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Information on EC 3.1.1.64 - retinoid isomerohydrolase and Organism(s) Homo sapiens

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     3 Hydrolases
         3.1 Acting on ester bonds
             3.1.1 Carboxylic-ester hydrolases
                3.1.1.64 retinoid isomerohydrolase
IUBMB Comments
This enzyme, which operates in the retinal pigment epithelium (RPE), catalyses the cleavage and isomerization of all-trans-retinyl fatty acid esters to 11-cis-retinol, a key step in the regeneration of the visual chromophore in the vertebrate visual cycle . Interaction of the enzyme with the membrane is critical for its enzymic activity .
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Homo sapiens
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
Synonyms
rpe65, isomerohydrolase, retinoid isomerase, retinoid isomerohydrolase, retinol isomerase, rpe65c, 13cimh, rpe65a, all-trans-reh, retinol isomerohydrolase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
all-trans-retinyl-palmitate hydrolase
-
-
esterase, all-trans-retinol palmitate
-
-
-
-
isomerohydrolase
-
-
Retinoid isomerase
-
-
retinoid isomerohydrolase
-
-
retinol hydrolase (ambiguous)
-
-
retinol isomerohydrolase
-
-
Rpe65
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hydrolysis of carboxylic ester
-
-
-
-
PATHWAY SOURCE
PATHWAYS
-
-
SYSTEMATIC NAME
IUBMB Comments
all-trans-retinyl ester acylhydrolase, 11-cis retinol forming
This enzyme, which operates in the retinal pigment epithelium (RPE), catalyses the cleavage and isomerization of all-trans-retinyl fatty acid esters to 11-cis-retinol, a key step in the regeneration of the visual chromophore in the vertebrate visual cycle [4]. Interaction of the enzyme with the membrane is critical for its enzymic activity [6].
CAS REGISTRY NUMBER
COMMENTARY hide
106389-24-6
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
all-trans-retinyl ester + H2O
11-cis-retinol + a fatty acid
show the reaction diagram
all-trans-retinyl palmitate + H2O
all-trans-retinol + palmitate
show the reaction diagram
-
-
-
?
an all-trans-retinyl ester + H2O
11-cis-retinol + a fatty acid
show the reaction diagram
additional information
?
-
-
RPE65 is not inherently 11-cis-specific and can produce both 11- and 13-cis isomers
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2,2'-dipyridyl
-
-
apo-cellular retinol-binding protein type 1
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-
-
FATP1c
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cytosolic C-terminal sequence from the fatty acid transport protein 1 (FATP1or SLC27A1, solute carrier family 27member1), interacts dose-dependently with the native RPE65 and markedly inhibits 11-cis retinol production by acting on the production of all-trans retinyl esters and the isomerase activity of RPE65
-
N-(12-chloro-11-oxododecyl)acetamide
-
-
Triacsin C
inhibitor of fatty acyl:CoA ligases, potently inhibits RPE65 isomerase activity in cellulo, competitive inhibitor
additional information
neither 8,11-eicosadiynoic acid nor 2-fluoropalmitic acid are selective or potent inhibitors of RPE65
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
additional information
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00104
an all-trans-retinyl ester
-
pH and temperature not specified in the publication
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0005
Triacsin C
Homo sapiens
pH 8.0, 37°C
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5 - 9
-
pH 5.0: 38.7% of maximal activity, pH 9.0: 46.1% of maximal activity
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
malignant melanoma cells are able to esterify all-trans retinol and subsequently isomerize all-trans retinyl esters into 11-cis retinol, whereas melanocytes are not able to catalyze these reactions
Manually annotated by BRENDA team
additional information
-
melanocytes do not express this enzyme at the protein level
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
-
RPE65 mutations are associated with inherited retinal dystrophies
metabolism
-
the enzyme catalyzes the key reaction in the retinoid visual cycle
physiological function
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
RPE65_HUMAN
533
0
60948
Swiss-Prot
other Location (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
61000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
hanging drop vapor diffusion method, using 100 mM MES, pH 6.0, 30% (w/v) polyethylene glycol 200, and 2 mM dithiothreitol, at 22°C
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
A132T
-
50% activity compared to the wild type enzyme
A434V
-
55% activity compared to the wild type enzyme
C106A
-
the mutation does not affect the palmitylation status of the fragment 98-118, the mutant remains associated with the membrane. The mutant has an intact enzymatic activity similar to that of wild type enzyme
C106Y
-
site-directed mutagenesis, the mutant exhibits 16% reduced activity compared to the wild-type enzyme
C106Y/K297G
-
site-directed mutagenesis, the mutant exhibits 26% reduced activity compared to the wild-type enzyme
C112A
-
the mutation abolishes palmitylation in fragment 98-118 and dissociates RPE65 from the membrane. The mutant has no enzymatic activity
C231S
-
55% activity compared to the wild type enzyme
C329S
-
26% activity compared to the wild type enzyme
C329S/C330S
-
less than 2% activity compared to the wild type enzyme
C330T
C330Y
-
less than 2% activity compared to the wild type enzyme
E417A
-
less than 2% activity compared to the wild type enzyme
E417D
E417Q
F61L
-
the mutant shows 1.02% activity compared to the wild type enzyme
F61W
-
the mutant shows 1.28% activity compared to the wild type enzyme
F61Y
-
the mutant shows 7.57% activity compared to the wild type enzyme
G40S
-
less than 2% activity compared to the wild type enzyme
G528V
-
less than 2% activity compared to the wild type enzyme
H180A
H182A
-
10% activity compared to the wild type enzyme
H182Y
-
10% activity compared to the wild type enzyme
H241A
H313A
H527A
H68A
-
less than 2% activity compared to the wild type enzyme
H68Y
-
less than 2% activity compared to the wild type enzyme
I220M
-
site-directed mutagenesis, the mutant exhibits 38% reduced activity compared to the wild-type enzyme
K294T
-
16% activity compared to the wild type enzyme
K297G
-
site-directed mutagenesis, the mutant exhibits 1.7fold increased activity compared to the wild-type enzyme
K297G/L510M
-
site-directed mutagenesis, the mutant exhibits 45% increased activity compared to the wild-type enzyme
K297G/N302I
-
site-directed mutagenesis, the mutant exhibits 7.7% increased activity compared to the wild-type enzyme
K297G/S533A
-
site-directed mutagenesis, the mutant exhibits 18% increased activity compared to the wild-type enzyme
L510M
-
site-directed mutagenesis, the mutant exhibits 29% reduced activity compared to the wild-type enzyme
N170K
-
site-directed mutagenesis, the mutant exhibits 1.6fold increased activity compared to the wild-type enzyme
N170K/C330T
-
site-directed mutagenesis, the mutant exhibits 15% reduced activity compared to the wild-type enzyme
N170K/I220M
-
site-directed mutagenesis, the mutant exhibits 69% reduced activity compared to the wild-type enzyme
N170K/K297G
-
site-directed mutagenesis, the mutant exhibits 67% increased activity compared to the wild-type enzyme
N170K/Q497P
-
site-directed mutagenesis, the mutant exhibits 16% increased activity compared to the wild-type enzyme
N302I
-
site-directed mutagenesis, the mutant exhibits 25% increased activity compared to the wild-type enzyme
P363T
-
the mutation is identified in patients with Leber's congenital amaurosis, significantly decreases the stability of the enzyme, alters subcellular localization mainly to the plasma membrane and abolishes its isomerohydrolase activity
Q497P
-
site-directed mutagenesis, the mutant exhibits 26% reduced activity compared to the wild-type enzyme
R44Q
-
less than 2% activity compared to the wild type enzyme
R91W
-
the mutation from patients with retinal dystrophies decreases the stability of RPE65 protein and abolishes its isomerohydrolase activity. The mutant shows significantly decreased protein levels but unchanged mRNA levels and has a half-life of less than 2 h when expressed in 293A cells compared with the wild type
S533A
-
site-directed mutagenesis, the mutant exhibits 23% increased activity compared to the wild-type enzyme
T147A
-
the mutant shows 12.63% activity compared to the wild type enzyme
T147C
-
the mutant shows 20.18% activity compared to the wild type enzyme
T147G
-
the mutant shows 30.02% activity compared to the wild type enzyme
T147S
-
the mutant shows 84% activity compared to the wild type enzyme
T147V
-
inactive
T147W
-
inactive
T147Y
-
inactive
T39R
-
site-directed mutagenesis, the mutant exhibits 22% increased activity compared to the wild-type enzyme
T39R/N170K
-
site-directed mutagenesis, the mutant exhibits 39% increased activity compared to the wild-type enzyme
T39R/N170K/C330T
-
site-directed mutagenesis, the mutant exhibits 8.4% increased activity compared to the wild-type enzyme
T39R/N170K/C330T/Q497P
-
site-directed mutagenesis, the mutant exhibits 23% reduced activity compared to the wild-type enzyme
T39R/N170K/I220M
-
site-directed mutagenesis, the mutant exhibits 10% increased activity compared to the wild-type enzyme
T39R/N170K/I220M/Q497P
-
site-directed mutagenesis, the mutant exhibits 8.6% increased activity compared to the wild-type enzyme
T39R/N170K/Q497P
-
site-directed mutagenesis, the mutant exhibits 11% increased activity compared to the wild-type enzyme
W331F
-
the mutant shows 8.34% activity compared to the wild type enzyme
W331L
-
inactive
W331Q
-
inactive
W331Y
-
the mutant shows 26.72% activity compared to the wild type enzyme
Y144D
-
the mutation is identified in patients with Leber's congenital amaurosis, significantly decreases the stability of the enzyme, alters subcellular localization mainly to the plasma membrane and abolishes its isomerohydrolase activity
Y239C
-
inactive
Y239D
-
inactive
Y239F
-
inactive
Y239L
-
inactive
Y239S
-
inactive
Y239T
-
inactive
Y239W
-
inactive
Y275F
-
the mutant shows 14.44% activity compared to the wild type enzyme
Y275I
-
inactive
Y275W
-
inactive
Y368F
-
56% activity compared to the wild type enzyme
Y368H
additional information
-
mutant enzymes' recombinant expression levels, overview
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
RPE65 is a relatively stable protein with a half-life longer than 10 h in the presence of cycloheximide
-
wild type RPE65 has a half-life of more than 10 h after the addition of cycloheximide
-
wild type RPE65 is a fairly stable protein, with an apparent half-life longer than 10 h, when expressed in 293A cells
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in 293-F cells
-
expressed in 293A-LRAT cells
-
expressed in Escherichia coli and in 293A-LRAT cells
-
expressed in QBI-293A cells
-
expressed in Sf9 cells and in 29T cells
-
recombinant expression of wild-type and mutant enzymes in HEK-293A-LRAT cells
-
transfection of HEK293-F cells
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Blaner, W.S.; Das, S.R.; Gouras, P.; Flood, M.T.
Hydrolysis of 11-cis- and all-trans-retinyl palmitate by homogenates of human retinal epithelial cells
J. Biol. Chem.
262
53-58
1987
Homo sapiens
Manually annotated by BRENDA team
Chen, Y.; Moiseyev, G.; Takahashi, Y.; Ma, J.X.
Impacts of two point mutations of RPE65 from Lebers congenital amaurosis on the stability, subcellular localization and isomerohydrolase activity of RPE65
FEBS Lett.
580
4200-4204
2006
Homo sapiens
Manually annotated by BRENDA team
Takahashi, Y.; Chen, Y.; Moiseyev, G.; Ma, J.X.
Two point mutations of RPE65 from patients with retinal dystrophies decrease the stability of RPE65 protein and abolish its isomerohydrolase activity
J. Biol. Chem.
281
21820-21826
2006
Homo sapiens
Manually annotated by BRENDA team
Guignard, T.J.; Jin, M.; Pequignot, M.O.; Li, S.; Chassigneux, Y.; Chekroud, K.; Guillou, L.; Richard, E.; Hamel, C.P.; Brabet, P.
FATP1 inhibits 11-cis retinol formation via interaction with the visual cycle retinoid isomerase RPE65 and LRAT
J. Biol. Chem.
285
18759-18768
2010
Homo sapiens
Manually annotated by BRENDA team
Redmond, T.M.; Poliakov, E.; Kuo, S.; Chander, P.; Gentleman, S.
RPE65, visual cycle retinol isomerase, is not inherently 11-cis-specific: support for a carbocation mechanism of retinol isomerization
J. Biol. Chem.
285
1919-1927
2010
Homo sapiens
Manually annotated by BRENDA team
Golczak, M.; Kiser, P.D.; Lodowski, D.T.; Maeda, A.; Palczewski, K.
Importance of membrane structural integrity for RPE65 retinoid isomerization activity
J. Biol. Chem.
285
9667-9682
2010
Homo sapiens
Manually annotated by BRENDA team
Nikolaeva, O.; Takahashi, Y.; Moiseyev, G.; Ma, J.X.
Negative charge of the glutamic acid 417 residue is crucial for isomerohydrolase activity of RPE65
Biochem. Biophys. Res. Commun.
391
1757-1761
2010
Homo sapiens
Manually annotated by BRENDA team
Takahashi, Y.; Moiseyev, G.; Chen, Y.; Ma, J.X.
Identification of conserved histidines and glutamic acid as key residues for isomerohydrolase activity of RPE65, an enzyme of the visual cycle in the retinal pigment epithelium
FEBS Lett.
579
5414-5418
2005
Homo sapiens
Manually annotated by BRENDA team
Moiseyev, G.; Takahashi, Y.; Chen, Y.; Kim, S.; Ma, J.X.
RPE65 from cone-dominant chicken is a more efficient isomerohydrolase compared with that from rod-dominant species
J. Biol. Chem.
283
8110-8117
2008
Bos taurus, Gallus gallus, Homo sapiens
Manually annotated by BRENDA team
Takahashi, Y.; Moiseyev, G.; Ablonczy, Z.; Chen, Y.; Crouch, R.K.; Ma, J.X.
Identification of a novel palmitylation site essential for membrane association and isomerohydrolase activity of RPE65
J. Biol. Chem.
284
3211-3218
2009
Bos taurus, Homo sapiens
Manually annotated by BRENDA team
Amann, P.M.; Luo, C.; Owen, R.W.; Hofmann, C.; Freudenberger, M.; Schadendorf, D.; Eichmueller, S.B.; Bazhin, A.V.
Vitamin A metabolism in benign and malignant melanocytic skin cells: importance of lecithin/retinol acyltransferase and RPE65
J. Cell. Physiol.
227
718-728
2012
Homo sapiens
Manually annotated by BRENDA team
Redmond, T.M.; Poliakov, E.; Yu, S.; Tsai, J.Y.; Lu, Z.; Gentleman, S.
Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle
Proc. Natl. Acad. Sci. USA
102
13658-13663
2005
Homo sapiens
Manually annotated by BRENDA team
Takahashi, Y.; Moiseyev, G.; Ma, J.X.
Identification of key residues determining isomerohydrolase activity of human RPE65
J. Biol. Chem.
289
6743-26751
2014
Homo sapiens
Manually annotated by BRENDA team
Eroglu, A.; Gentleman, S.; Poliakov, E.; Redmond, T.M.
Inhibition of RPE65 retinol isomerase activity by inhibitors of lipid metabolism
J. Biol. Chem.
291
4966-4973
2016
Homo sapiens (Q16518)
Manually annotated by BRENDA team
Kolesnikov, A.; Tang, P.; Kefalov, V.
Examining the role of cone-expressed RPE65 in mouse cone function
Sci. Rep.
8
14201
2018
Homo sapiens (Q16518), Homo sapiens, Mus musculus (Q91ZQ5), Mus musculus
Manually annotated by BRENDA team