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Enzyme inactivation through sulfhydryl oxidation by physiologic NO-carriers

Nature Structural Biology volume 5, pages 267–271 (1998)Cite this article

Abstract

Nitric oxide (NO) is a pluripotent regulatory molecule, yet the molecular mechanisms by which it exerts its effects are largely unknown. Few physiologic target molecules of NO have been identified, and even for these, the modifications caused by NO remain uncharacterized. Human glutathione reductase (hGR), a central enzyme of cellular antioxidant defense, is inhibited by S-nitrosoglutathione (GSNO) and by diglutathionyl-dinitroso-iron (DNIC-[GSH]2), two in vivo transport forms of NO. Here, crystal structures of hGR inactivated by GSNO and DNIC-[GSH]2 at 1.7 Å resolution provide the first picture of enzyme inactivation by NO-carriers: in GSNO-modified hGR, the active site residue Cys 63 is oxidized to an unusually stable cysteine sulfenic acid (R-SOH), whereas modification with DNIC-[GSH]2 oxidizes Cys 63 to a cysteine sulfinic acid (R-SO2H). Our results illustrate that various forms of NO can mediate distinct chemistry, and that sulfhydryl oxidation must be considered as a major mechanism of NO action.

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Author notes

  1. Katja Becker and Savvas N. Savvides: K.B. and S.N.S. contributed equally to this study.

Authors and Affiliations

  1. Biochemistry Center, Im Neuenheimer Feld 328, University of Heidelberg, 69120, Heidelberg, Germany

    Katja Becker, Michael Keese & R. Heiner Schirmer

  2. Section of Biochemistry, Molecular and Cell Biology, 223 Biotechnology Building, Cornell University, Ithaca, New York, 14853, USA

    Savvas N. Savvides & P. Andrew Karplus

Authors
  1. Katja Becker
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  2. Savvas N. Savvides
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  3. Michael Keese
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  4. R. Heiner Schirmer
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  5. P. Andrew Karplus
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Correspondence to Katja Becker.

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Becker, K., Savvides, S., Keese, M. et al. Enzyme inactivation through sulfhydryl oxidation by physiologic NO-carriers. Nat Struct Mol Biol 5, 267–271 (1998). https://doi.org/10.1038/nsb0498-267

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