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Molecular and Cellular Biology, April 1999, p. 2650-2656, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Differential Protein S-Thiolation of Glyceraldehyde-3-Phosphate Dehydrogenase Isoenzymes Influences Sensitivity to Oxidative Stress

Chris M. Grant,1,* Kathryn A. Quinn,2 and Ian W. Dawes1

Cooperative Research Center for Food Industry Innovation, School of Biochemistry & Molecular Genetics,1 and Center for Thrombosis and Vascular Research, School of Pathology,2 University of New South Wales, Sydney, Australia

Received 25 September 1998/Returned for modification 11 November 1998/Accepted 21 December 1998

The irreversible oxidation of cysteine residues can be prevented by protein S-thiolation, in which protein -SH groups form mixed disulfides with low-molecular-weight thiols such as glutathione. We report here the identification of glyceraldehyde-3-phosphate dehydrogenase as the major target of protein S-thiolation following treatment with hydrogen peroxide in the yeast Saccharomyces cerevisiae. Our studies reveal that this process is tightly regulated, since, surprisingly, despite a high degree of sequence homology (98% similarity and 96% identity), the Tdh3 but not the Tdh2 isoenzyme was S-thiolated. The glyceraldehyde-3-phosphate dehydrogenase enzyme activity of both the Tdh2 and Tdh3 isoenzymes was decreased following exposure to H2O2, but only Tdh3 activity was restored within a 2-h recovery period. This indicates that the inhibition of the S-thiolated Tdh3 polypeptide was readily reversible. Moreover, mutants lacking TDH3 were sensitive to a challenge with a lethal dose of H2O2, indicating that the S-thiolated Tdh3 polypeptide is required for survival during conditions of oxidative stress. In contrast, a requirement for the nonthiolated Tdh2 polypeptide was found during exposure to continuous low levels of oxidants, conditions where the Tdh3 polypeptide would be S-thiolated and hence inactivated. We propose a model in which both enzymes are required during conditions of oxidative stress but play complementary roles depending on their ability to undergo S-thiolation.

* Corresponding author. Mailing address: School of Biochemistry & Molecular Genetics, University of New South Wales, Sydney, NSW 2052, Australia. Phone: 61 (2) 9385 2031. Fax: 61 (2) 9385 1050. E-mail: c.grant{at}unsw.edu.au.

Molecular and Cellular Biology, April 1999, p. 2650-2656, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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