On the activation of soluble guanylyl cyclase by nitric oxide
On the activation of soluble guanylyl cyclase by nitric oxide
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DOI：
10.1073/pnas.012368499
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发表时间：
2002-01-08
影响因子：
11.1
通讯作者：
Garthwaite, J
中科院分区：
文献类型：
--
作者：
Bellamy, TC;Wood, J;Garthwaite, J
可溶性鸟苷酸环化酶（sGC）是细胞间信使一氧化氮（NO）的主要细胞受体，并通过升高细胞内cGMP水平介导广泛的生理效应。对于我们理解NO信号如何被感受性细胞解码并转化为有用的生理反应的关键是对NO激活sGC的机制的分子和动力学细节的理解。已知NO与受体上的血红素辅基结合并引发构象变化，从而使cGMP合成的催化作用增加数百倍。血红素在β 1亚基的His-105处共价连接到sGC，并且先前认为NO对sGC的活化分两步进行：NO与血红素结合以形成双配体状态，然后断裂与His-105的键，从而触发催化活性的增加。最近对sGC活化动力学的研究[Zhao，Y.，布兰迪什，体育，D.C.，D. P. & Marletta，M. A.等人（1999）Proc. Acad. Sci. USA，96，14753-14758]，然而，提出了NO调节sGC活性的另外的机制，即通过影响His-105键的裂解速率。假设酶上存在第二个（未鉴定的）NO结合位点，并建议对细胞NO信号转导至关重要。在这里，我们表明，这是不必要的假设任何这样的额外的机制，因为所获得的结果是预测的sGC激活与一个单一的NO结合事件的简单模型。
Soluble guanylyl cyclase (sGC) is the major cellular receptor for the intercellular messenger nitric oxide (NO) and mediates a wide range of physiological effects through elevation of intracellular cGMP levels. Critical to our understanding of how NO signals are decoded by receptive cells and translated into a useful physiological response is an appreciation of the molecular and kinetic details of the mechanism by which NO activates sGC. It is known that NO binds to a haem prosthetic group on the receptor and triggers a conformational change that increases the catalysis of cGMP synthesis by several hundred-fold. The haem is covalently attached to sGC at His-105 of the beta1 subunit, and it was thought previously that activation of sGC by NO occurs in two steps: binding of NO to the haem to form a biliganded state and then rupture of the bond to His-105 triggering an increase in catalytic activity. A recent investigation of the kinetics of sGC activation [Zhao, Y., Brandish, P. E., Ballou, D. P. & Marletta, M. A. (1999) Proc. Natl. Acad. Sci. USA, 96, 14753-14758], however, proposed an additional mechanism by which NO regulates sGC activity, namely, by influencing the rate of cleavage of the His-105 bond. The existence of a second (unidentified) NO-binding site on the enzyme was hypothesized and suggested to be fundamental to cellular NO-signal transduction. Here, we show that it is unnecessary to postulate any such additional mechanism because the results obtained are predicted by the simpler model of sGC activation with a single NO-binding event.