YC-1 activation of human soluble guanylyl cyclase has both heme-dependent and heme-independent components
YC-1 activation of human soluble guanylyl cyclase has both heme-dependent and heme-independent components
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DOI：
10.1073/pnas.231486198
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发表时间：
2001-11-06
影响因子：
11.1
通讯作者：
Murad, F
中科院分区：
文献类型：
--
作者：
Martin, E;Lee, YC;Murad, F
YC-1 [3-（5 '-羟甲基-2'-呋喃基）-1-苄基吲唑]是可溶性鸟苷酸环化酶（sGC）的变构激活剂。YC-1增加了酶的催化速率，并使酶对其气态活化剂一氧化氮或一氧化碳敏感。在其他研究中，对实验动物施用YC-1导致富含血小板的血栓形成的抑制和平均动脉压的降低，这与cGMP水平的增加相关。然而，YC-1与sGC相互作用和酶激活的细节是不完整的。尽管文献中的证据表明YC-1对sGC的激活是严格的血红素依赖性的，但本报告提供了YC-1对sGC的血红素依赖性和血红素非依赖性激活的证据。1H-（1，2，4）恶二唑（4，3-a）喹喔啉-1-酮对sGC血红素的氧化完全抑制了对NO的反应，但仅部分减弱了YC-1的激活。我们还观察到YC-1对缺乏血红素的突变型sGC的激活。这些发现表明，YC-1激活sGC可以发生独立的血红素，但激活显着增加时，血红素部分存在于酶。
YC-1 [3-(5'-hydroxymethyl-2'furyl)-1-benzyl indazole] is an allosteric activator of soluble guanylyl cyclase (sGC). YC-1 increases the catalytic rate of the enzyme and sensitizes the enzyme toward its gaseous activators nitric oxide or carbon monoxide. In other studies the administration of YC-1 to experimental animals resulted in the inhibition of the platelet-rich thrombosis and a decrease of the mean arterial pressure, which correlated with increased cGMP levels. However, details of YC-1 interaction with sGC and enzyme activation are incomplete. Although evidence in the literature indicates that YC-1 activation of sGC is strictly heme-dependent, this report presents evidence for both heme-dependent and heme-independent activation of sGC by YC-1. The oxidation of the sGC heme by 1H-(1,2,4)oxadiazole(4,3-a)quinoxalin-1-one completely inhibited the response to NO, but only partially attenuated activation by YC-1. We also observed activation by YC-1 of a mutant sGC, which lacks heme. These findings indicate that YC-1 activation of sGC can occur independently of heme, but that activation is substantially increased when the heme moiety is present in the enzyme.