Kinetic and Cellular Characterization of Novel Inhibitors of S-Nitrosoglutathione Reductase
Kinetic and Cellular Characterization of Novel Inhibitors of S-Nitrosoglutathione Reductase
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DOI：
10.1074/jbc.m109.019919
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发表时间：
2009-09-04
影响因子：
4.8
通讯作者：
Sanghani, Sonal P.
中科院分区：
文献类型：
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作者：
Sanghani, Paresh C.;Davis, Wilhelmina I.;Sanghani, Sonal P.
S-亚硝基谷胱甘肽还原酶 (GSNOR) 是一种醇脱氢酶，参与体内 S-亚硝基硫醇 (SNO) 的调节。小鼠敲除研究表明，GSNOR 调节气道平滑肌张力以及肺和心脏中 β-肾上腺素能受体的功能。 GSNOR 已成为开发治疗肺部和心血管疾病的治疗方法的目标。我们报告了三种化合物，它们将 GSNOR 底物 S-亚硝基谷胱甘肽 (GSNO) 排除在 GSNOR 的结合位点之外，并导致 SNO 在细胞内积累。新抑制剂选择性抑制乙醇脱氢酶中的 GSNOR。使用这些抑制剂，我们证明 GSNOR 限制一氧化氮介导的 NF-κ B 抑制和可溶性鸟苷酸环化酶的激活。我们的研究结果表明 GSNOR 抑制剂是调节一氧化氮生物活性和评估 SNO 在体内作用的新工具。
S-Nitrosoglutathione reductase (GSNOR) is an alcohol dehydrogenase involved in the regulation of S-nitrosothiols (SNOs) in vivo. Knock-out studies in mice have shown that GSNOR regulates the smooth muscle tone in airways and the function of beta-adrenergic receptors in lungs and heart. GSNOR has emerged as a target for the development of therapeutic approaches for treating lung and cardiovascular diseases. We report three compounds that exclude GSNOR substrate, S-nitrosoglutathione (GSNO) from its binding site in GSNOR and cause an accumulation of SNOs inside the cells. The new inhibitors selectively inhibit GSNOR among the alcohol dehydrogenases. Using the inhibitors, we demonstrate that GSNOR limits nitric oxide-mediated suppression of NF-kappa B and activation of soluble guanylyl cyclase. Our findings reveal GSNOR inhibitors to be novel tools for regulating nitric oxide bioactivity and assessing the role of SNOs in vivo.