Biology:Retinol dehydrogenase

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Retinol dehydrogenase
Identifiers
EC number1.1.1.105
CAS number9033-53-8
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

In enzymology, a retinol dehydrogenase (RDH) (EC 1.1.1.105) is an enzyme that catalyzes the chemical reaction

retinol + NAD+ [math]\displaystyle{ \rightleftharpoons }[/math] retinal + NADH + H+

Sometimes, in addition to or along with NAD+, NADP+ can act as a preferred cofactor in the reaction as well. The substrate of the enzyme can be all-trans- or -cis- retinol. There are at least over 20 different isolated enzymes with RDH activity to date.[1] Thus, the two substrates of this enzyme are retinol and NAD+, whereas its 3 products are retinal, NADH (or NADPH in the case where NADP+ is a cofactor), and H+.[1]

This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-OH group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is retinol:NAD+ oxidoreductase. Other names in common use include retinol (vitamin A1) dehydrogenase, MDR, microsomal retinol dehydrogenase, all-trans retinol dehydrogenase, retinal reductase, and retinene reductase. This enzyme participates in retinol metabolism.[2] Occasionally, the literature refers to retinol dehydrogenase as an enzyme that oxidizes retinol in general, such as class IV alcohol dehydrogenase (ADH4), which reportedly is the most efficient retinol oxidation in the human alcohol dehydrogenase (ADH) family.[3][4]

Structure

Image 1: Wild-type human sigma (class IV) alcohol dehydrogenase (1D1S) has retinol dehydrogenase activity. Zinc molecules are depicted as red balls, while NAD molecules are purple. Note that the enzyme exists as two protein units in this figure. (PDB file from RCSB)[5]
Image 2: Wild-type human sigma (class IV) alcohol dehydrogenase (1D1S). Retinols will bind between the catalytic zinc molecules (red balls) and the NAD molecule (purple).[6] (PDB file from RCSB)[5]

As one of the most important RDH, 11-cis-retinol dehydrogenase catalyzes the 11-cis retinaldehyde (the most common visual pigments in higher animals) formation. The enzyme is mainly expressed in the retinal pigment epithelium (RPE) and is part of short-chain dehydrogenase (SDR) / reductase superfamily. The integral membrane enzyme is anchored to the membranes by its two hydrophobic chains. The catalytic domain of 11-cis-retinol dehydrogenase is restricted to the lumenal compartment, suggesting its origin from compartmentalized process. 11-cis-retinol dehydrogenase is also mainly associated to the smooth endoplasmic reticulum of RPE cells.[7] The 32-kDa integral membrane protein protein (p32) was found to act as the stereospecific 11-cis-retinol dehydrogenase in the presence of NAD+ cofactor, and p32 catalyzes the biosynthesis of 11-cis retinal commonly found visual chromophore.[8]

One of the widely studied genes of retinol dehydrogenase RDH12, which encodes retinol dehydrogenase is part of the superfamily of short-chained alcohol dehydrogenases and reductases. RDH12 is mainly expressed in neuroretina and is composed of 7 exons encoding a 360-amino acid peptide.[9]

Zinc molecules serve as the ligand cofactor with the cofactor NAD. The retinol will interact with the enzyme at the area between those two cofactors.[6]

However, not all retinol dehydrogenases in visual cycle are identified, and this remains challenging to scientists due to the overlapping expressions and activity redundancy among two large RDH and RDH-like producing classes: microsomal short-chain dehydrogenase/reductase and cytosolic medium-chain alcohol dehydrogenases.[10]

In Bovine, retinol dehydrogenase is found as a part of retinal rod outer segments and shows difficulty when separating from membrane. Its Stokes radius is 8.5 nm in Lubrol 12A9 mixed micelle.[11]

Function

Retinoid dehydrogenases/reductases (oxidoreductases), including retinol dehydrogenase, catalyze the key oxidation-reduction reactions in the visual cycle, converting vitamin A to 11-cis retinal, which is the chromophore of the rod and cone photoreceptors. It is believed that RDHs at rod and cone are different, but related and can catalyze the same reaction. RDH12 is the primary enzyme that reduces all-trans retinal released from bleached photopigments during recovery phase in the visual cycle. The RDH12 enzyme can use either cis or trans retinoid isomers as substrates and can also function as both dehydrogenase (i.e. retinol to retinal) and reductase (i.e. retinal to retinol).[12][13]

The conversion of retinol to retinal is the rate-limiting step in the retinoic acid biosynthesis. In vertebrates, the retinoic acid is the ligand that controls nuclear receptor signaling pathway, which is responsible for growth and development as well as epithelial maintenance, therefore can be used for cancer and acne treatment. In human, ADH4 can exhibit at least 10 folds higher Vmax/Km than other ADH.[4]

Image 3: The visual phototransduction cycle yields 11-cis-retinal from 11-cis-retinol using 11-cis-retinol dehydrogenase.[10][12][14]

Some retinol dehydrogenases are in extra-ocular tissues, such as human retinol dehydrogenase-4 (RoDH-4), which converts retinol and 1-cis-retinol to different aldehydes in liver and skin. It was also found that 13-cis-retinoic acid (isotretinoin), 3,4-didehydroretinoic acid, and 3,4-didehydroretinol can act as competitive inhibitor of the 3α-hydroxysteroid dehydrogenase oxidative activity of the enzyme. This can potentially explain how isotretinoin, the active ingredient is Roaccutane (Accutane), can suppress sebaceous glands and be used for severe acne treatment.[15]

Disease relevance

The missense mutation in gene rdh5, which codes for microsomal 11-cis-retinol dehydrogenase (RDH5), causes fundus albipunctatus, whose symptoms include retinal white-spot accumulation, stationary night blindness caused by delay in cone and rod photopigment regeneration, and elderly cone dystrophy.[1][16]

At least 20 mutations in rdh12 gene, which encodes retinol dehydrogenase, can be associated to diseases, including severe and early-onset autosomal recessive retinal dystrophy (arRD), or Leber congenital amaurosis. Patients suffer from cone and rod malfunction since childhood and develop legal blindness when reaching adulthood. This suggests that RDH12 might play a central role in the visual cycle and can be a promising therapeutic target.[9][12] A possible mechanism of the accelerated degradation among RDH12 mutants is the polyubiquitination by cytosolic ubiquitin ligases and subsequent degradation by proteosome. Its conformation aberration provokes the aforementioned accelerated degradation.[17]

References

  1. ↑ 1.0 1.1 1.2 "Understanding retinol metabolism: structure and function of retinol dehydrogenases". J. Biol. Chem. 281 (19): 13001–4. May 2006. doi:10.1074/jbc.R500027200. PMID 16428379. 
  2. ↑ "Retinol and alcohol dehydrogenases in retina and liver". Biochim. Biophys. Acta 128 (1): 48–54. 1966. doi:10.1016/0926-6593(66)90140-8. PMID 5972368. 
  3. ↑ "The complete structure of human class IV alcohol dehydrogenase (retinol dehydrogenase) determined from the ADH7 gene". J. Biol. Chem. 269 (22): 15606–12. June 1994. PMID 8195208. 
  4. ↑ 4.0 4.1 "Kinetic mechanism of human class IV alcohol dehydrogenase functioning as retinol dehydrogenase". J. Biol. Chem. 277 (28): 25209–16. July 2002. doi:10.1074/jbc.M201947200. PMID 11997393. 
  5. ↑ 5.0 5.1 "Methionine-141 directly influences the binding of 4-methylpyrazole in human sigma sigma alcohol dehydrogenase". Protein Sci. 8 (12): 2639–44. December 1999. doi:10.1110/ps.8.12.2639. PMID 10631979. 
  6. ↑ 6.0 6.1 "RCSB PDB-101". http://www.rcsb.org/pdb/101/motm.do?momID=13. 
  7. ↑ "Intracellular localization and membrane topology of 11-cis retinol dehydrogenase in the retinal pigment epithelium suggest a compartmentalized synthesis of 11-cis retinaldehyde". J. Cell Sci. 112 (4): 549–58. February 1999. PMID 9914166. 
  8. ↑ "The retinal pigment epithelial-specific 11-cis retinol dehydrogenase belongs to the family of short chain alcohol dehydrogenases". J. Biol. Chem. 270 (3): 1107–12. January 1995. doi:10.1074/jbc.270.3.1107. PMID 7836368. 
  9. ↑ 9.0 9.1 "Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset severe retinal dystrophy". Nat. Genet. 36 (8): 850–4. August 2004. doi:10.1038/ng1394. PMID 15258582. 
  10. ↑ 10.0 10.1 "The 11-cis-retinol dehydrogenase activity of RDH10 and its interaction with visual cycle proteins". Invest. Ophthalmol. Vis. Sci. 50 (11): 5089–97. November 2009. doi:10.1167/iovs.09-3797. PMID 19458327. 
  11. ↑ "Retinol dehydrogenase from bovine retinal rod outer segments. Kinetic mechanism of the solubilized enzyme". J. Biol. Chem. 257 (19): 11836–41. October 1982. PMID 6749847. 
  12. ↑ 12.0 12.1 12.2 "Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle". Hum. Mol. Genet. 14 (24): 3865–75. December 2005. doi:10.1093/hmg/ddi411. PMID 16269441. 
  13. ↑ "Role of photoreceptor-specific retinol dehydrogenase in the retinoid cycle in vivo". J. Biol. Chem. 280 (19): 18822–32. May 2005. doi:10.1074/jbc.M501757200. PMID 15755727. 
  14. ↑ "upload.wikimedia.org". http://upload.wikimedia.org/wikipedia/commons/0/09/Visual_cycle_v2.png. 
  15. ↑ "13-cis-retinoic acid competitively inhibits 3 alpha-hydroxysteroid oxidation by retinol dehydrogenase RoDH-4: a mechanism for its anti-androgenic effects in sebaceous glands?". Biochem. Biophys. Res. Commun. 303 (1): 273–8. March 2003. doi:10.1016/S0006-291X(03)00332-2. PMID 12646198. 
  16. ↑ "Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus". Nat. Genet. 22 (2): 188–91. June 1999. doi:10.1038/9707. PMID 10369264. 
  17. ↑ "Disease-associated variants of microsomal retinol dehydrogenase 12 (RDH12) are degraded at mutant-specific rates". FEBS Lett. 584 (3): 507–10. February 2010. doi:10.1016/j.febslet.2009.12.009. PMID 20006610. 



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