis of multiple systems, including heart and vasculature, lungs, and gastrointestinal tract. Embryos carrying a targeted knockout of Rdh10 died by E12.5, while embryos carrying various mutant alleles survived until E13.5-E15.5, or until late gestation. Testicular cell-specific conditional knockout of Rdh10 shows that deficiency of RDH10 in both Sertoli and germ cells completely impairs testicular RA signaling in juvenile animals. Spermatogenesis progressively recovers in adult Rdh10 conditional knockout mice, suggesting that RDH10 is not essential for adult spermatogenesis. In mice, targeted knockout of Dhrs3 results in an about 30% increase in RA levels, reduction in the levels of retinol and retinyl esters, and embryonic lethality late in gestation
malfunction
-
Rdh8-/- Rdh12-/- double knockout mice show that Rdh8 accounts for 70% of all-trans RDH activity. Rdh12-/- mice display normal retinal morphology at 6 weeks of age. There is no significant difference in rhodopsin levels, indicating efficient regeneration of the chromophore. No difference in all-trans RDH activity in dissected retinae or isolated rod outer segments (ROS) between wild-type and Rdh12-/- mice is observed, suggesting that other enzymes may be compensating for the loss of Rdh12 activity. Knockout mice do show a delayed dark adaptation and accumulation of all-trans retinal after bleaching, indicating an important role of RDH12 under conditions of excess illumination. Retinal homogenates show decreased all-trans retinal reduction, and increased A2E levels. Rdh8-/- Rdh12-/- double knockouts also show mild light-dependent retinal degeneration, with delayed dark adaptation and reduced all-trans RDH activity with a build-up of all-trans retinal, a subsequent accumulation of toxic A2E is observed. Double knockout mice regenerate the visual pigment in vivo and triple knockout Rdh8-/- Rdh12-/- Rdh5-/- mice also have the ability to regenerate 11-cis retinal
malfunction
isolated retinas from Rgr+/+ and Rgr-/- mice are exposed to continuous light, and cone photoresponses are recorded. Cones in Rgr-/- retinas lose sensitivity at a significantly faster rate than cones in Rgr+/+ retinas. A similar effect is seen in Rgr+/+ retinas following treatment with alpha-aminoadipic acid. These results indicate that maintenance and recovery of cone sensitivity in isolated mouse retinas requires a light-driven visual cycle that depends on RGR opsin. Thus, ciliary photoreceptors of vertebrates, like the rhabdomeric photoreceptors of invertebrates, can use light itself to regenerate visual pigment
malfunction
RDH10 is not required for the function of the retina visual cycle. Transgenic mice expressing RDH10 ectopically in rod cells show, that rod dark adaptation is unaffected by the expression of RDH10 and transgenic rods are unable to use cis-retinol for pigment regeneration. Lack of phenotype of mice lacking RDH10 in the entire retina
physiological function
Rdh12 is able to efficiently detoxify 4-hydroxynonenal in cells, most probably through its ability to reduce it to a nontoxic alcohol. Cells expressing Rdh12 show significantly less formation of Michael adducts with lysine, histidine, or cysteine residues of proteins thereby inhibiting their physiological functions. Microsomes from retinas of Rdh12 knockout mice form significantly more Michael adducts with microsomal proteins in the presence of 4-hydroxynonenal than wild-type. RDH12 also protects against light-induced apoptosis of photoreceptors
physiological function
-
RDH12 activity in the photoreceptor inner segments is also key enzyme function. RDH12 in inner segments can protect vital cell organelles against aldehyde toxicity caused by an intracellular leak of all-trans-retinal, as well as other aldehydes originating both inside and outside the cell
physiological function
DHRS3 activity requires the presence of retinol dehydrogenase RDH10 to display its full catalytic activity. The retinol dehydrogenase activity of RDH10 is reciprocally activated by retinaldehyde reductase DHRS3. At E13.5, DHRS3-null embryos have 4fold lower levels of retinol and retinyl esters, but only slightly elevated levels of retinoic acid. The membrane-associated retinaldehyde reductase and retinol dehydrogenase activities are decreased by 4- and 2fold, respectively, in Dhrs3-/- embryos, and Dhrs3-/- mouse embryonic fibroblasts exhibit reduced metabolism of both retinaldehyde andretinol. Neither RDH10 nor DHRS3 has to be itself catalytically active to activate each other
physiological function
energy status regulates all-trans-retinoic acid biosynthesis at the rate-limiting step, catalyzed by retinol dehydrogenases. Six h after re-feeding, isoform Rdh10 expression is decreased 4563% in liver, pancreas, and kidney, relative to mice fasted 16 h. All-trans-retinoic acid in the liver is decreased 44% 3 h after reduced Rdh expression. Oral gavage with glucose or injection with insulin decreases Rdh10 mRNA 50% or greater in mouse liver
physiological function
the retinol dehydrogenase activity of RDH10 is reciprocally activated by retinaldehyde reductase DHRS3. At E13.5, DHRS3-null embryos have 4fold lower levels of retinol and retinyl esters, but only slightly elevated levels of retinoic acid. The membrane-associated retinaldehyde reductase and retinol dehydrogenase activities are decreased by 4- and 2fold, respectively, in Dhrs3-/- embryos, and Dhrs3-/- mouse embryonic fibroblasts exhibit reduced metabolism of both retinaldehyde andretinol. Neither RDH10 nor DHRS3 has to be itself catalytically active to activate each other
physiological function
-
the enzyme affects dorsal pancreas development and participates in the terminal differentiation of endocrine cells
physiological function
-
all-trans retinal in mouse photoreceptors is reduced predominantly by Rdh8 and Rdh12. Rdh8 and Rdh12 were responsible for over 98% of all-trans RDH activity, withRdh8 accounts for 70% of all-trans RDH activity. The majority of all-trans retinal is reduced by Rdh8 in the outer segments, but some all-trans retinal can leak into the inner segments, where it is reduced by Rdh12. The role of RDH12 in the visual cycle is minimal, but possibly plays a protective role in the clearance of alltrans retinal in periods of intense illumination. Another possible role of RDH12 is protection against toxic lipid peroxidation products, like nonanal and 4-HNE, produced from the oxidative attack of polyunsaturated fatty acids in lipid membranes. A buildup of either all-trans retinal or lipid peroxidation products is damaging to photoreceptors. All-trans retinal accumulation leads to the production of toxic N-retinylidene-N-retinylethanolamine (A2E), and lipid peroxidation products are inherently toxic. RDH12 appears to have two possible roles. RDHs do not appear to be necessary for the regeneration of the visual pigment in mice, but are needed for clearance of all-trans retinal in periods of excess illumination. It is possible that murine RDHs compensate for each other
physiological function
bis-retinoids are a major component of lipofuscin that accumulates in the retinal pigment epithelium (RPE) in aging and age-related macular degeneration (AMD). Bis-retinoids are known to originate from retinaldehydes required for the light response of photoreceptor cells, relative contributions of the chromophore, 11-cis retinal, and photoisomerization product, all-trans retinal, are analyzed, overview. In photoreceptor outer segments, all-trans retinal, but not 11-cis retinal, is reduced by retinol dehydrogenase 8 (RDH8). The reductase activity of RDH8 keeps in check the generation of bis-retinoids from all-trans retinal released by photoactivated rhodopsin. There is no significant increase in lipofuscin precursor fluorescence in wild-type mouse rods following light
physiological function
enzyme retinol dehydrogenase 10 (Rdh10) is crucial for the production of retinoic acid (RA) during embryogenesis, its function is necessary for spontaneous fetal mouth movement that facilitates palate shelf elevation. Proper retinoid signaling and pharyngeal patterning are crucial for the fetal mouth movement needed for palate formation. Vitamin A metabolism and RA production are essential for viability in the early organogenesis stages of development
physiological function
pigment regeneration is critical for the function of cone photoreceptors in bright and rapidly-changing light conditions. This process is facilitated by the recently-characterized retina visual cycle, in which Müller cells recycle spent all-trans-retinol visual chromophore back to 11-cis-retinol. This 11-cis-retinol is oxidized selectively in cones to the 11-cis-retinal used for pigment regeneration. Retinol dehydrogenase 10 (RDH10) is responsible for the oxidation of 11-cis-retinol in the cone visual cycle, but RDH10 is not the dominant retina 11-cis-RDH, overview. Cone RDH10 is not required for normal cone dark adaptation
physiological function
the enzyme is involved in retinoic acid biosynthesis, overview. The NAD(H)-dependent oxidoreductases usually function in the oxidative direction in intact cells, whereas the NADP(H)-dependent enzyme function in the reductive direction. RDH10 acts as a high-affinity retinol dehydrogenase with a preference for NAD+ as cofactor. DHRS3 acts as an NADP(H)-dependent retinaldehyde reductase
physiological function
cone-specific 11-cis-RDH is likely to be important in regulating access to the retina visual cycle. Retinol dehydrogenase 10, RDH10 (UniProt ID Q8VCH7), is not the dominant retina 11-cis-RDH. Cone RDH10 is not required for the normal function of dark-adapted cones and for normal cone dark adaptation, as well as for the retina visual cycle
physiological function
the retinal RPE G-protein-coupled receptor, RGR opsin, and retinol dehydrogenase-10 (Rdh10) convert all-trans-retinol to 11-cis-retinol during exposure to visible light. RGR opsin is a non-visual opsin in intracellular membranes of RPE and Müller cells. The interaction between RGR and Rdh10 is specific. RGR opsin is a critical component of the Müller-cell visual cycle, and that regeneration of cone visual pigment can be driven by light, role of RGR opsin in the regeneration of cone visual pigment. Cones are responsible for vision in bright light and operate at high rates of opsin photoisomerization. Recovery of cone sensitivity is shown to be limited by chromophore supply. Only 11-cis-retinal (11cRAL) can regenerate bleached opsin. Coupled photoisomerization and oxidoreduction of vitamin A by RGR opsin and Rdh10, overview
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). RDH11_MOUSE
316
0
35148
Swiss-Prot
Secretory Pathway (Reliability: 1)
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
T49M
inactive. Mutation is associated with Lebr congenital amaurosis. Mutant is not able to detoxify 4-hydroxynonenal in cells
additional information
additional information
generation of RDH11 knockout (KO) mice, phenotypes, overview
additional information
-
generation of Rdh13 knockout mice. No obvious difference in phenotype or function between Rdh13 knockout and wild-type mice. But in Rdh13-/- mice subjected to intense light exposure, the photoreceptor outer-plus-inner-segment and outer nuclear layer are dramatically shorter, and the amplitudes of a- and b-waves under scotopic conditions are significantly attenuated. Increased expression levels of CytC, CytC-responsive apoptosis proteinase activating factor-1 and caspases 3, and other mitochondria apoptosis-related genes, e.g. nuclear factor-kappa B P65 and B-cell lymphoma 2-associated X protein, are observed in Rdh13-/- mice
additional information
generation of embryonic stage-specific inactivation of retinol dehydrogenase 10 (Rdh10). Stage-specific inactivation of retinol metabolism in Rdh10delta/flox mutant embryos serves as a model for vitamin A/retinoid-deficient cleft palate. Conditional inactivation of Rdh10 causes cleft palate. Nuclear fluorescence imaging of Rdh10flox + control and Rdh10delta/flox mutant embryos at E16.5 reveals complete cleft of the secondary palate in 36% of mutant embryos. For insight into the tissue architecture in cleft palates of Rdh10delta/flox mutant embryos, hematoxylin and eosin staining of paraffin sections is performed. At E13.5, the palate shelf morphology of Rdh10delta/flox mutant embryos resembled that of Rdh10flox/+ control littermates, with palate shelves aligned vertically on either side of the tongue. Using the ubiquitously expressed Cre-ERT2, the genotype of embryos with a floxed allele changes following administration of tamoxifen. Embryos with a pre-tamoxifen genotype of Rdh10flox/+ become Rdh10delta/+ post-tamoxifen. Embryos with a pretamoxifen genotype of Rdh10delta/flox or Rdh10flox/flox become Rdh10delta/delta post-tamoxifen treatment. Cleft palate was not observed in any Rdh10flox/+ control embryos. Rdh10delta/flox mutants have abnormally positioned tongues that obstruct palate shelf elevation, mutant morphologies, overview. No defect in the intrinsic tongue muscles is detected in mutant embryos relative to control littermates. The morphogenesis of tongue musculature is grossly normal in retinoid-deficient embryos, suggesting the abnormal tongue shape does not result from aberrant muscle morphogenesis. Spontaneous fetal mouth movement in utero is restricted in Rdh10delta/flox mutant embryos. Rdh10delta/flox mutant embryos have defects in motor nerves of the posterior pharyngeal arches. Retinoid-deficient embryos develop defects in the pharyngeal skeleton. Retinoid-deficient embryos develop defects in the pharyngeal skeleton
additional information
generation of enzyme Rdh8-/- knockout mice. Cyclic-light-reared Rdh8-/- mice accumulates A2E and RPE lipofuscin approximately 1.5times and approximately 2times faster, respectively, than dark-reared mice. Moving Rdh8-/- mice from cyclic-light to darkness results in bis-retinoid A2E levels less than expected to have accumulated before the move. A2E levels are significantly higher in cyclic-light compared to dark-reared animals at 2, 3, and 6 months of age. In Rdh8-/- mice, the potential contribution of elevated all-trans-retinal to bis-retinoid formation can be maximized
additional information
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generation of enzyme Rdh8-/- knockout mice. Cyclic-light-reared Rdh8-/- mice accumulates A2E and RPE lipofuscin approximately 1.5times and approximately 2times faster, respectively, than dark-reared mice. Moving Rdh8-/- mice from cyclic-light to darkness results in bis-retinoid A2E levels less than expected to have accumulated before the move. A2E levels are significantly higher in cyclic-light compared to dark-reared animals at 2, 3, and 6 months of age. In Rdh8-/- mice, the potential contribution of elevated all-trans-retinal to bis-retinoid formation can be maximized
additional information
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generation of Rdh8-/- Rdh12-/- double knockout mice. The Rdh12-/- mouse model is generated by replacement of exons 1-3 of the Rdh12 gene with a neomycin cassette. Rdh12-/- mice display normal retinal morphology at 6 weeks of age. There is no significant difference in rhodopsin levels, indicating efficient regeneration of the chromophore. No difference in all-trans RDH activity in dissected retinae or isolated rod outer segments (ROS) between wild-type and Rdh12-/- mice is observed
additional information
RDH10 enzyme knockout and overexpression in retina cell. Rdh10 mRNA levels are substantially reduced in retinas obtained from Pdgfra-Cre Rdh10flox/flox mice through a knockout in Müller cells. Similarly, the expression of Rdh10 is also dramatically reduced in Six3-Cre Rdh10flox/flox retinas, demonstrating its suppression in the entire retina. In contrast, Rdh10 mRNA levels are notably increased in transgenic Rdh10+ mice. The deletion of RDH10 in cones does not affect the overall number of cone cells or their function, and cone dark adaptation in vivo is unaffected by cone-specific deletion of RDH10
additional information
generation and analysis of RGR knockout mouse microsomes
additional information
generation of mice lacking RDH10 either in cone photoreceptors, Müller cells, or the entire retina. In vivo electroretinography and transretinal recordings reveal normal cone photoresponses in all RDH10-deficient mouse lines. Notably, their cone-driven dark adaptation both in vivo and in isolated retina is unaffected, indicating that RDH10 is not required for the function of the retina visual cycle. Generation of transgenic mice expressing RDH10 ectopically in rod cells. Rod dark adaptation is unaffected by the expression of RDH10 and transgenic rods are unable to use cis-retinol for pigment regeneration. Lack of phenotype of mice lacking RDH10 in the entire retina
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
cloned as a gene regulated by the transcription factor sterol regulatory element binding proteins and previously named SCALD for short chain aldehyde reductase
gene Rdh10, recombinant enzyme expression in HEK-293T cells, coexpression with with bovine RGR
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
oral gavage with glucose or injection with insulin decreases Rdh10 mRNA 50% or greater in mouse liver
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pharmacology
enzyme RDH8 is a therapeutic target for controlling bis-retinoid A2E cytotoxicity
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Maeda, A.; Maeda, T.; Imanishi, Y.; Kuksa, V.; Alekseev, A.; Bronson, J.D.; Zhang, H.; Zhu, L.; Sun, W.; Saperstein, D.A.; Rieke, F.; Baehr, W.; Palczewski, K.
Role of photoreceptor-specific retinol dehydrogenase in the retinoid cycle in vivo
J. Biol. Chem.
280
18822-18832
2005
Mus musculus
Kasus-Jacobi, A.; Ou, J.; Birch, D.G.; Locke, K.G.; Shelton, J.M.; Richardson, J.A.; Murphy, A.J.; Valenzuela, D.M.; Yancopoulos, G.D.; Edwards, A.O.
Functional characterization of mouse RDH11 as a retinol dehydrogenase involved in dark adaptation in vivo
J. Biol. Chem.
280
20413-20420
2005
Homo sapiens (O75911), Homo sapiens (Q8TC12), Homo sapiens (Q92781), Homo sapiens (Q96NR8), Homo sapiens (Q9HBH5), Homo sapiens (Q9NYR8), Mus musculus (Q9QYF1), Mus musculus
Liden, M.; Eriksson, U.
Understanding retinol metabolism: Structure and function of retinol dehydrogenases
J. Biol. Chem.
281
13001-13004
2006
Bos taurus, Mus musculus
Maeda, A.; Maeda, T.; Imanishi, Y.; Sun, W.; Jastrzebska, B.; Hatala, D.A.; Winkens, H.J.; Hofmann, K.P.; Janssen, J.J.; Baehr, W.; Driessen, C.A.; Palczewski, K.
Retinol dehydrogenase (RDH12) protects photoreceptors from light-induced degeneration in mice
J. Biol. Chem.
49
37697-37704
2006
Mus musculus
Kanan, Y.; Wicker, L.D.; Al-Ubaidi, M.R.; Mandal, N.A.; Kasus-Jacobi, A.
Retinol dehydrogenases RDH11 and RDH12 in the mouse retina: expression levels during development and regulation by oxidative stress
Invest. Ophthalmol. Vis. Sci.
49
1071-1078
2008
Mus musculus, Mus musculus (Q8BYK4), Mus musculus (Q9QYF1)
Keller, B.; Adamski, J.
RDH12, a retinol dehydrogenase causing Lebers congenital amaurosis, is also involved in steroid metabolism
J. Steroid Biochem. Mol. Biol.
104
190-194
2007
Homo sapiens, Mus musculus
Maeda, A.; Maeda, T.; Sun, W.; Zhang, H.; Baehr, W.; Palczewski, K.
Redundant and unique roles of retinol dehydrogenases in the mouse retina
Proc. Natl. Acad. Sci. USA
104
19565-19570
2007
Mus musculus (Q8BYK4)
Lei, Z.; Chen, W.; Zhang, M.; Napoli, J.L.
Reduction of all-trans-retinal in the mouse liver peroxisome fraction by the short-chain dehydrogenase/reductase RRD: induction by the PPAR alpha ligand clofibrate
Biochemistry
42
4190-4196
2003
Mus musculus
Pares, X.; Farres, J.; Kedishvili, N.; Duester, G.
Medium- and short-chain dehydrogenase/reductase gene and protein families: Medium-chain and short-chain dehydrogenases/reductases in retinoid metabolism
Cell. Mol. Life Sci.
65
3936-3949
2008
Homo sapiens, Mus musculus, Rattus norvegicus
Marchette, L.D.; Thompson, D.A.; Kravtsova, M.; Ngansop, T.N.; Mandal, M.N.; Kasus-Jacobi, A.
Retinol dehydrogenase 12 detoxifies 4-hydroxynonenal in photoreceptor cells
Free Radic. Biol. Med.
48
16-25
2010
Mus musculus (Q8BYK4), Mus musculus (Q9QYF1), Mus musculus
Chen, C.; Thompson, D.A.; Koutalos, Y.
Reduction of all-trans-retinal in vertebrate rod photoreceptors requires the combined action of RDH8 and RDH12
J. Biol. Chem.
287
24662-24670
2012
Mus musculus, Mus musculus C57BL/6 x 129/Sv
Wang, H.; Cui, X.; Gu, Q.; Chen, Y.; Zhou, J.; Kuang, Y.; Wang, Z.; Xu, X.
Retinol dehydrogenase 13 protects the mouse retina from acute light damage
Mol. Vis.
18
1021-1030
2012
Mus musculus, Mus musculus C57BL/6 x 129/Sv
Adams, M.K.; Belyaeva, O.V.; Wu, L.; Kedishvili, N.Y.
The retinaldehyde reductase activity of DHRS3 is reciprocally activated by retinol dehydrogenase 10 to control retinoid homeostasis
J. Biol. Chem.
289
14868-14880
2014
Homo sapiens (O75911), Mus musculus (O88876), Mus musculus (Q8VCH7), Mus musculus
Obrochta, K.M.; Krois, C.R.; Campos, B.; Napoli, J.L.
Insulin regulates retinol dehydrogenase expression and all-trans-retinoic acid biosynthesis through FoxO1
J. Biol. Chem.
290
7259-7268
2015
Mus musculus (Q8VCH7)
Arregi, I.; Climent, M.; Iliev, D.; Strasser, J.; Gouignard, N.; Johansson, J.K.; Singh, T.; Mazur, M.; Semb, H.; Artner, I.; Minichiello, L.; Pera, E.M.
Retinol dehydrogenase-10 regulates pancreas organogenesis and endocrine cell differentiation via paracrine retinoic acid signaling
Endocrinology
157
4615-4631
2016
Mus musculus
Jiang, W.; Napoli, J.
The retinol dehydrogenase Rdh10 localizes to lipid droplets during acyl ester biosynthesis
J. Biol. Chem.
288
589-597
2013
Mus musculus
Kolesnikov, A.V.; Maeda, A.; Tang, P.H.; Imanishi, Y.; Palczewski, K.; Kefalov, V.J.
Retinol dehydrogenase 8 and ATP-binding cassette transporter 4 modulate dark adaptation of M-cones in mammalian retina
J. Physiol.
593
4923-4941
2015
Mus musculus
Belyaeva, O.V.; Adams, M.K.; Popov, K.M.; Kedishvili, N.Y.
Generation of retinaldehyde for retinoic acid biosynthesis
Biomolecules
10
5
2019
Homo sapiens (Q8IZV5), Mus musculus (Q8VCH7)
Friedl, R.M.; Raja, S.; Metzler, M.A.; Patel, N.D.; Brittian, K.R.; Jones, S.P.; Sandell, L.L.
RDH10 function is necessary for spontaneous fetal mouth movement that facilitates palate shelf elevation
Dis. Model. Mech.
12
dmm039073
2019
Mus musculus (Q8VCH7)
Sarkar, H.; Moosajee, M.
Retinol dehydrogenase 12 (RDH12) Role in vision, retinal disease and future perspectives
Exp. Eye Res.
188
107793
2019
Homo sapiens (Q96NR8), Homo sapiens, Mus musculus
Boyer, N.P.; Thompson, D.A.; Koutalos, Y.
Relative contributions of all-trans and 11-cis retinal to formation of lipofuscin and A2E accumulating in mouse retinal pigment epithelium
Invest. Ophthalmol. Vis. Sci.
62
1
2021
Mus musculus (D3Z6W3), Mus musculus
Belyaeva, O.V.; Wu, L.; Shmarakov, I.; Nelson, P.S.; Kedishvili, N.Y.
Retinol dehydrogenase 11 is essential for the maintenance of retinol homeostasis in liver and testis in mice
J. Biol. Chem.
293
6996-7007
2018
Mus musculus (Q9QYF1)
Xue, Y.; Sato, S.; Razafsky, D.; Sahu, B.; Shen, S.Q.; Potter, C.; Sandell, L.L.; Corbo, J.C.; Palczewski, K.; Maeda, A.; Hodzic, D.; Kefalov, V.J.
The role of retinol dehydrogenase 10 in the cone visual cycle
Sci. Rep.
7
2390
2017
Mus musculus (Q8VCH7)
Morshedian, A.; Kaylor, J.J.; Ng, S.Y.; Tsan, A.; Frederiksen, R.; Xu, T.; Yuan, L.; Sampath, A.P.; Radu, R.A.; Fain, G.L.; Travis, G.H.
Light-driven regeneration of cone visual pigments through a mechanism involving RGR opsin in Mueller glial cells
Neuron
102
1172-1183.e5
2019
Gallus gallus (A0A3Q3ATC8), Homo sapiens (Q8IZV5), Mus musculus (Q8VCH7)
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