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Heme-assisted S-nitrosation desensitizes ferric soluble guanylate cyclase to nitric oxide.

Publication ,  Journal Article
Fernhoff, NB; Derbyshire, ER; Underbakke, ES; Marletta, MA
Published in: The Journal of biological chemistry
December 2012

Nitric oxide (NO) signaling regulates key processes in cardiovascular physiology, specifically vasodilation, platelet aggregation, and leukocyte rolling. Soluble guanylate cyclase (sGC), the mammalian NO sensor, transduces an NO signal into the classical second messenger cyclic GMP (cGMP). NO binds to the ferrous (Fe(2+)) oxidation state of the sGC heme cofactor and stimulates formation of cGMP several hundred-fold. Oxidation of the sGC heme to the ferric (Fe(3+)) state desensitizes the enzyme to NO. The heme-oxidized state of sGC has emerged as a potential therapeutic target in the treatment of cardiovascular disease. Here, we investigate the molecular mechanism of NO desensitization and find that sGC undergoes a reductive nitrosylation reaction that is coupled to the S-nitrosation of sGC cysteines. We further characterize the kinetics of NO desensitization and find that heme-assisted nitrosothiol formation of β1Cys-78 and β1Cys-122 causes the NO desensitization of ferric sGC. Finally, we provide evidence that the mechanism of reductive nitrosylation is gated by a conformational change of the protein. These results yield insights into the function and dysfunction of sGC in cardiovascular disease.

Duke Scholars

Published In

The Journal of biological chemistry

DOI

EISSN

1083-351X

ISSN

0021-9258

Publication Date

December 2012

Volume

287

Issue

51

Start / End Page

43053 / 43062

Related Subject Headings

  • Sulfhydryl Compounds
  • Soluble Guanylyl Cyclase
  • Receptors, Cytoplasmic and Nuclear
  • Rats
  • Protein Binding
  • Oxidation-Reduction
  • Nucleotides
  • Nitrosation
  • Nitric Oxide
  • Mutant Proteins
 

Citation

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Fernhoff, N. B., Derbyshire, E. R., Underbakke, E. S., & Marletta, M. A. (2012). Heme-assisted S-nitrosation desensitizes ferric soluble guanylate cyclase to nitric oxide. The Journal of Biological Chemistry, 287(51), 43053–43062. https://doi.org/10.1074/jbc.m112.393892
Fernhoff, Nathaniel B., Emily R. Derbyshire, Eric S. Underbakke, and Michael A. Marletta. “Heme-assisted S-nitrosation desensitizes ferric soluble guanylate cyclase to nitric oxide.The Journal of Biological Chemistry 287, no. 51 (December 2012): 43053–62. https://doi.org/10.1074/jbc.m112.393892.
Fernhoff NB, Derbyshire ER, Underbakke ES, Marletta MA. Heme-assisted S-nitrosation desensitizes ferric soluble guanylate cyclase to nitric oxide. The Journal of biological chemistry. 2012 Dec;287(51):43053–62.
Fernhoff, Nathaniel B., et al. “Heme-assisted S-nitrosation desensitizes ferric soluble guanylate cyclase to nitric oxide.The Journal of Biological Chemistry, vol. 287, no. 51, Dec. 2012, pp. 43053–62. Epmc, doi:10.1074/jbc.m112.393892.
Fernhoff NB, Derbyshire ER, Underbakke ES, Marletta MA. Heme-assisted S-nitrosation desensitizes ferric soluble guanylate cyclase to nitric oxide. The Journal of biological chemistry. 2012 Dec;287(51):43053–43062.

Published In

The Journal of biological chemistry

DOI

EISSN

1083-351X

ISSN

0021-9258

Publication Date

December 2012

Volume

287

Issue

51

Start / End Page

43053 / 43062

Related Subject Headings

  • Sulfhydryl Compounds
  • Soluble Guanylyl Cyclase
  • Receptors, Cytoplasmic and Nuclear
  • Rats
  • Protein Binding
  • Oxidation-Reduction
  • Nucleotides
  • Nitrosation
  • Nitric Oxide
  • Mutant Proteins