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J. Biol. Chem., Vol. 279, Issue 47, 49447-49454, November 19, 2004

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Identification and Characterization of a Pi Isoform of Glutathione S-Transferase (GSTP1) as a Zeaxanthin-binding Protein in the Macula of the Human Eye^*

Prakash Bhosale, Alexander J. Larson, Jeanne M. Frederick, Katie Southwick¶, Craig D. Thulin¶, and Paul S. Bernstein, A Sybil B. Harrington Research to Prevent Blindness Scholar in macular degeneration research||

From the Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah 84132 and ^¶Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602

Uptake, metabolism, and stabilization of xanthophyll carotenoids in the retina are thought to be mediated by specific xanthophyll-binding proteins (XBPs). A membrane-associated XBP was purified from human macula using ion-exchange chromatography followed by gel-exclusion chromatography. Two-dimensional gel electrophoresis showed a prominent spot of 23 kDa and an isoelectric point of 5.7. Using mass spectral sequencing methods and the public NCBI database, it was identified as a Pi isoform of human glutathione S-transferase (GSTP1). Dietary (3R,3'R)-zeaxanthin displayed the highest affinity with an apparent K_d of 0.33 µM, followed by (3R,3'S-meso)-zeaxanthin with an apparent K_d of 0.52 µM. (3R,3'R,6'R)-Lutein did not display any high-affinity binding to GSTP1. Other human recombinant glutathione S-transferase (GST) proteins, GSTA1 and GSTM1, exhibited only low affinity binding of xanthophylls. (3R,3'S-meso)-Zeaxanthin, an optically inactive nondietary xanthophyll carotenoid present in the human macula, exhibited a strong induced CD spectrum in association with human macular XBP that was nearly identical to the CD spectrum induced by GSTP1. Like-wise, dietary (3R,3'R)-zeaxanthin displayed alterations in its CD spectrum in association with GSTP1 and XBP. Other mammalian xanthophyll carrier proteins such as tubulin, high-density lipoprotein, low-density lipoprotein, albumin, and -lactoglobulin did not bind zeaxanthins with high affinity, and they failed to induce or alter xanthophyll CD spectra to any significant extent. Immunocytochemistry with an antibody to GSTP1 on human macula sections showed highest labeling in the outer and inner plexiform layers. These results indicate that GSTP1 is a specific XBP in human macula that interacts with (3R,3'S-meso)-zeaxanthin and dietary (3R,3'R)-zeaxanthin in contrast to apparently weaker interactions with (3R,3'R,6'R)-lutein.

Received for publication, May 13, 2004 , and in revised form, September 7, 2004.

^* This work was supported in part by National Institutes of Health Grant EY-11600, Kemin Foods (Des Moines, IA), and Research to Prevent Blindness, Inc. (New York, NY). 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.

Supported by National Eye Institute Grant EY-08123 and a center grant from the Foundation Fighting Blindness to the University of Utah.

^|| To whom correspondence should be addressed: Dept. of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, 50 N. Medical Dr., Salt Lake City, UT 84132. Tel.: 801-581-6078; Fax: 801-581-3357; E-mail: paul.bernstein{at}hsc.utah.edu.

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