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J. Biol. Chem., Vol. 281, Issue 26, 18112-18119, June 30, 2006

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Characterization of Native Retinal Fluorophores Involved in Biosynthesis of A2E and Lipofuscin-associated Retinopathies^*

Tam V. Bui¹, Yun Han¹, Roxana A. Radu, Gabriel H. Travis², and Nathan L. Mata³

From the Sytera, Inc., La Jolla, California 92037 and the University of California Los Angeles Jules Stein Eye Institute, Los Angeles, California 90095

Mutations in the photoreceptor-specific ABCA4 gene are associated with several inherited retinal and macular degenerations. A prominent phenotype of these diseases is the accumulation of cytotoxic lipofuscin fluorophores such as A2E within the retinal pigment epithelium. Another compound, dihydro-N-retinylidene-N-retinylphosphatidyl-ethanolamine (A2PE-H₂), also accumulates in retinas of mice and humans harboring ABCA4 mutations and was proposed to be a precursor of A2E. The role of A2PE-H₂ in the biogenesis of A2E and its relationship to other retinal fluorophores has not been previously investigated. We report spectral properties and structural relationships of the principal retinal fluorophores that accumulate in retina and retinal pigment epithelium of abca4^–/– mice. A long wavelength fluorescence emission intrinsic to abca4^–/– retinal explants is shown to emanate from A2PE-H₂. All-trans retinal dimer conjugates, which were also identified in the retinal explants, possessed distinct fluorescence and structural properties and, unlike A2PE-H₂, did not accumulate in an age-dependent manner. Derivative absorbance and fluorescence spectroscopy revealed that A2PE-H₂, A2E, and N-retinylidene-N-retinyl-phosphatidylethanolamine (A2PE), a known precursor of A2E, share common electronic and resonant structures. Importantly, collision-induced dissociation of A2PE-H₂ produced daughter ions that were identical to authentic A2E and its daughter ions. Finally, intravitreal administration of A2PE-H₂ to wild-type mice resulted in the formation of A2PE and A2E. These data validate a previously hypothesized biosynthetic pathway for A2E and implicate A2PE-H₂ as a precursor in this pathway. Fluorescence properties of A2PE-H₂ and other related fluorophores characterized in this report have significance for evaluation of human retinal diseases characterized by aberrant fundus autofluorescence.

Received for publication, February 13, 2006 , and in revised form, April 5, 2006.

^* This work was supported in part by a private endowment from Avalon Ventures, La Jolla, CA and by grants from the National Eye Institute and the Foundation Fighting Blindness. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² The Charles Kenneth Feldman and Jules and Doris Stein Research to Prevent Blindness Professor.

³ A corresponding member of the Jules Stein Eye Institute. To whom correspondence should be addressed: Sytera, Inc., 505 Coast Blvd. So., Ste. 412, La Jolla, CA 92037. Tel.: 858-754-3024; Fax: 858-754-3007; E-mail: nmata{at}sytera.com.

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