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首页> 外文期刊>The Biochemical Journal >Effects of nitroglycerin/L-cysteine on soluble guanylate cyclase: evidence for an activation/inactivation equilibrium controlled by nitric oxide binding and haem oxidation.
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Effects of nitroglycerin/L-cysteine on soluble guanylate cyclase: evidence for an activation/inactivation equilibrium controlled by nitric oxide binding and haem oxidation.

机译:硝酸甘油/ L-半胱氨酸对可溶性鸟苷酸环化酶的影响:一氧化氮结合和血红素氧化控制激活/失活平衡的证据。

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摘要

GTN (nitroglycerin; glycerol trinitrate) causes dilation of blood vessels via activation of nitric oxide (NO)-sensitive sGC (soluble guanylate cyclase), a heterodimeric haem protein that catalyses the conversion of GTP into cGMP. Activation of sGC by GTN requires enzymatic or non-enzymatic bioactivation of the nitrate. Based on insufficient NO release and lack of spectroscopic evidence for formation of NO-sGC, the cysteine (Cys)-dependent activation of sGC by GTN was proposed to occur in an NO-independent manner. This extraordinary claim is questioned by the present findings. First, the effect of GTN/Cys was blocked by the NO scavenger oxyhaemoglobin, the superoxide-generating compound flavin mononucleotide and the haem-site sGC inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one). Secondly, at equi-effective concentrations, GTN/Cys and the NO donor 2,2-diethyl-1-nitroso-oxyhydrazine released identical amounts of NO. Finally, at sufficiently high rates of NO release, activation of sGC by GTN/Cyswas accompanied by a shift of the Soret band from 431 to 399 nm, indicating formation of NO-sGC. In the absence of Cys, GTN caused haem oxidation, apparent as a shift of the Soret band to 392 nm, which was accompanied by inactivation of the NO-stimulated enzyme. These results suggest that the effect of GTN/Cys is the result of an activation/inactivation equilibrium that is controlled by the rate of NO release and haem oxidation.
机译:GTN(硝酸甘油;三硝酸甘油)通过一氧化氮(NO)敏感的sGC(可溶性鸟苷酸环化酶)的活化引起血管扩张,sGC是一种异二聚体血红素蛋白,可催化GTP转化为cGMP。 GTN对sGC的激活需要对硝酸盐进行酶促或非酶促生物激活。基于NO释放不足和形成NO-sGC的光谱学证据不足,提出了GTN的半胱氨酸(Cys)依赖性激活sGC以NO非依赖性方式发生。这一发现对这一非同寻常的主张提出了质疑。首先,GNO / Cys的作用被NO清除剂血红蛋白,产生超氧化物的黄素单核苷酸和血红素位sGC抑制剂ODQ(1H- [1,2,4]恶二唑并[4,3-a]喹喔啉-1一)。其次,在同等有效浓度下,GTN / Cys和NO供体2,2-二乙基-1-亚硝基氧基肼释放出相同量的NO。最后,在足够高的NO释放速率下,GTN / Cys对sGC的激活伴随有Soret谱带从431 nm到399 nm的转变,表明NO-sGC的形成。在没有Cys的情况下,GTN引起血红素氧化,明显是Soret谱带移至392 nm,同时伴随着NO刺激酶的失活。这些结果表明,GTN / Cys的作用是活化/失活平衡的结果,该平衡受NO释放和血红素氧化的速率控制。

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