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Information on EC 1.3.99.23 - all-trans-retinol 13,14-reductase and Organism(s) Mus musculus and UniProt Accession Q64FW2
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1.3.99.23 all-trans-retinol 13,14-reductaseIUBMB Comments
The reaction is only known to occur in the opposite direction to that given above, with the enzyme being specific for all-trans-retinol as substrate. Neither all-trans-retinoic acid nor 9-cis, 11-cis or 13-cis-retinol isomers are substrates. May play a role in the metabolism of vitamin A.
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The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Bacteria, Archaea, Eukaryota
The expected taxonomic range for this enzyme is: Bacteria, Archaea, Eukaryota
Reaction Schemes
Synonyms
retsat, retinol saturase, retsat a, 13,14-dihydroretinol saturase, all-trans-13,14-dihydroretinol saturase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
retinol saturase
retinol saturase
regulates retinoid metabolism and sensitivity to oxidative stress
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PATHWAY SOURCE
PATHWAYS
KEGG
SYSTEMATIC NAME
IUBMB Comments
all-trans-13,14-dihydroretinol:acceptor 13,14-oxidoreductase
The reaction is only known to occur in the opposite direction to that given above, with the enzyme being specific for all-trans-retinol as substrate. Neither all-trans-retinoic acid nor 9-cis, 11-cis or 13-cis-retinol isomers are substrates. May play a role in the metabolism of vitamin A.
CAS REGISTRY NUMBER
COMMENTARY
149147-14-8
-
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
all-trans-13,14-dihydroretinol + FAD
all-trans-retinol + FADH2
-
-
-
?
all-trans-13,14-dihydroretinol + NAD+
all-trans-retinol + NADH + H+
-
-
-
?
all-trans-13,14-dihydroretinol + NADP+
all-trans-retinol + NADPH + H+
-
-
-
?
all-trans-retinol + reduced acceptor
all-trans-13,14-dihydroretinol + acceptor
-
-
-
?
(R)-all-trans-13,14-dihydroretinol + acceptor
all-trans-retinol + reduced acceptor
-
retinol saturase catalyzes the saturation of all-trans-retinol to produce (R)-all-trans-13,14-dihydroretinol
-
-
r
all-trans-13,14-didehydroretinol + reduced acceptor
all-trans-13,14-dihydro-3,4-didehydroretinol + acceptor
-
-
-
-
?
all-trans-13,14-dihydroretinol + acceptor
all-trans-retinol + reduced acceptor
-
-
-
-
?
all-trans-retinol + reduced acceptor
all-trans-13,14-dihydroretinol + acceptor
-
-
-
-
?
additional information
?
-
the recombinant enzyme expressed in HEK-293 cells is inactive on lycopene, and instead catalyzed saturation of all trans-retinol at the 13-14 double bond to generate all-trans-13,14-dihydroretinol. Saturation introduces a chiral C13 atom, RetSat selectively produces (R)-all-trans-13,14-dihydroretinol. The enzyme is inactive on lycopene
-
-
-
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-13,14-dihydroretinol + FAD
all-trans-retinol + FADH2
-
-
-
?
all-trans-13,14-dihydroretinol + NAD+
all-trans-retinol + NADH + H+
-
-
-
?
all-trans-13,14-dihydroretinol + NADP+
all-trans-retinol + NADPH + H+
-
-
-
?
all-trans-retinol + reduced acceptor
all-trans-13,14-dihydroretinol + acceptor
-
-
-
?
(R)-all-trans-13,14-dihydroretinol + acceptor
all-trans-retinol + reduced acceptor
-
retinol saturase catalyzes the saturation of all-trans-retinol to produce (R)-all-trans-13,14-dihydroretinol
-
-
r
all-trans-13,14-dihydroretinol + acceptor
all-trans-retinol + reduced acceptor
-
-
-
-
?
all-trans-retinol + reduced acceptor
all-trans-13,14-dihydroretinol + acceptor
-
-
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
retinol saturase (RetSat) is an NADH/NADPH- or FADH-dependent oxidoreductase
-
additional information
the N-terminal signal peptide (aa 1-18) serves as a docking site for either FAD or NAD+/NADP+ cofactors
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
a short hairpin RNA targeting retinol saturase strongly protects cells from tert-butylhydroperoxide and H2O2 by specifically reducing the expression of retinol saturase
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
pluripotent embryonal carcinoma cells with high enzyme mRNA level, quantitative real-time PCR expression analysis
additional information
Retsat expression is well detectable in undifferentiated precursor cells
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
the enzyme has an N-terminal signal peptide (aa 1-18), that targets the nascent protein to the membrane of the endoplasmic reticulum, and a dinucleotide-binding domain (aa 73-118). There are several hydrophobic stretches, such as aa 567-587, that may be transmembrane domains. RetSat is predominantly in the endoplasmic reticulum (ER) where it colocalizes with the ER marker protein disulfide isomerase
additional information
perinuclear staining in cells overexpressing RetSat and nuclear staining of endogenous RetSat in primary mouse hepatocytes are observed
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
metabolism
-
retinol signaling plays an important role in the establishment and maintenance of cellular phenotype in embryonic and adult vertebrate tissues. all-trans-Retinoic acid functions as the activating ligand for a family of ligand-activated transcription factors, the retinoic acid receptors, which form heterodimers with the retinoid X receptors to regulate gene transcription. Through its activation of the receptors, all-trans-retinoic acid regulates the expression of over 500 protein-coding genes
physiological function
-
RetSat is required for adipocyte differentiation in the 3T3-L1 cell culture model, analysis of the mechanism involved in this putative proadipogenic effect of RetSat, overview. RetSat-null mice have normal levels of retinol and retinyl palmitate in liver, serum, and adipose tissue, but, in contrast to wild-type mice, are deficient in the production of all-trans-13,14-dihydroretinol from dietary vitamin A. Despite accumulating more fat, RetSat-null mice maintained on either low-fat or high-fat diets gain weight and have similar rates of food intake as age- and gender-matched wild-type control littermates, ablation of RetSat does not result in alterations in total body weight gain but could still affect the relative composition and size of adipose stores, phenotype, overview
additional information
malfunction
deletion of the N-terminal signal peptide prevents endoplasmic reticulum localization and lowers protein stability. When depleting RetSat in 3T3-L1 preadipocytes (a widely used cell model for adipogenesis), adipocyte differentiation is impaired. Surprisingly, supplementing these cells with all-trans-13,14-dihydroretinol failed to rescue differentiation. Differentiation of RetSat-depleted cells is rescued by adding a synthetic PPARgamma agonist, and RetSat overexpression induced PPARgamma activity during differentiation. Retsat deletion causes impaired long-term phagocytosis of apoptotic cells by peritoneal and bone marrow-derived macrophages. This effect can be rescued by providing the recombinant bridging molecule milk fat globule EGF-factor 8, whose expression is lower in RetSat-deficient macrophages. Female Retsat knockout mice are prone to develop mild systemic lupus erythematosus-like autoimmunity upon aging, and display increased spleen weights, delayed clearance of apoptotic cells, and deposition of immune complexes in organs such as the kidney. RetSat depletion in NIH3T3 cells strongly increased cell viability upon exposure to tertbutyl hydroperoxide (BHP) or H2O2. Fibroblasts depleted of RetSat are not protected from UV light or paraquat-induced stress, suggesting that loss of RetSat increases resistance selectively to damage elicited by peroxides
malfunction
liver-specific depletion of RetSat in dietary obese mice lowers hepatic and circulating TGs and normalizes hyperglycemia. Mechanistically, RetSat depletion reduces the activity of carbohydrate response element binding protein (ChREBP), a cellular hexose-phosphate sensor and inducer of lipogenesis. RetSat depletion impairs the nuclear accumulation of ChREBP. Defects upon RetSat depletion are rescued by ectopic expression of ChREBP but not by its putative enzymatic product 13,14-dihydroretinol, suggesting that RetSat affects hepatic glucose sensing independent of retinol conversion. RetSat depletion in adipocyte precursor cells impaires their adipogenic conversion in vitro, and the enzyme expression in adipose tissue is downregulated in obesity. Several glycolytic genes, including aldolase (Aldoa), phosphofructokinase, liver (Pfkl) and pyruvate kinase, liver (Pklr) are downregulated upon RetSat depletion, enzyme expression analysis
physiological function
cellular RetSat protein localizes primarily to the endoplasmic reticulum and catalyzes the conversion of retinol to 13,14-dihydroretinol (13,14-dhretinol), a retinoid metabolite that can act as precursor for the generation of 13,14-dihydroretinoic acid. Retinol saturase coordinates liver metabolism by regulating ChREBP activity. The oxidoreductase retinol saturase (RetSat) is involved in the development of fatty liver. Hepatic RetSat expression correlates with steatosis and serum triglycerides (TGs) in humans. RetSat is elevated in obese mouse liver and controls lipid metabolism
physiological function
retinol saturase (RetSat) is an oxidoreductase that is expressed in metabolically active tissues and is highly regulated in conditions related to insulin resistance and type 2 diabetes. RetSat has been implicated in adipocyte differentiation, hepatic glucose and lipid metabolism, macrophage function, vision, and the generation of reactive oxygen species (ROS). Function of RetSat and dihydroretinol in retinoid homeostasis, overview. RetSat enhances adipocyte differentiation independently of dihydroretinol formation. RetSat may drive differentiation by activating PPARgamma. RetSat is required for glucose-induced ChREBP activity and its nuclear accumulation in primary mouse hepatocytes, thus identifying RetSat as novel upstream regulator of this glucose-sensing transcription factor. RetSat regulation of carbohydrate response element-binding protein (ChREBP) is independent of dihydroretinol formation. In NIH3T3 cells RetSat is a major mediator of oxidative stress sensitivity
additional information
-
RetSat deficiency leads to up-regulation of PPARgamma and PPARgamma target expression
additional information
-
the mouse pluripotent P-19 cell metabolizes retinol to all-trans-retinoic acid, analysis of expression of enzymes in the cell involved in the pathway, 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). RETST_MOUSE
609
1
67334
Swiss-Prot
Secretory Pathway (Reliability: 1)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
E34A
-
mutant, mutation within the highly conserved region of the dinucleotide-binding motif
E96A
-
mutant, mutation within the highly conserved region of the dinucleotide-binding motif
additional information
additional information
mice with germline deletion of Retsat show no differences in hepatic triglycerides, cholesterol, phospholipids, or non-esterified fatty acids (NEFAs) when analyzed on a mixed 129Sv/C57BL/6 background. When backcrossed to C57BL/6N, hepatic triglycerides are increased, irrespective of feeding normal chow or HFD, whereas the abundance of many polar unsaturated lipid species is decreased. Although showing increased body weight, the whole-body and liver-specific insulin sensitivity of RetSat-deficient mice is not impaired. In contrast to these results are findings from adult C57BL/6J mice with acute liver-specific RetSat depletion. When fed normal chow, liver-specific RetSat knockdown does not induce major abnormalities. But when fed on a HFD, these mice accumulate fewer triglycerides in liver and show lower levels of triglycerides and NEFAs in the circulation. Moreover, blood glucose and insulin levels are reduced, in conjunction with increased glucose tolerance but comparable insulin sensitivity. Mechanistically, this is associated with decreased mRNA, protein, and target gene expression of carbohydrate response element-binding protein (ChREBP)
additional information
mouse hepatocytes and 3T3-L1 adipocytes are depleted of RetSat by siRNA for 48 h, phenotype, detailed overview
additional information
-
generation of RetSat-/- mice, phenotype in comparison to wild-type mice, overview
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
the cDNA for the mouse enzyme is cloned from reverse transcribed RNA of retina and retinal pigment endothelium and used to establish human embryonic kidney (HEK-293) cells with or without ectopic protein expression
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
forkhead box O1 (FOXO1), a transcription factor under the control of insulin that regulates gluconeogenesis, shows binding near to the Retsat gene in mouse liver and transactivates its expression in primary hepatocytes. Retsat is also expressed in stem cells and is regulated by zinc-finger protein X-linked (Zfx). Zfx deletion in embryonic and hematopoietic stem cells of mice reduced Retsat mRNA expression. RetSat mRNA and protein expression is robustly upregulated during the differentiation of white pre-adipocytes of murine origin
major transcriptional regulators of RetSat are the nuclear peroxisome proliferator-activated receptor alpha (PPARalpha) in organs such as liver and PPARgamma in adipose tissue through a PPAR-response element (PPRE) in intron 1 of the murine genes
incubation of mature adipocytes with pioglitazone or the non-thiazolidinedione ligand GW7845 increases RetSat mRNA expression, peroxisome proliferator activated receptor gamma, PPARgamma, is required for RetSat expression in mature adipocytes
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
analysis
-
the mouse pluripotent P-19 cell metabolizes retinol to atRA and thus can be used in a cell-based screen for disruptors of the pathway. The disruption of the pathway is easily detected and quantitated, the P-19 cell provides an in vitro model system for identifying and exploring the mechanism of action of chemicals that interfere with the critical cellular pathway
medicine
-
RetSat plays an important role in the biology of adipocytes, where it favors normal differentiation, yet is reduced in the obese state, RetSat is thus a novel target for therapeutic intervention in metabolic disease
additional information
-
conserved function but altered specificity of RetSat in vertebrates
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Moise, A.R.; Kuksa, V.; Imanishi, Y.; Palczewski, K.
Identification of all-trans-retinol:all-trans-13,14-dihydroretinol saturase
J. Biol. Chem.
279
50230-50242
2004
Mus musculus (Q64FW2), Mus musculus
Moise, A.R.; Kuksa, V.; Blaner, W.S.; Baehr, W.; Palczewski, K.
Metabolism and transactivation activity of 13,14-dihydroretinoic acid
J. Biol. Chem.
280
27815-27825
2005
Mus musculus
Moise, A.R.; Isken, A.; Dominguez, M.; Lera, A.R.; Lintig, J.; Palczewski, K.
Specificity of zebrafish retinol saturase: formation of all-trans-13,14-dihydroretinol and all-trans-7,8-dihydroretinol
Biochemistry
46
1811-1820
2007
Danio rerio, Danio rerio (Q5BLE8), Mus musculus
Nagaoka-Yasuda, R.; Matsuo, N.; Perkins, B.; Limbaeck-Stokin, K.; Mayford, M.
An RNAi-based genetic screen for oxidative stress resistance reveals retinol saturase as a mediator of stress resistance
Free Radic. Biol. Med.
43
781-788
2007
Mus musculus (Q64FW2)
Schupp, M.; Lefterova, M.I.; Janke, J.; Leitner, K.; Cristancho, A.G.; Mullican, S.E.; Qatanani, M.; Szwergold, N.; Steger, D.J.; Curtin, J.C.; Kim, R.J.; Suh, M.J.; Suh, M.; Albert, M.R.; Engeli, S.; Gudas, L.J.; Lazar, M.A.
Retinol saturase promotes adipogenesis and is downregulated in obesity
Proc. Natl. Acad. Sci. USA
106
1105-1110
2009
Homo sapiens, Mus musculus
Moise, A.R.; Lobo, G.P.; Erokwu, B.; Wilson, D.L.; Peck, D.; Alvarez, S.; Dominguez, M.; Alvarez, R.; Flask, C.A.; de Lera, A.R.; von Lintig, J.; Palczewski, K.
Increased adiposity in the retinol saturase-knockout mouse
FASEB J.
24
1261-1270
2010
Mus musculus
Chen, Y.; Reese, D.H.
The retinol signaling pathway in mouse pluripotent P19 cells
J. Cell. Biochem.
112
2865-2872
2011
Mus musculus
Heidenreich, S.; Witte, N.; Weber, P.; Goehring, I.; Tolkachov, A.; von Loeffelholz, C.; Doecke, S.; Bauer, M.; Stockmann, M.; Pfeiffer, A.F.H.; Birkenfeld, A.L.; Pietzke, M.; Kempa, S.; Muenzner, M.; Schupp, M.
Retinol saturase coordinates liver metabolism by regulating ChREBP activity
Nat. Commun.
8
384
2017
Homo sapiens (Q6NUM9), Homo sapiens, Mus musculus (Q64FW2), Mus musculus C57BL/6J (Q64FW2)
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