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J. Biol. Chem., Vol. 276, Issue 51, 48483-48493, December 21, 2001
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From the Departments of The regeneration of 11-cis-retinal,
the universal chromophore of the vertebrate retina, is a complex
process involving photoreceptors and adjacent retinal pigment
epithelial cells (RPE). 11-cis-Retinal is coupled to opsins
in both rod and cone photoreceptor cells and is photoisomerized to
all-trans-retinal by light. Here, we show that RPE
microsomes can catalyze the reverse isomerization of
11-cis-retinol to all-trans-retinol (and
13-cis-retinol), and membrane exposure to UV light further
enhances the rate of this reaction. This conversion is inhibited when
11-cis-retinol is in a complex with cellular
retinaldehyde-binding protein (CRALBP), providing a clear demonstration
of the protective effect of retinoid-binding proteins in retinoid
processes in the eye, a function that has been long suspected but never
proven. The reverse isomerization is nonenzymatic and specific to
alcohol forms of retinoids, and it displays stereospecific preference
for 11-cis-retinol and 13-cis-retinol but is
much less efficient for 9-cis-retinol. The mechanism of reverse isomerization was investigated using stable isotope-labeled retinoids and radioactive tracers to show that this reaction occurs with the retention of configuration of the C-15 carbon of
retinol through a mechanism that does not eliminate the hydroxyl group, in contrast to the enzymatic all-trans-retinol to
11-cis-retinol reaction. The activation energy for the
conversion of 11-cis-retinol to
all-trans-retinol is 19.5 kcal/mol, and 20.1 kcal/mol for isomerization of 13-cis-retinol to
all-trans-retinol. We also demonstrate that the reverse
isomerization occurs in vivo using exogenous
11-cis-retinol injected into the intravitreal space of wild
type and Rpe65
Isomerization of 11-cis-Retinoids to
All-trans-retinoids in Vitro and in
Vivo*
§,,, and§¶
Ophthalmology,
¶ Pharmacology, and § Chemistry, University of
Washington, Seattle, Washington 98195
/ mice, which have defective forward
isomerization. This study demonstrates an uncharacterized activity of
RPE microsomes that could be important in the normal flow of retinoids
in the eye in vivo during dark adaptation.
*
This work was supported by National Institutes of Health
Grants EY07031 (vision training grant; to J. K. M.), EY09339 and EY66-3988 (Research to Prevent Blindness, Inc. (RPB) to the
Department of Ophthalmology at the University of Washington), by the
Ruth and Milton Steinbach Fund, by the Alcon Research Institute, and by
the E. K. Bishop Foundation.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Ophthalmology, University of Washington, Box 356485, Seattle, WA
98195-6485. Tel.: 206-543-9074; Fax: 206-221-6784; E-mail:
palczews@u.washington.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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