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A nitric oxide/cysteine interaction mediates the activation of soluble guanylate cyclase.

Publication ,  Journal Article
Fernhoff, NB; Derbyshire, ER; Marletta, MA
Published in: Proceedings of the National Academy of Sciences of the United States of America
December 2009

Nitric oxide (NO) regulates a number of essential physiological processes by activating soluble guanylate cyclase (sGC) to produce the second messenger cGMP. The mechanism of NO sensing was previously thought to result exclusively from NO binding to the sGC heme; however, recent studies indicate that heme-bound NO only partially activates sGC and additional NO is involved in the mechanism of maximal NO activation. Furthermore, thiol oxidation of sGC cysteines results in the loss of enzyme activity. Herein the role of cysteines in NO-stimulated sGC activity investigated. We find that the thiol modifying reagent methyl methanethiosulfonate specifically inhibits NO activation of sGC by blocking a non-heme site, which defines a role for sGC cysteine(s) in mediating NO binding. The nature of the NO/cysteine interaction was probed by examining the effects of redox active reagents on NO-stimulated activity. These results show that NO binding to, and dissociation from, the critical cysteine(s) does not involve a change in the thiol redox state. Evidence is provided for non-heme NO in the physiological activation of sGC in context of a primary cell culture of human umbilical vein endothelial cells. These findings have relevance to diseases involving the NO/cGMP signaling pathway.

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Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

December 2009

Volume

106

Issue

51

Start / End Page

21602 / 21607

Related Subject Headings

  • Soluble Guanylyl Cyclase
  • Receptors, Cytoplasmic and Nuclear
  • Rats
  • Oxidation-Reduction
  • Nitric Oxide
  • Indicators and Reagents
  • Humans
  • Guanylate Cyclase
  • Enzyme Activation
  • Cysteine
 

Citation

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Fernhoff, N. B., Derbyshire, E. R., & Marletta, M. A. (2009). A nitric oxide/cysteine interaction mediates the activation of soluble guanylate cyclase. Proceedings of the National Academy of Sciences of the United States of America, 106(51), 21602–21607. https://doi.org/10.1073/pnas.0911083106
Fernhoff, Nathaniel B., Emily R. Derbyshire, and Michael A. Marletta. “A nitric oxide/cysteine interaction mediates the activation of soluble guanylate cyclase.Proceedings of the National Academy of Sciences of the United States of America 106, no. 51 (December 2009): 21602–7. https://doi.org/10.1073/pnas.0911083106.
Fernhoff NB, Derbyshire ER, Marletta MA. A nitric oxide/cysteine interaction mediates the activation of soluble guanylate cyclase. Proceedings of the National Academy of Sciences of the United States of America. 2009 Dec;106(51):21602–7.
Fernhoff, Nathaniel B., et al. “A nitric oxide/cysteine interaction mediates the activation of soluble guanylate cyclase.Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 51, Dec. 2009, pp. 21602–07. Epmc, doi:10.1073/pnas.0911083106.
Fernhoff NB, Derbyshire ER, Marletta MA. A nitric oxide/cysteine interaction mediates the activation of soluble guanylate cyclase. Proceedings of the National Academy of Sciences of the United States of America. 2009 Dec;106(51):21602–21607.
Journal cover image

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

December 2009

Volume

106

Issue

51

Start / End Page

21602 / 21607

Related Subject Headings

  • Soluble Guanylyl Cyclase
  • Receptors, Cytoplasmic and Nuclear
  • Rats
  • Oxidation-Reduction
  • Nitric Oxide
  • Indicators and Reagents
  • Humans
  • Guanylate Cyclase
  • Enzyme Activation
  • Cysteine