Kinetic and Cellular Characterization of Novel Inhibitors of S-Nitrosoglutathione Reductase

We report three compounds that exclude GSNOR substrate, S-nitrosoglutathione from its binding site in GSNOR and cause an accumulation of SNOs inside the cells

Paresh C. Sanghani

2009

Scholarcy highlights

  • GSNOR has become an important target for developing agents that modulate NO bioactivity inside cells
  • We demonstrate that GSNOR limits nitric oxide-mediated suppression of NF-␬B and activation of soluble guanylyl cyclase
  • Among the key cellular processes regulated by GSNOR are the activation of the transcription factor NF-␬B and soluble guanylyl cyclase
  • GSNOR—A high throughput screening approach was used for identifying novel inhibitors of GSNOR
  • Screening for GSNOR inhibitors was performed in the presence of saturating and unsaturating concentrations of NADϩ and the alcohol substrate, octanol, to increase the probability of identifying compounds that bind only in the GSNO binding site of GSNOR
  • Our studies reveal that denitrosylation affected by GSNOR limits the NO-mediated activation of guanylyl cyclase and the suppression of NF-␬B
  • We report novel tools that regulate GSNOR function inside the cells that will allow exploration of the cellular and pharmacological effects of inhibiting an important nitric oxide deactivation pathway

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