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Science 23 April 2004:
Vol. 304. no. 5670, pp. 596 - 600
DOI: 10.1126/science.1095569
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Reports

Regeneration of Peroxiredoxins by p53-Regulated Sestrins, Homologs of Bacterial AhpD

Andrei V. Budanov,1,2* Anna A. Sablina,1,3* Elena Feinstein,4 Eugene V. Koonin,5 Peter M. Chumakov1,2{dagger}

Acting as a signal, hydrogen peroxide circumvents antioxidant defense by overoxidizing peroxiredoxins (Prxs), the enzymes that metabolize peroxides. We show that sestrins, a family of proteins whose expression is modulated by p53, are required for regeneration of Prxs containing Cys-SO2H, thus reestablishing the antioxidant firewall. Sestrins contain a predicted redox-active domain homologous to AhpD, the enzyme catalyzing the reduction of a bacterial Prx, AhpC. Purified Hi95 (sestrin 2) protein supports adenosine triphosphate–dependent reduction of overoxidized PrxI in vitro, indicating that unlike AhpD, which is a disulfide reductase, sestrins are cysteine sulfinyl reductases. As modulators of peroxide signaling and antioxidant defense, sestrins constitute potential therapeutic targets.

1 Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
2 Engelhardt Institute of Molecular Biology, 119991, Moscow, Russia.
3 Cancer Research Center, 1154785 Moscow, Russia.
4 Quark Biotech Incorporated, Ness Ziona, 70400 Israel.
5 National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.



* These authors contributed equally to this work.

{dagger} To whom corresponding should be addressed. E-mail: chumakp{at}ccf.org

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