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Information on EC 1.1.1.300 - NADP-retinol dehydrogenase and Organism(s) Homo sapiens and UniProt Accession Q8NBN7
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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: Homo sapiens
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
NRDRA1
alternatively spliced variant with a complete deletion of exons 3-6
NRDRB2
alternatively spliced variant with a complete deletion of exons 3 and 6
RDH10
RDH11
RDH12
retinol dehydrogenase 11
retinol dehydrogenase 12
additional information
enzyme additionally displays high aldehyde reductase activity in retinoic acid metabolism
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
11-cis-retinal + NADH + H+
11-cis-retinol + NAD+
NADH much less efficient than NADPH
-
-
r
11-cis-retinol + NADP+
11-cis-retinal + NADPH
-
-
-
?
11-cis-retinol + NADP+
11-cis-retinal + NADPH + H+
possibly involved in the production of 11-cis-retinal from 11-cis-retinol during regeneration of the cone visual pigments
-
-
r
all-trans retinal + NADH + H+
all-tans-retinol + NAD+
NADH much less efficient than NADPH
-
-
r
all-trans-retinal + NADPH + H+
all-tans-retinol + NADP+
-
-
-
r
all-trans-retinol + NAD+
all-trans-retinal + NADH + H+
low activity with NAD+ as cofactor
-
-
r
cis-6-nonenal + NADPH + H+
?
-
good substrate of RDH11 and RDH12, while RHD10 has very low activity towards this substrate
-
-
?
estrone + NADH + H+
estradiol + NAD+
no substrate for wild-type, but substrate for mutant M144G
-
-
?
retinol bound to cellular retinol binding protein + NADP+
retinal bound to cellular retinol binding protein + NADPH
-
-
-
-
?
trans-2-nonenal + NADPH + H+
?
-
good substrate of RDH11 and RDH12, while RHD10 has very low activity towards this substrate
-
-
?
all-trans-retinal + NADPH + H+
all-trans-retinol + NADP+
greater catalytic efficiency in the reductive than in the oxidative direction. Localization of RDH13 at the entrance to the mitochondrial matrix suggests that it may function to protect mitochondria against oxidative stress associated with the highly reactive retinaldehyde produced from dietary beta-carotene
-
-
?
all-trans-retinal + NADPH + H+
all-trans-retinol + NADP+
prefers NADPH to NADH as a cofactor. Activity in presence of 1 mM NADPH is about 20fold greater than that in the presence of 1 mM NADH
-
-
?
11-cis-retinal + NADPH + H+
11-cis-retinol + NADP+
-
-
-
r
9-cis-retinol + NADP+
9-cis-retinal + NADPH + H+
possibly involved in the first step of 9-cis-retinoic acid production
-
-
r
all-trans-retinal + NAD(P)H + H+
all-trans-retinol + NAD(P)+
-
-
r
all-trans-retinal + NADPH + H+
all-trans-retinol + NADP+
-
-
-
r
all-trans-retinal + NADPH + H+
all-trans-retinol + NADP+
involved in the regeneration of bleached visual pigments in photoreceptor cells, involved in retinol metabolism outside of photoreceptor cells
-
-
?
all-trans-retinol + NADP+
all-trans-retinal + NADPH + H+
-
the enzyme plays a role in retinoid metabolism
-
-
r
all-trans-retinol + NADP+
all-trans-retinal + NADPH + H+
involved in retinoid homeostasis in the prostate
-
-
r
all-trans-retinol + NADP+
all-trans-retinal + NADPH + H+
possibly involved in the first step of all-trans-retinoic acid production
-
-
?
all-trans-retinol + NADP+
all-trans-retinal + NADPH + H+
more efficient in the reductive direction
-
-
r
n-nonanal + NADPH + H+
n-nonanol + NADP+
might play a role in detoxification of lipid peroxidation products
-
-
r
retinal + NADPH + H+
retinol + NADP+
reaction of the retinoid oxidoreductive complex (ROC) composed of RDH10 (SDR16C4)and DHRS3 (EC 1.2.1.36)
-
-
ir
retinol + NADP+
retinal + NADPH + H+
important for the maintenance of retinoid homeostasis
-
-
r
retinol + NADP+
retinal + NADPH + H+
important for the maintenance of retinoid homeostasis, low activity of the NRDRB1 splice variant possibly contributes to a disturbed retinoid homeostasis leading to abnormal differentiation and high susceptibility to human papilloma virus in the cervical epithelium
-
-
r
additional information
?
-
no significant conversion of 17beta-, 3alpha- and 11beta-hydroxysteroids
-
-
?
additional information
?
-
-
no significant conversion of 17beta-, 3alpha- and 11beta-hydroxysteroids
-
-
?
additional information
?
-
-
clear specificity for pro-S hydrogen of NADPH and for pro-R-hydrogen on C15 of the retinols, no steroid dehydrogenase activity
-
-
?
additional information
?
-
clear specificity for pro-S hydrogen of NADPH and for pro-R-hydrogen on C15 of the retinols, no steroid dehydrogenase activity
-
-
?
additional information
?
-
clear specificity for pro-S hydrogen of NADPH and for pro-R-hydrogen on C15 of the retinols, no steroid dehydrogenase activity
-
-
?
additional information
?
-
-
although bi-directional in vitro, in living cells, RDH12 acts exclusively as a retinaldehyde reductase, shifting the retinoid homeostasis toward the increased levels of retinol and decreased levels of bioactive retinoic acid. The retinaldehyde reductase activity of RDH12 protects the cells from retinaldehyde-induced cell death
-
-
?
additional information
?
-
-
isoform RDH12 additionally cataylzes the reduction of dihydrotestosterone to androstanediol
-
-
?
additional information
?
-
the enzymes utilizes retinol bound to cellular retinol binding protein type I at a much lower rate than free retinol
-
-
?
additional information
?
-
-
RDH10 is essential for retinoic acid biosynthesis during embryogenesis
-
-
?
additional information
?
-
it is unlikely that 11-cis retinal is metabolised by RDH12 in vivo, as according to the visual cycle, 11-cis retinal that enters the photoreceptors is likely to be sequestered by opsins. Binding of cellular-retinol-binding-protein, CRBP1, to all-trans retinol prevents its oxidation by RDH12
-
-
-
additional information
?
-
-
it is unlikely that 11-cis retinal is metabolised by RDH12 in vivo, as according to the visual cycle, 11-cis retinal that enters the photoreceptors is likely to be sequestered by opsins. Binding of cellular-retinol-binding-protein, CRBP1, to all-trans retinol prevents its oxidation by RDH12
-
-
-
additional information
?
-
purified RDH12 displays a about 2000fold higher affinity for NADP+ and NADPH than for NAD+ and NADH, and has a greater affinity for retinaldehydes than retinols. RDH12 functions as a retinal reductase, with highest activity towards all-trans retinal, followed by 11-cis retinal. RDH12 has also been shown to convert dihydrotestosterone (DHT) to androstanediol
-
-
-
additional information
?
-
-
purified RDH12 displays a about 2000fold higher affinity for NADP+ and NADPH than for NAD+ and NADH, and has a greater affinity for retinaldehydes than retinols. RDH12 functions as a retinal reductase, with highest activity towards all-trans retinal, followed by 11-cis retinal. RDH12 has also been shown to convert dihydrotestosterone (DHT) to androstanediol
-
-
-
additional information
?
-
RDH11 is able to reduce both all-trans- and cis-retinaldehydes into all-trans- and -cis-retinol (Vitamin A)
-
-
-
additional information
?
-
-
RDH11 is able to reduce both all-trans- and cis-retinaldehydes into all-trans- and -cis-retinol (Vitamin A)
-
-
-
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+
greater catalytic efficiency in the reductive than in the oxidative direction. Localization of RDH13 at the entrance to the mitochondrial matrix suggests that it may function to protect mitochondria against oxidative stress associated with the highly reactive retinaldehyde produced from dietary beta-carotene
-
-
?
11-cis-retinol + NADP+
11-cis-retinal + NADPH + H+
possibly involved in the production of 11-cis-retinal from 11-cis-retinol during regeneration of the cone visual pigments
-
-
r
9-cis-retinol + NADP+
9-cis-retinal + NADPH + H+
possibly involved in the first step of 9-cis-retinoic acid production
-
-
r
n-nonanal + NADPH + H+
n-nonanol + NADP+
might play a role in detoxification of lipid peroxidation products
-
-
r
all-trans-retinal + NADPH + H+
all-trans-retinol + NADP+
involved in the regeneration of bleached visual pigments in photoreceptor cells, involved in retinol metabolism outside of photoreceptor cells
-
-
?
all-trans-retinol + NADP+
all-trans-retinal + NADPH + H+
-
the enzyme plays a role in retinoid metabolism
-
-
r
all-trans-retinol + NADP+
all-trans-retinal + NADPH + H+
involved in retinoid homeostasis in the prostate
-
-
r
all-trans-retinol + NADP+
all-trans-retinal + NADPH + H+
possibly involved in the first step of all-trans-retinoic acid production
-
-
?
retinol + NADP+
retinal + NADPH + H+
important for the maintenance of retinoid homeostasis
-
-
r
retinol + NADP+
retinal + NADPH + H+
important for the maintenance of retinoid homeostasis, low activity of the NRDRB1 splice variant possibly contributes to a disturbed retinoid homeostasis leading to abnormal differentiation and high susceptibility to human papilloma virus in the cervical epithelium
-
-
r
additional information
?
-
-
although bi-directional in vitro, in living cells, RDH12 acts exclusively as a retinaldehyde reductase, shifting the retinoid homeostasis toward the increased levels of retinol and decreased levels of bioactive retinoic acid. The retinaldehyde reductase activity of RDH12 protects the cells from retinaldehyde-induced cell death
-
-
?
additional information
?
-
-
RDH10 is essential for retinoic acid biosynthesis during embryogenesis
-
-
?
additional information
?
-
it is unlikely that 11-cis retinal is metabolised by RDH12 in vivo, as according to the visual cycle, 11-cis retinal that enters the photoreceptors is likely to be sequestered by opsins. Binding of cellular-retinol-binding-protein, CRBP1, to all-trans retinol prevents its oxidation by RDH12
-
-
-
additional information
?
-
-
it is unlikely that 11-cis retinal is metabolised by RDH12 in vivo, as according to the visual cycle, 11-cis retinal that enters the photoreceptors is likely to be sequestered by opsins. Binding of cellular-retinol-binding-protein, CRBP1, to all-trans retinol prevents its oxidation by RDH12
-
-
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
NADH
prefers NADPH to NADH as a cofactor. Activity in presence of 1 mM NADPH is about 20fold greater than that in the presence of 1 mM NADH
NADPH
prefers NADPH to NADH as a cofactor. Activity in presence of 1 mM NADPH is about 20fold greater than that in the presence of 1 mM NADH
additional information
purified RDH12 displays a about 2000fold higher affinity for NADP+ and NADPH than for NAD+ and NADH
-
additional information
-
purified RDH12 displays a about 2000fold higher affinity for NADP+ and NADPH than for NAD+ and NADH
-
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1,2-diheptanoyl-sn-glycero-3-phosphocholine
substitution of the detergent 1,2-diheptanoyl-sn-glycero-3-phosphocholine for Tween-20 results in complete inactivation of the enzyme
(3beta)-3-[(3-carboxypropanoyl)oxy]-11-oxoolean-12-en-30-oic acid
-
0.5 mM, 60% of inhibition
selenoprotein F
SELENOF, cloned from a human fetal brain cDNA library, interacts with RDH11 and blocks its enzyme activity to reduce all-trans-retinaldehyde. The reductase activity of RDH11 affected by selenoprotein F
-
additional information
-
not inhibitory: methylpyrazole, phenylmethylsulfonylfluoride
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.004
all-trans-retinol
Km-value for all-trans-retinol is similar to that for retinal however, the rate of retinol oxidation by RDH13 is extremely low
6
NADH
pH and temperature not specified in the publication. The apparent Km value for NADH is three orders of magnitude higher than that for NADPH
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.63
-
eluate after purification, the specific activity of the purified enzyme with all-trans-retinal as substrate is 13fold higher than that of the microsomal preparation of wild-type
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
high RDH10 expression level, 13.89%, 43.59%, 70.59%, and 90.24% expression of RDH10 in glioma of grade I, II, III, and IV (WHO grading), respectively
detected in 54% of cervical tumor tissue samples but not in normal cervical tissue
detected in cervical tumor tissue samples where NRDRB1 could not be detected
RDH11 is involved in the retinal pigment epithelium (RPE) during the retinoid visual cycle
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
RDH13 is localized on the outer side of the inner mitochondrial membrane
additional information
-
rod
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
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
evolution
human retinol dehydrogenase 11 RDH11 belongs to the short-chain dehydrogenases/ reductases (SDR) family
evolution
retinol dehydrogenase-10 (RDH10) is a member of the short-chain dehydrogenase/reductase family
evolution
retinol dehydrogenases (RDHs) are members of the short chain dehydrogenases/reductases (SDR) family of enzymes. The SDRs are typically 250-350 amino acids in length and have a relatively low sequence similarity of about 15-30%. Common to all SDRs is the highly conserved Rossman fold, which is composed of a central beta-sheet flanked by 3-4 alpha-helices, forming the cofactor binding site. The SDRs have two conserved domains: the cofactor binding site (GXXXGXG) and the catalytic site (YXXXK)
evolution
the enzyme belongs to the the short-chain dehydrogenase/reductase (SDR) superfamily, NAD(P)-dependent enzymes, and short-chain dehydrogenase/reductase 16C family (SDR16C)
malfunction
mutations in RDH12 are primarily associated with Leber congenital amaurosis (LCA) type 13, an early onset retinal dystrophy, presenting in early childhood and accounting for approximately 10% of all LCA cases, clinical phenotypes of autosomal recessive RDH12 LCA, overview. One case of a heterozygous variant has also been implicated in autosomal dominant retinitis pigmentosa (RP)
malfunction
mutations in the gene encoding retinol dehydrogenase 10 (Rdh10) lead to craniofacial, limb, and organ abnormalities. This phenotype, called RDH10trex, is caused by the severely reduced ability of mutant RDH10 to oxidize retinol to retinaldehyde, resulting in insufficient RA signaling
malfunction
mutations in the retinol dehydrogenase 12 (RDH12) gene are primarily associated with Leber congenital amaurosis (LCA) type 13, a severe early onset autosomal recessive retinal dystrophy. This is a progressive disorder with significant decline from 10 years of age, which leads to complete blindness in adulthood. RDH12-LCA is characterized by macular atrophy, which extends peripherally in a variegated pattern corresponding to the retinal vasculature, and midperipheral pigmentary retinopathy. A heterozygous deletion (F254Lfs*24 ) in retinol dehydrogenase 12 (RDH12) causes familial autosomal dominant retinitis pigmentosa. Mutation E260R, a single base pair deletion resulting in a frameshift and premature termination, causes a milder late onset (average age of diagnosis is 28.5 years) retinitis pigmentosa (RP) phenotype, with intraretinal bone spicule pigmentation and attenuation of retinal arterioles. Phenotypes, overview
malfunction
shRNA-mediated RDH10 knockdown induces glioma cell cycle arrest, impairs glioma cell proliferation in vitro, and promotes glioma apoptosis. RDH10 knockdown significantly represses several key cancer pathways including TWEAK, TNFR1 and P53. RDH10 knockdown inhibits glioma cell growth by down-regulating the TWEAK-NF-kappaB axis
malfunction
the cofactor binding mutants, RDH10 G43A/G47A/G49A-HA and DHRS3 G49A/G51A-FLAG, retain the capacity to form complexes with wild-type protein partners. Similarly, active site mutants, RDH10 Y210A-HA and DHRS3 Y188A-FLAG, retain the capacity to form complexes with wild-type protein partners. Thus, catalytically active proteins are not necessary for complex formation
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 faster rate than cones in Rgr+/+ retinas
metabolism
interaction of selenoprotein F (SELENOF) with retinol dehydrogenase 11 (RDH11) implying a role of selenoprotein F in vitamin A metabolism. Selenoprotein F has been reported to play important roles in oxidative stress, endoplasmic reticulum (ER) stress, and carcinogenesis. Both of selenoprotein F and RDH11 might reduce all-trans-retinaldehyde into all-trans-retinol, but overexpressed selenoprotein F and RDH11 inhibit the enzyme activity of each other
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
metabolism
the oxidation of all-trans-retinol to all-trans-retinal represents the first and rate-limiting step of the all-trans-retinoic acid (RA) synthesis pathway and it is the target of mechanisms that fine-tune RA levels within the cell. RDH10 is one enzyme responsible for the oxidation of all-trans-retinol to all-trans-retinaldehyde, and together with the all-trans-retinaldehyde reductase DHRS3 forms an oligomeric protein complex. The resulting retinoid oxidoreductase complex (ROC) is bifunctional and has the capacity to regulate steady-state levels of the direct precursor of RA, all-trans-retinaldehyde. By coupling retinol dehydrogenase and retinaldehyde reductase activities, an elegant system is formed that can fine-tune steady-state levels of all-trans-retinaldehyde, and consequently RA, concentrations within the cell. DHRS3 is a critical regulator of RA synthesis. Formation of ROC influences the catalytic properties of both RDH10 and DHRS3 subunits
metabolism
the oxidation of all-trans-retinol to all-trans-retinal represents the first and rate-limiting step of the all-trans-retinoic acid (RA) synthesis pathway and it is the target of mechanisms that fine-tune RA levels within the cell. RDH10 is one enzyme responsible for the oxidation of all-trans-retinol to all-trans-retinaldehyde, and together with the all-trans-retinaldehyde reductase DHRS3 forms an oligomeric protein complex. The resulting retinoid oxidoreductase complex (ROC) is bifunctional and has the capacity to regulate steady-state levels of the direct precursor of RA, all-trans-retinaldehyde. By coupling retinol dehydrogenase and retinaldehyde reductase activities, an elegant system is formed that can fine-tune steady-state levels of all-trans-retinaldehyde, and consequently RA, concentrations within the cell. Formation of ROC influences the catalytic properties of both RDH10 and DHRS3 subunits
physiological function
the retinol dehydrogenase activity of RDH10 is activated by retinaldehyde reductase DHRS3. In turn, DHRS3 requires the presence of retinol dehydrogenase RDH10 to display its full catalytic activity. Neither RDH10 nor DHRS3 has to be itself catalytically active to activate each other
physiological function
-
the enzyme accelerates erythroid cell proliferation by upregulating the STAT5 signaling pathway
physiological function
RDH11 is an enzyme for the reduction of all-trans-retinaldehyde to all-trans-retinol (vitamin A). It is involved in the retinal pigment epithelium (RPE) during the retinoid visual cycle. Interaction of selenoprotein F (SELENOF) with retinol dehydrogenase 11 (RDH11) is analyzed by yeast two-hybrid system and determination of production of retinol. The production of retinol is decreased by SELENOF overexpression, resulting in more retinaldehyde
physiological function
retinol dehydrogenase 12 (RDH12) is an NADPH-dependent retinal reductase that functions as part of the visual cycle, involving a series of enzymatic reactions that regenerates the visual pigment, 11-cis retinal, overview of the visual cycle and the role of RDH12. A number of RDHs are involved in the visual cycle, and vary in substrate and coenzyme specificity. RDH12 functions as a retinal reductase, with highest activity towards all-trans retinal, followed by 11-cis retinal. Enzyme RDH12 has also been shown to convert dihydrotestosterone (DHT) to androstanediol, suggesting a possible involvement in steroid metabolism. RDH12 can also act on medium chain aldehydes, produced from lipid peroxidation of unsaturated fatty acids metabolising the lipid derived medium chain aldehyde nonanal, and inhibiting the reduction of all-trans retinal in RDH12 transfected HEK-293 cells, indicating that RDH12 can protect cells from nonanal induced toxity, but RDH12 does not protect cells against 4-hydroxynonenal (4-HNE), the most abundant lipid peroxidation product, although HEK-293 cells stably transfected with RDH12 do protect from 4-HNE-induced cell death
physiological function
retinol dehydrogenase-10 (RDH10) plays an important role in retinoic acid (RA) synthesis, and it promotes development and progression of human glioma via the TWEAK-NF-kappaB axis. RDH10 is highly expressed in human gliomas, and its expression correlates with tumor grade and patient survival times, RDH10 expression is associated with development and progression of human glioma. RDH10 is overexpressed in human gliomas and predicts a high grade and poor prognosis. RDH10 regulates the cell cycle progression, as its loss causes an S and G2/M phase arrest, RDH10 regulates expression of glioma genes, it affects expression of genes involved in cancer, apoptosis, growth and proliferation, motility, and cell cycle
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 enzymes function in the reductive direction. RDH10 acts as a high-affinity retinol dehydrogenase with a preference for NAD+ as cofactor
physiological function
the retinoid oxidoreductase complex (ROC) is bifunctional and has the capacity to regulate steady-state levels of the direct precursor of RA, all-trans-retinaldehyde. By coupling retinol dehydrogenase and retinaldehyde reductase activities, an elegant system is formed that can fine-tune steady-state levels of all-trans-retinaldehyde, and consequently RA, concentrations within the cell. Formation of ROC influences the catalytic properties of both RDH10 and DHRS3 subunits. Catalytically active enzymes are not necessary for complex formation. As the rate-limiting step of RA synthesis, the conversion of all-trans-retinol to all-trans-retinaldehyde is a target of mechanisms that regulate RA synthesis. ROC, consisting of the retinol dehydrogenase RDH10 and the retinaldehyde reductase DHRS3, is a critical component of RA synthesis regulation
physiological function
the retinoid oxidoreductase complex (ROC) is bifunctional and has the capacity to regulate steady-state levels of the direct precursor of RA, all-trans-retinaldehyde. By coupling retinol dehydrogenase and retinaldehyde reductase activities, an elegant system is formed that can fine-tune steady-state levels of all-trans-retinaldehyde, and consequently RA, concentrations within the cell. Formation of ROC influences the catalytic properties of both RDH10 and DHRS3 subunits. DHRS3 is a critical regulator of RA synthesis. Catalytically active enzymes are not necessary for complex formation. As the rate-limiting step of RA synthesis, the conversion of all-trans-retinol to all-trans-retinaldehyde is a target of mechanisms that regulate RA synthesis. ROC, consisting of the retinol dehydrogenase RDH10 and the retinaldehyde reductase DHRS3, is a critical component of RA synthesis regulation
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
additional information
in RDH12, the cofactor binding site is located at positions 46-52 and the catalytic site at positions 200-204
additional information
-
in RDH12, the cofactor binding site is located at positions 46-52 and the catalytic site at positions 200-204
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). RDH13_HUMAN
331
0
35932
Swiss-Prot
Secretory Pathway (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A269Gfs*2
naturally occuring mutation, the mutant enzyme shows highly reduced activity
E260R
naturally occuring mutation, a single base pair deletion resulting in a frameshift and premature termination, mutants display a milder late onset (average age of diagnosis is 28.5 years) retinitis pigmentosa (RP) phenotype, with intraretinal bone spicule pigmentation and attenuation of retinal arterioles, phenotypes, overview
E260Rfs*18
naturally occuring mutation, autosomal dominant RDH12 variant, the heterozygous single base pair deletion c.776delG results in a frameshift and premature termination at codon 277, in 19 affected members of a large 6 generation family
F254Lfs*24
naturally occuring mutation c.759del, the mutation results in a frameshift and premature termination identified in two unrelated individuals with familial autosomal dominant retinitis pigmentosa (RP), phenotypes, overview
G43A/G47A/G49A
site-directed mutagenesis, the cofactor binding mutants, RDH10 G43A/G47A/G49A-HA and DHRS3 G49A/G51A-FLAG, retain the capacity to form complexes with wild-type protein partners
G49A/G51A
site-directed mutagenesis, the cofactor binding mutants, RDH10 G43A/G47A/G49A-HA and DHRS3 G49A/G51A-FLAG, retain the capacity to form complexes with wild-type protein partners
I51N
M144G
gain-of-function mutant, enables estrone to bind and be reduced as an additional substrate
Q189X
-
mutation found in an individual affected by autosomal recessive childhood-onset severe retinal dystrophy
R25G/K26I
-
The mutation allows the enzyme to flip its orientation in the membrane. The mutant is glycosylated in intact cells.
R62X
-
mutation found in an individual affected by autosomal recessive childhood-onset severe retinal dystrophy
S175P
-
site-directed mutagenesis, no catalytic activity. Protein is stable and abundantly expressed
T49M
Y226C
additional information
I51N
-
site-directed mutagenesis, significant activity in vitro. Dramatically reduced affinity for NADPH results in loss of function within cells
I51N
-
site-directed mutagenesis, the catalytically active I51N variant of RDH12 undergoes accelerated degradation through the ubiquitin-proteosome system, which results in reduced level of the protein in the cell. The RDH12 mutant has lost its retinaldehyde reductase activity. Inhibitors of proteosome activity, e.g. MG132, or dimethyl sulfoxide can partially restore the activity
I51N
naturally occuring mutation, when transiently transfected in HEK-293 cells, the mutant degrades at a faster rate than the wild-type protein with significantly lower half-lif, the mutant loses its ability to protect against 4-HNE induced apoptosis
T49M
-
mutation found in an individual affected by autosomal recessive childhood-onset severe retinal dystrophy
T49M
-
site-directed mutagenesis, significant activity in vitro. Dramatically reduced affinity for NADPH results in loss of function within cells
T49M
-
site-directed mutagenesis, the catalytically active T49M variant of RDH12 undergoes accelerated degradation through the ubiquitin-proteosome system, which results in reduced level of the protein in the cell.The RDH12 mutant has lost its retinaldehyde reductase activity. Inhibitors of proteosome activity, e.g. MG132, or dimethyl sulfoxide can partially restore the activity
T49M
naturally occuring mutation, the mutant enzyme shows highly reduced activity, when transiently transfected in HEK-293 cells, the mutant degrades at a faster rate than the wild-type protein with significantly lower half-life, the mutant loses its ability to protect against 4-HNE induced apoptosis
Y226C
-
mutation present in all individuals affected by autosomal recessive childhood-onset severe retinal dystrophy from three Austrian kindreds, enzyme expressed in COS-7 cells shows diminished activity
Y226C
naturally occuring mutation, autosomal recessive biallelic mutation causing severe retinal dystrophy
additional information
-
transfection with retinol dehydrogenase 12 protects cells against nonanal-induced toxicity but is ineffective against 4-hydroxynonenal
additional information
according to the human gene mutation database (HGMD, April 2019), 80 RDH12 mutations have been reported, 51 of which are missense and 12 are nonsense mutations, the mutations span the entire gene, including the conserved regions, with no specific hotspots. In COS-7 cells transiently transfected with various RDH12 missense mutants, 11 out of 14 variants show significantly reduced enzyme activity, 5-18% of wild-type levels. They also show decreased expression levels, most likely as a result of protein instability
additional information
-
according to the human gene mutation database (HGMD, April 2019), 80 RDH12 mutations have been reported, 51 of which are missense and 12 are nonsense mutations, the mutations span the entire gene, including the conserved regions, with no specific hotspots. In COS-7 cells transiently transfected with various RDH12 missense mutants, 11 out of 14 variants show significantly reduced enzyme activity, 5-18% of wild-type levels. They also show decreased expression levels, most likely as a result of protein instability
additional information
lentiviral-mediated shRNA efficiently inhibits RDH10 expression. RDH10 knockdown impairs glioma cell proliferation in vitro
additional information
-
lentiviral-mediated shRNA efficiently inhibits RDH10 expression. RDH10 knockdown impairs glioma cell proliferation in vitro
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-80°C, buffer containing 1 mM 1,2-diheptanoyl-sn-glycero-3-phosphocholine, stable for several months
-
8°C, in a refrigerator, the enzyme is nearly fully active for at least one month
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant enzyme complex ROC from Sopodoptera frugiperda Sf9 cells by anti-HA affinity chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in native, soluble form in Escherichia coli BL21-AI and as GFP-fusion protein in HeLa-cells
expression in HEK-293 cell
full-length short-chain dehydrogenase/reductase cDNA expressed in Escherichia coli, truncated cDNA expressed in SF9 insect cells, enzyme belongs to the short-chain dehydrogenase/reductase superfamily
gene Rdh10, recombinant enzyme expression in HEK-293T cells, coexpression with with bovine RGR
gene rdh11, co-expression of GFP-tagged or EYFP-tagged RDH11 with HA-tagged selenoprotein F in HEK-293T cells
gene RDH12, 7 coding exons, located on chromosome 14q24.1, stable recombinant expression in HEK-293 cells, transient recombinant expression in COS-7 cells
recombinant expression of the enzyme complex ROC formed by HA-tagged RDH10 and FLAT-tagged DHRS3, via a baculovirus expression system in Sopodoptera frugiperda Sf9 cells. Protein production method, overview
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
-
enzyme is associated with retinal dystrophy and encodes an enzyme with unique, nonredundant role in the photoreceptor cells
medicine
-
transfection with retinol dehydrogenase 12 protects cells against nonanal-induced toxicity but is ineffective against 4-hydroxynonenal. 4-Hydroxynonenal strongly inhibits the activities of lecithin:retinol acyl transferase and aldehyde dehydrogenase, resulting in decreased levels of retinyl esters and retinoic acid and accumulation of unesterified retinol
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Haeseleer, F.; Huang, J.; Lebiodas, L.; Saari, J.C.; Palczewski, K.
Molecular characterization of a novel short-chain dehydrogenase/reductase that reduces all-trans-retinal
J. Biol. Chem.
273
21790-21799
1998
Homo sapiens (O75911)
Belyaeva, O.V.; Stetsenko, A.V.; Nelson, P.; Kedishvili, N.Y.
Properties of short-chain dehydrogenase/reductase RalR1: characterization of purified enzyme, its orientation in the microsomal membrane, and distribution in human tissues and cell lines
Biochemistry
42
14838-14845
2003
Homo sapiens
Kedishvili, N.Y.; Chumakova, O.V.; Chetyrkin, S.V.; Belyaeva, O.V.; Lapshina, E.A.; Lin, D.W.; Matsumura, M.; Nelson, P.S.
Evidence that the human gene for prostate short-chain dehydrogenase/reductase (PSDR1) encodes a novel retinal reductase (RalR1)
J. Biol. Chem.
277
28909-28915
2002
Homo sapiens, Homo sapiens (Q8TC12)
Haeseleer, F.; Jang, G.F.; Imanishi, Y.; Driessen, C.A.; Matsumura, M.; Nelson, P.S.; Palczewski, K.
Dual-substrate specificity short chain retinol dehydrogenases from the vertebrate retina
J. Biol. Chem.
277
45537-45546
2002
Homo sapiens, Homo sapiens (Q96NR8), Homo sapiens (Q9HBH5)
Markova, N.G.; Pinkas-Sarafova, A.; Karaman-Jurukovska, N.; Jurukovski, V.; Simon, M.
Expression pattern and biochemical characteristics of a major epidermal retinol dehydrogenase
Mol. Genet. Metab.
78
119-135
2003
Homo sapiens
Janecke, A.R.; Thompson, D.A.; Utermann, G.; Becker, C.; Hubner, C.A.; Schmid, E.; McHenry, C.L.; Nair, A.R.; Ruschendorf, F.; Heckenlively, J.; Wissinger, B.; Nurnberg, P.; Gal, A.
Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset severe retinal dystrophy
Nat. Genet.
36
850-854
2004
Homo sapiens
Gallego, O.; Belyaeva, O.V.; Porte, S.; Ruiz, F.X.; Stetsenko, A.V.; Shabrova, E.V.; Kostereva, N.V.; Farres, J.; Pares, X.; Kedishvili, N.Y.
Comparative functional analysis of human medium-chain dehydrogenases, short-chain dehydrogenases/reductases and aldo-keto reductases with retinoids
Biochem. J.
399
101-109
2006
Homo sapiens (Q8TC12)
Belyaeva, O.V.; Korkina, O.V.; Stetsenko, A.V.; Kim, T.; Nelson, P.S.; Kedishvili, N.Y.
Biochemical properties of purified human retinol dehydrogenase 12 (RDH12): catalytic efficiency toward retinoids and C9 aldehydes and effects of cellular retinol-binding protein type I (CRBPI) and cellular retinaldehyde-binding protein (CRALBP) on the oxidation and reduction of retinoids
Biochemistry
44
7035-7047
2005
Homo sapiens, Homo sapiens (Q96NR8)
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
Lee, S.; Belyaeva, O.V.; Kedishvili, N.Y.
Effect of lipid peroxidation products on the activity of human retinol dehydrogenase 12 (RDH12) and retinoid metabolism
Biochim. Biophys. Acta
1782
421-425
2008
Homo sapiens
Belyaeva, O.V.; Korkina, O.V.; Stetsenko, A.V.; Kedishvili, N.Y.
Human retinol dehydrogenase 13 (RDH13) is a mitochondrial short-chain dehydrogenase/reductase with a retinaldehyde reductase activity
FEBS J.
275
138-147
2008
Homo sapiens (Q8NBN7), Homo sapiens
Song, X.H.; Liang, B.; Liu, G.F.; Li, R.; Xie, J.P.; Du, K.; Huang, D.Y.
Expression of a novel alternatively spliced variant of NADP(H)-dependent retinol dehydrogenase/reductase with deletion of exon 3 in cervical squamous carcinoma
Int. J. Cancer
120
1618-1626
2007
Homo sapiens (Q9BTZ2), Homo sapiens
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
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
Yao, Y.; Han, W.; Zhou, Y.; Luo, Q.; Li, Z.
Catalytic reaction mechanism of human photoreceptor retinol dehydrogenase: A theoretical study
J. Theor. Comput. Chem.
7
565-578
2008
Homo sapiens
-
Haller, F.; Moman, E.; Hartmann, R.W.; Adamski, J.; Mindnich, R.
Molecular framework of steroid/retinoid discrimination in 17beta-hydroxysteroid dehydrogenase type 1 and photoreceptor-associated retinol dehydrogenase
J. Mol. Biol.
399
255-267
2010
Danio rerio, Homo sapiens (Q9NYR8), Homo sapiens
Lee, S.A.; Belyaeva, O.V.; Kedishvili, N.Y.
Evidence that proteosome inhibitors and chemical chaperones can rescue the activity of retinol dehydrogenase 12 mutant T49M
Chem. Biol. Interact.
191
55-59
2011
Homo sapiens
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
Lhor, M.; Methot, M.; Horchani, H.; Salesse, C.
Structure of the N-terminal segment of human retinol dehydrogenase 11 and its preferential lipid binding using model membranes
Biochim. Biophys. Acta
1848
878-885
2015
Homo sapiens
Kummalue, T.; Inoue, T.; Miura, Y.; Narusawa, M.; Inoue, H.; Komatsu, N.; Wanachiwanawin, W.; Sugiyama, D.; Tani, K.
Ribosomal protein L11- and retinol dehydrogenase 11-induced erythroid proliferation without erythropoietin in UT-7/Epo erythroleukemic cells
Exp. Hematol.
43
414-423.e1
2015
Homo sapiens
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)
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
Sarkar, H.; Dubis, A.M.; Downes, S.; Moosajee, M.
Novel heterozygous deletion in retinol dehydrogenase 12 (RDH12) causes familial autosomal dominant retinitis pigmentosa
Front. Genet.
11
335
2020
Homo sapiens (Q96NR8)
Adams, M.K.; Belyaeva, O.V.; Kedishvili, N.Y.
Generation and isolation of recombinant retinoid oxidoreductase complex
Methods Enzymol.
637
77-93
2020
Homo sapiens (O75911), Homo sapiens (Q8IZV5)
Tian, J.; Liu, J.; Li, J.; Zheng, J.; Chen, L.; Wang, Y.; Liu, Q.; Ni, J.
The interaction of selenoprotein F (SELENOF) with retinol dehydrogenase 11 (RDH11) implied a role of SELENOF in vitamin A metabolism
Nutr. Metab.
15
7
2018
Homo sapiens (Q8TC12), Homo sapiens
Guan, F.; Wang, L.; Hao, S.; Wu, Z.; Bai, J.; Kang, Z.; Zhou, Q.; Chang, H.; Yin, H.; Li, D.; Tian, K.; Ma, J.; Zhang, G.; Zhang, J.
Retinol dehydrogenase-10 promotes development and progression of human glioma via the TWEAK-NF-kappaB axis
Oncotarget
8
105262-105275
2017
Homo sapiens (Q8IZV5), Homo sapiens
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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