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J. Biol. Chem., Vol. 282, Issue 7, 4382-4392, February 16, 2007

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Mechanisms Involved in the Protection of UV-induced Protein Inactivation by the Corneal Crystallin ALDH3A1^*

Tia Estey, Miriam Cantore, Philip A. Weston, John F. Carpenter, J. Mark Petrash^¶, and Vasilis Vasiliou¹

From the Center for Pharmaceutical Biotechnology and Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, Colorado 80262 and the ^¶Department of Ophthalmology and Visual Science, Washington University School of Medicine, St. Louis, Missouri 63119

Various lines of evidence have shown that ALDH3A1 (aldehyde dehydrogenase 3A1) plays a critical and multifaceted role in protecting the cornea from UV-induced oxidative stress. ALDH3A1 is a corneal crystallin, which is defined as a protein recruited into the cornea for structural purposes without losing its primary function (i.e. metabolism). Although the primary role of ALDH3A1 in the metabolism of toxic aldehydes has been clearly demonstrated, including the detoxification of aldehydes produced during UV-induced lipid peroxidation, the structural role of ALDH3A1 in the cornea remains elusive. We therefore examined the potential contribution of ALDH3A1 in maintaining the optical integrity of the cornea by suppressing the aggregation and/or inactivation of other proteins through chaperone-like activity and other protective mechanisms. We found that ALDH3A1 underwent a structural transition near physiological temperatures to form a partially unfolded conformation that is suggestive of chaperone activity. Although this structural transition alone did not correlate with any protection, ALDH3A1 substantially reduced the inactivation of glucose-6-phosphate dehydrogenase by 4-hydroxy-2-nonenal and malondialdehyde when co-incubated with NADP⁺, reinforcing the importance of the metabolic function of this corneal enzyme in the detoxification of toxic aldehydes. A large excess of ALDH3A1 also protected glucose-6-phosphate dehydrogenase from inactivation because of direct exposure to UVB light, which suggests that ALDH3A1 may shield other proteins from damaging UV rays. Collectively, these data demonstrate that ALDH3A1 can reduce protein inactivation and/or aggregation not only by detoxification of reactive aldehydes but also by directly absorbing UV energy. This study provides for the first time mechanistic evidence supporting the structural role of the corneal crystallin ALDH3A1 as a UV-absorbing constituent of the cornea.

Received for publication, August 8, 2006 , and in revised form, November 9, 2006.

^* This work was supported by NEI Grants EY11490 (to V. V.) and EY13987 (to J. M. P.) from the National Institutes of Health, an American Foundation of Pharmaceutical Education predoctoral fellowship, and a National Institutes of Health training grant (to T. E.). 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 To whom correspondence should be addressed. Tel.: 303-315-6153; Fax: 303-315-6281; E-mail: vasilis.vasiliou{at}uchsc.edu.

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