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Volume 271, Number 52, Issue of December 27, 1996 pp. 33539-33544
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Specifically Targeted Modification of Human Aldose Reductase by Physiological Disulfides

(Received for publication, May 21, 1996, and in revised form, August 21, 1996)

Mario Cappiello , Margaret Voltarelli , Ilaria Cecconi , Pier Giuseppe Vilardo , Massimo Dal Monte , Isabella Marini , Antonella Del Corso , David K. Wilson ^§ , Florante A. Quiocho ^§ , J. Mark Petrash ^¶ and Umberto Mura

From the  Dipartimento di Fisiologia e Biochimica, Università di Pisa, via S. Maria 55, 56100 Pisa, Italy, the ^§ Howard Hughes Medical Institute and Department of Biochemistry, Baylor College of Medicine, Houston, Texas 77030, the ^¶ Departments of Ophthalmology and Visual Sciences and of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, and the  Dipartimento di Scienze Biomediche, Università di Modena, via Campi 287, 41100 Modena, Italy

Aldose reductase is inactivated by physiological disulfides such as GSSG and cystine. To study the mechanism of disulfide-induced enzyme inactivation, we examined the rate and extent of enzyme inactivation using wild-type human aldose reductase and mutants containing cysteine-to-serine substitutions at positions 80 (C80S), 298 (C298S), and 303 (C303S). The wild-type, C80S, and C303S enzymes lost >80% activity following incubation with GSSG, whereas the C298S mutant was not affected. Loss of activity correlated with enzyme thiolation. The binary enzyme-NADP⁺ complex was less susceptible to enzyme thiolation than the apoenzyme. These results suggest that thiolation of human aldose reductase occurs predominantly at Cys-298. Energy minimization of a hypothetical enzyme complex modified by glutathione at Cys-298 revealed that the glycyl carboxylate of glutathione may participate in a charged interaction with His-110 in a manner strikingly similar to that involving the carboxylate group of the potent aldose reductase inhibitor Zopolrestat. In contrast to what was observed with GSSG and cystine, cystamine inactivated the wild-type enzyme as well as all three cysteine mutants. This suggests that cystamine-induced inactivation of aldose reductase does not involve modification of cysteines exclusively at position 80, 298, or 303.

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