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Literature summary for 1.3.99.23 extracted from
- Retinol saturase more than the name suggests (2020), Trends Pharmacol. Sci., 41, 418-427 .
Cloned(Commentary)
| Cloned (Comment) | Organism |
|---|---|
| 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 | Mus musculus |
Protein Variants
| Protein Variants | Comment | Organism |
|---|---|---|
| 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) | Mus musculus |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| endoplasmic reticulum membrane | RetSat is predominantly in the endoplasmic reticulum (ER) where it colocalizes with the ER marker protein disulfide isomerase | Homo sapiens | 5789 | - |
| endoplasmic reticulum membrane | 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 | Mus musculus | 5789 | - |
| additional information | perinuclear staining in cells overexpressing RetSat and nuclear staining of endogenous RetSat in primary mouse hepatocytes are observed | Mus musculus | - |
- |
Molecular Weight [Da]
| Molecular Weight [Da] | Molecular Weight Maximum [Da] | Comment | Organism |
|---|---|---|---|
| 67000 | - |
about | Mus musculus |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| 10'-apo-beta-carotene-3,10'-diol + acceptor | Danio rerio | i.e. galloxanthin | 11',12'-dihydro-10'-apo-beta-carotene-3,10'-diol + reduced acceptor | - |
? |  |
| all-trans-13,14-dihydroretinol + FAD | Mus musculus | - |
all-trans-retinol + FADH2 | - |
? | |
| all-trans-13,14-dihydroretinol + FAD | Danio rerio | - |
all-trans-retinol + FADH2 | - |
? | |
| all-trans-13,14-dihydroretinol + FAD | Homo sapiens | - |
all-trans-retinol + FADH2 | - |
? | |
| all-trans-13,14-dihydroretinol + FAD | Rattus norvegicus | - |
all-trans-retinol + FADH2 | - |
? | |
| all-trans-13,14-dihydroretinol + NAD+ | Mus musculus | - |
all-trans-retinol + NADH + H+ | - |
? | |
| all-trans-13,14-dihydroretinol + NAD+ | Danio rerio | - |
all-trans-retinol + NADH + H+ | - |
? | |
| all-trans-13,14-dihydroretinol + NAD+ | Homo sapiens | - |
all-trans-retinol + NADH + H+ | - |
? | |
| all-trans-13,14-dihydroretinol + NAD+ | Rattus norvegicus | - |
all-trans-retinol + NADH + H+ | - |
? | |
| all-trans-13,14-dihydroretinol + NADP+ | Mus musculus | - |
all-trans-retinol + NADPH + H+ | - |
? | |
| all-trans-13,14-dihydroretinol + NADP+ | Danio rerio | - |
all-trans-retinol + NADPH + H+ | - |
? | |
| all-trans-13,14-dihydroretinol + NADP+ | Homo sapiens | - |
all-trans-retinol + NADPH + H+ | - |
? | |
| all-trans-13,14-dihydroretinol + NADP+ | Rattus norvegicus | - |
all-trans-retinol + NADPH + H+ | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Danio rerio | Q5BLE8 | - |
- |
| Homo sapiens | Q6NUM9 | - |
- |
| Mus musculus | Q64FW2 | - |
- |
| Rattus norvegicus | Q8VHE9 | - |
- |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| adipose tissue | - |
Homo sapiens | - |
| brown adipose tissue | - |
Mus musculus | - |
| embryonic stem cell | - |
Mus musculus | - |
| fibroblast | - |
Mus musculus | - |
| heart | low enzyme content | Mus musculus | - |
| intestine | - |
Mus musculus | - |
| kidney | - |
Homo sapiens | - |
| kidney | high enzyme content | Mus musculus | - |
| liver | - |
Homo sapiens | - |
| liver | high enzyme content | Mus musculus | - |
| additional information | Retsat expression is well detectable in undifferentiated precursor cells | Mus musculus | - |
| NIH-3T3 cell | - |
Mus musculus | - |
| skeletal muscle | low enzyme content | Mus musculus | - |
| white adipose tissue | - |
Mus musculus | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| 10'-apo-beta-carotene-3,10'-diol + acceptor | i.e. galloxanthin | Danio rerio | 11',12'-dihydro-10'-apo-beta-carotene-3,10'-diol + reduced acceptor | - |
? | |
| all-trans-13,14-dihydroretinol + FAD | - |
Mus musculus | all-trans-retinol + FADH2 | - |
? | |
| all-trans-13,14-dihydroretinol + FAD | - |
Danio rerio | all-trans-retinol + FADH2 | - |
? | |
| all-trans-13,14-dihydroretinol + FAD | - |
Homo sapiens | all-trans-retinol + FADH2 | - |
? | |
| all-trans-13,14-dihydroretinol + FAD | - |
Rattus norvegicus | all-trans-retinol + FADH2 | - |
? | |
| all-trans-13,14-dihydroretinol + NAD+ | - |
Mus musculus | all-trans-retinol + NADH + H+ | - |
? | |
| all-trans-13,14-dihydroretinol + NAD+ | - |
Danio rerio | all-trans-retinol + NADH + H+ | - |
? | |
| all-trans-13,14-dihydroretinol + NAD+ | - |
Homo sapiens | all-trans-retinol + NADH + H+ | - |
? | |
| all-trans-13,14-dihydroretinol + NAD+ | - |
Rattus norvegicus | all-trans-retinol + NADH + H+ | - |
? | |
| all-trans-13,14-dihydroretinol + NADP+ | - |
Mus musculus | all-trans-retinol + NADPH + H+ | - |
? | |
| all-trans-13,14-dihydroretinol + NADP+ | - |
Danio rerio | all-trans-retinol + NADPH + H+ | - |
? | |
| all-trans-13,14-dihydroretinol + NADP+ | - |
Homo sapiens | all-trans-retinol + NADPH + H+ | - |
? | |
| all-trans-13,14-dihydroretinol + NADP+ | - |
Rattus norvegicus | all-trans-retinol + NADPH + H+ | - |
? | |
| all-trans-7,8-dihydroretinol + acceptor | - |
Danio rerio | all-trans-retinol + reduced 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. In contrast to the murine protein, zebrafish RetSat saturates either the 7-8 or the 13-14 double bonds of the retinol side chain. Zebra fish RetSat expressed in HEK-293 cells catalyzes the formation of 11',12'-dihydro-10'-apo-beta-carotene-3,10'-diol (dihydrogalloxanthin) from 10'-apo-beta-carotene-3,10'-diol (galloxanthin) | Danio rerio | ? | - |
- |
|
| 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 | Mus musculus | ? | - |
- |
|
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| rat mammary tumor 7 | - |
Rattus norvegicus |
| retinol saturase | - |
Mus musculus |
| retinol saturase | - |
Danio rerio |
| retinol saturase | - |
Homo sapiens |
| retinol saturase | - |
Rattus norvegicus |
| RetSat | - |
Mus musculus |
| RetSat | - |
Danio rerio |
| RetSat | - |
Homo sapiens |
| RetSat | - |
Rattus norvegicus |
| Rmt7 | - |
Rattus norvegicus |
Cofactor
| Cofactor | Comment | Organism | Structure |
|---|---|---|---|
| FAD | - |
Mus musculus | |
| FAD | - |
Danio rerio | |
| FAD | - |
Homo sapiens | |
| FAD | - |
Rattus norvegicus | |
| additional information | the N-terminal signal peptide (aa 1-18) serves as a docking site for either FAD or NAD+/NADP+ cofactors | Mus musculus | |
| NAD+ | - |
Mus musculus | |
| NAD+ | - |
Danio rerio | |
| NAD+ | - |
Homo sapiens | |
| NAD+ | - |
Rattus norvegicus | |
| NADP+ | - |
Mus musculus | |
| NADP+ | - |
Danio rerio | |
| NADP+ | - |
Homo sapiens | |
| NADP+ | - |
Rattus norvegicus | |
Expression
| Organism | Comment | Expression |
|---|---|---|
| Homo sapiens | 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 human genes | additional information |
| Mus musculus | 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 | additional information |
| Mus musculus | 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 | up |
| Homo sapiens | RetSat mRNA and protein expression is robustly upregulated during the differentiation of white pre-adipocytes of human origin | up |
General Information
| General Information | Comment | Organism |
|---|---|---|
| evolution | The zebrafish RetSat enzyme exists in two isozymes, a and b, where a ist the active form and b (UniProt ID B0S6C5) is inactive | Danio rerio |
| 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 | Mus musculus |
| malfunction | Retsat shows reduced transcript levels in mammary adenocarcinomas and hyperplastic bladder tissue compared with normal control tissues in rats. RETSAT mutations have been identified in rare undifferentiated tongue sarcoma and malignant melanoma. These findings link low expression or mutation of RetSat to tumor development | Rattus norvegicus |
| metabolism | RetSat is involved in hepatic glucose and lipid metabolism | Mus musculus |
| metabolism | RetSat is involved in hepatic glucose and lipid metabolism | Danio rerio |
| metabolism | RetSat is involved in hepatic glucose and lipid metabolism | Homo sapiens |
| 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) | Danio rerio |
| 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 | Mus musculus |
| 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 expression in liver correlates with obesity, hepatic steatosis, and the expression of carbohydrate response element-binding protein (ChREBP) target genes | Homo sapiens |
| 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). The regulation of RetSat by Zfx in stem cells and its role in retinoid homeostasis may imply relevance for cell proliferation and tumorigenesis | Rattus norvegicus |
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