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Literature summary for 1.1.1.300 extracted from
- Retinol dehydrogenase 12 (RDH12) Role in vision, retinal disease and future perspectives (2019), Exp. Eye Res., 188, 107793 .
Cloned(Commentary)
| Cloned (Comment) | Organism |
|---|---|
| gene RDH12, 7 coding exons, located on chromosome 14q24.1, stable recombinant expression in HEK-293 cells, transient recombinant expression in COS-7 cells | Homo sapiens |
Protein Variants
| Protein Variants | Comment | Organism |
|---|---|---|
| A269Gfs*2 | naturally occuring mutation, the mutant enzyme shows highly reduced activity | Homo sapiens |
| C201R | naturally occuring mutation in the active site, inactive mutant | Homo sapiens |
| 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 | Homo sapiens |
| 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 | Homo sapiens |
| 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 | Homo sapiens |
| additional information | 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 | Mus musculus |
| 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 | Homo sapiens |
| Y226C | naturally occuring mutation, autosomal recessive biallelic mutation causing severe retinal dystrophy | Homo sapiens |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| all-trans-retinal + NADPH + H+ | Mus musculus | - |
all-trans-retinol + NADP+ | - |
? |  |
| all-trans-retinal + NADPH + H+ | Homo sapiens | - |
all-trans-retinol + NADP+ | - |
? | |
| additional information | Homo sapiens | 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 | ? | - |
- |
|
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | Q96NR8 | - |
- |
| Mus musculus | - |
- |
- |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| eye | inner segments of the photoreceptors | Homo sapiens | - |
| kidney | - |
Homo sapiens | - |
| liver | - |
Homo sapiens | - |
| photoreceptor cell | inner segments | Homo sapiens | - |
| skin | - |
Homo sapiens | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| 11-cis-retinal + NADPH + H+ | - |
Mus musculus | 11-cis-retinol + NADP+ | - |
? | |
| 11-cis-retinal + NADPH + H+ | - |
Homo sapiens | 11-cis-retinol + NADP+ | - |
? | |
| all-trans-retinal + NADPH + H+ | - |
Mus musculus | all-trans-retinol + NADP+ | - |
? | |
| all-trans-retinal + NADPH + H+ | - |
Homo sapiens | all-trans-retinol + NADP+ | - |
? | |
| 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 | Homo sapiens | ? | - |
- |
|
| 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 | Homo sapiens | ? | - |
- |
|
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| ? | x * 35000, about, sequence calculation | Homo sapiens |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| RDH12 | - |
Mus musculus |
| RDH12 | - |
Homo sapiens |
| retinol dehydrogenase 12 | - |
Mus musculus |
| retinol dehydrogenase 12 | - |
Homo sapiens |
Cofactor
| Cofactor | Comment | Organism | Structure |
|---|---|---|---|
| additional information | purified RDH12 displays a about 2000fold higher affinity for NADP+ and NADPH than for NAD+ and NADH | Homo sapiens | |
| NADP+ | - |
Homo sapiens | |
| NADPH | - |
Homo sapiens | |
General Information
| General Information | Comment | Organism |
|---|---|---|
| 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) | Homo sapiens |
| 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) | Homo sapiens |
| 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 | Mus musculus |
| additional information | in RDH12, the cofactor binding site is located at positions 46-52 and the catalytic site at positions 200-204 | Homo sapiens |
| 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 | Mus musculus |
| 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 | Homo sapiens |
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