MetaCyc Enzyme: retinoid isomerohydrolase

Gene: RPE65 Accession Number: HS04044 (MetaCyc)

Synonyms: RP20, LCA2, retinal pigment epithelium-specific 65 kDa protein, retinol isomerase, retinal pigment epithelium-specific protein (65kD)

Species: Homo sapiens

The first description of RPE65 as an RPE-specific protein with an apparent molecular mass of 63 kD was published in 1991 [Sagara91]. RPE65 was initially thought to be a receptor for serum retinol binding protein (RBP). In 1997 it was shown that mutations in RPE65 were found in patients with Leber congenital amaurosis (LCA), a severe retinopathy resulting in early childhood blindness [Marlhens97, Gu97, Morimura98, Simovich01]. RPE65-null mice were shown to develop early-onset blindness and displayed a metabolic dysfunction characterized by near-complete absence of ocular 11-cis retinoids in addition to substantial accumulation of all-trans-retinyl esters in the RPE [Redmond98].

The localization of the gene encoding the protein was localized to human chromosome 1p31 [Hamel94, Nicoletti95].

The true function of RPE65 was only revealed in 2005,when three independent groups proposed it to be the actual isomerohydrolase that simultaneously hydrolyzes all-trans-retinyl esters and produces 11-cis-retinol [Jin05a, Moiseyev06, Redmond05]. The assay was difficult to develop since it requires the enzyme LRAT in the reaction mixture to provide the retinyl ester substrates, and the all-trans-retinyl ester must be incorporated into the phospholipid membrane to serve as a substrate [Nikolaeva09].

A conclusive evidence for its activity was obtained when purified RPE65 enzyme possessed retinoid isomerase activity when reconstituted with retinyl ester-containing phospholipid vesicles [Nikolaeva09].

RPE65 interacts directly with the membrane in a highly specific manner, and this interaction is critical for its enzymatic activity [Golczak10].

Map Position: [67,812,054 <- 67,833,251]

Molecular Weight of Polypeptide: 60.948 kD (from nucleotide sequence)

pI: 6.41 [Hamel93]

Unification Links: ArrayExpress:Q16518 , Entrez-gene:6121 , Entrez:AAA99012 , Entrez:AAC14586 , Entrez:AAC39660 , PhosphoSite:Q16518 , PhylomeDB:Q16518 , Pride:Q16518 , Protein Model Portal:Q16518 , SMR:Q16518 , String:9606.ENSP00000262340 , UniProt:Q16518

Relationship Links: InterPro:IN-FAMILY:IPR004294 , Panther:IN-FAMILY:PTHR10543 , Pfam:IN-FAMILY:PF03055

Gene-Reaction Schematic: ?

Gene-Reaction Schematic

Instance reaction of [an all-trans-retinyl ester + H2O → 11-cis-retinol + a fatty acid + H+] (
i1: all-trans-retinyl palmitate + H2O → 11-cis-retinol + palmitate + H+ (

GO Terms:

Biological Process: GO:0006776 - vitamin A metabolic process
GO:0007601 - visual perception
Molecular Function: GO:0005515 - protein binding

Created 10-Aug-2011 by Caspi R , SRI International

Enzymatic reaction of: all-trans-retinyl-palmitate hydrolase (retinoid isomerohydrolase)

EC Number:

all-trans-retinyl palmitate + H2O <=> 11-cis-retinol + palmitate + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the direction in which it was curated.

The reaction is physiologically favored in the direction shown.

Enzymatic reaction of: all-trans-retinyl-ester hydrolase (retinoid isomerohydrolase)

EC Number:

an all-trans-retinyl ester + H2O <=> 11-cis-retinol + a fatty acid + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the direction in which it was curated.

The reaction is physiologically favored in the direction shown.

In Pathways: the visual cycle I (vertebrates)


Schematic showing introns, exons and/or isoforms of RPE65


Golczak10: Golczak M, Kiser PD, Lodowski DT, Maeda A, Palczewski K (2010). "Importance of membrane structural integrity for RPE65 retinoid isomerization activity." J Biol Chem 285(13);9667-82. PMID: 20100834

Gu97: Gu SM, Thompson DA, Srikumari CR, Lorenz B, Finckh U, Nicoletti A, Murthy KR, Rathmann M, Kumaramanickavel G, Denton MJ, Gal A (1997). "Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy." Nat Genet 17(2);194-7. PMID: 9326941

Hamel93: Hamel CP, Tsilou E, Pfeffer BA, Hooks JJ, Detrick B, Redmond TM (1993). "Molecular cloning and expression of RPE65, a novel retinal pigment epithelium-specific microsomal protein that is post-transcriptionally regulated in vitro." J Biol Chem 268(21);15751-7. PMID: 8340400

Hamel94: Hamel CP, Jenkins NA, Gilbert DJ, Copeland NG, Redmond TM (1994). "The gene for the retinal pigment epithelium-specific protein RPE65 is localized to human 1p31 and mouse 3." Genomics 20(3);509-12. PMID: 8034329

Jin05a: Jin M, Li S, Moghrabi WN, Sun H, Travis GH (2005). "Rpe65 is the retinoid isomerase in bovine retinal pigment epithelium." Cell 122(3);449-59. PMID: 16096063

Marlhens97: Marlhens F, Bareil C, Griffoin JM, Zrenner E, Amalric P, Eliaou C, Liu SY, Harris E, Redmond TM, Arnaud B, Claustres M, Hamel CP (1997). "Mutations in RPE65 cause Leber's congenital amaurosis." Nat Genet 17(2);139-41. PMID: 9326927

Moiseyev06: Moiseyev G, Takahashi Y, Chen Y, Gentleman S, Redmond TM, Crouch RK, Ma JX (2006). "RPE65 is an iron(II)-dependent isomerohydrolase in the retinoid visual cycle." J Biol Chem 281(5);2835-40. PMID: 16319067

Morimura98: Morimura H, Fishman GA, Grover SA, Fulton AB, Berson EL, Dryja TP (1998). "Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis." Proc Natl Acad Sci U S A 95(6);3088-93. PMID: 9501220

Nicoletti95: Nicoletti A, Wong DJ, Kawase K, Gibson LH, Yang-Feng TL, Richards JE, Thompson DA (1995). "Molecular characterization of the human gene encoding an abundant 61 kDa protein specific to the retinal pigment epithelium." Hum Mol Genet 4(4);641-9. PMID: 7633413

Nikolaeva09: Nikolaeva O, Takahashi Y, Moiseyev G, Ma JX (2009). "Purified RPE65 shows isomerohydrolase activity after reassociation with a phospholipid membrane." FEBS J 276(11);3020-30. PMID: 19490105

Redmond05: Redmond TM, Poliakov E, Yu S, Tsai JY, Lu Z, Gentleman S (2005). "Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle." Proc Natl Acad Sci U S A 102(38);13658-63. PMID: 16150724

Redmond98: Redmond TM, Yu S, Lee E, Bok D, Hamasaki D, Chen N, Goletz P, Ma JX, Crouch RK, Pfeifer K (1998). "Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle." Nat Genet 20(4);344-51. PMID: 9843205

Sagara91: Sagara H, Hirosawa K (1991). "Monoclonal antibodies which recognize endoplasmic reticulum in the retinal pigment epithelium." Exp Eye Res 53(6);765-71. PMID: 1783014

Simovich01: Simovich MJ, Miller B, Ezzeldin H, Kirkland BT, McLeod G, Fulmer C, Nathans J, Jacobson SG, Pittler SJ (2001). "Four novel mutations in the RPE65 gene in patients with Leber congenital amaurosis." Hum Mutat 18(2);164. PMID: 11462243

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 19.0 on Sat Oct 10, 2015, biocyc13.