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Selected Works of Eric Underbakke
Article
Heme-assisted S-Nitrosation Desensitizes Ferric Soluble Guanylate Cyclase to Nitric Oxide
Journal of Biological Chemistry (2012)
  • Nathaniel B. Fernhoff, University of California, Berkeley
  • Emily R. Derbyshire, University of California, Berkeley
  • Eric S. Underbakke, University of California, Berkeley
  • Michael A. Marletta, The Scripps Research Institute
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Abstract
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 (Fe2+) oxidation state of the sGC heme cofactor and stimulates formation of cGMP several hundred-fold. Oxidation of the sGC heme to the ferric (Fe3+) 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.
Disciplines
Publication Date
2012
DOI
10.1074/jbc.M112.393892
Publisher Statement
This research was originally published in Journal of Biological Chemistry. Nathaniel B. Fernhoff, Emily R. Derbyshire, Eric S. Underbakke and Michael A. Marletta. Heme-assisted S-Nitrosation Desensitizes Ferric Soluble Guanylate Cyclase to Nitric Oxide. Journal of Biological Chemistry. 2012; 287:43053-43062. © the American Society for Biochemistry and Molecular Biology
Citation Information
Nathaniel B. Fernhoff, Emily R. Derbyshire, Eric S. Underbakke and Michael A. Marletta. "Heme-assisted S-Nitrosation Desensitizes Ferric Soluble Guanylate Cyclase to Nitric Oxide" Journal of Biological Chemistry Vol. 287 Iss. 51 (2012) p. 43053 - 43062
Available at: http://works.bepress.com/eric-underbakke/4/