Insight into the rescue of oxidized soluble guanylate cyclase by the activator cinaciguat.
Insight into the rescue of oxidized soluble guanylate cyclase by the activator cinaciguat.
复制标题
DOI：
10.1002/cbic.201100809
复制
发表时间：
2012-05-07
期刊：
影响因子：
3.2
通讯作者：
Marletta, Michael A.
中科院分区：
文献类型：
--
作者：
Surmeli, Nur Basak;Marletta, Michael A.
可溶性鸟苷酸环化酶（sGC）是哺乳动物一氧化氮（NO）信号通路的关键受体，参与血管舒张、血小板聚集和神经传递等重要生理过程。[1-5] NO直接激活sGC，导致鸟苷5′-三磷酸（GTP）生成第二信使环鸟苷3′，5′-单磷酸（cGMP）增加，进而介导上述多种生理功能。[6] sGC是一种异二聚体血红蛋白；最常见的是α1/β1异构体。β1亚基的n端含有血红素-一氧化氮/氧结合（H-NOX）结构域，这是一种在原核生物和真核生物中发现的保守气敏结构域。[7-9] α1和β1亚基的c端共同形成催化结构域，负责依赖Mg2+的GTP转化为cGMP。NO通过与H-NOX结构域的亚铁血红素结合而激活sGC，导致Fe2+-His键的断裂。[9-11]亚铁血红素对no介导的sGC功能至关重要；NO是铁sGC的差配体，不能激活酶。[12,13] sGC具有很强的抗分子氧（O2）氧化性；不能形成铁氧配合物当然有助于这种稳定性。然而，在氧化应激条件下，活性氧可以氧化sGC血红素，导致病变组织对NO的敏感性降低。[14-16]这种对NO的脱敏导致对NO供体的治疗产生耐受性。[17-19]虽然体内sGC氧化的程度尚不清楚，但病理条件下sGC的氧化被认为是心血管疾病发展和no -供体治疗有效性降低的重要因素。[17-19]因此，sGC已成为治疗心血管和肺部疾病的一个有前景的药理靶点。[17,19,20]自从sGC作为心血管疾病的治疗靶点出现以来，已经开发了两类分子：sGC刺激剂和sGC激活剂。sGC刺激剂，如YC-1（发现的第一个sGC刺激剂）和BAY 41-2272，直接作用于天然的亚铁sGC。[21-24]相比之下，最近发现的sGC活化剂，如BAY 58-2667 （cinaciguat，图1A）和HMR-1766，对氧化（铁）和/或不含血红素的sGC都有影响。[25,26]其中一种活化剂Cinaciguat可以使氧化和/或载脂蛋白sGC的活性增加200倍先前的研究表明，cinaciguat与sGC的铁态、铁态和载子态结合，但只激活sGC的氧化态或载子态
Soluble guanylate cyclase (sGC) is a key receptor in the mammalian nitric oxide (NO) signaling pathway, which is involved in important physiological processes such as vasodilation, platelet aggregation, and neurotransmission.[1–5] NO directly activates sGC, leading to increased formation of the second messenger cyclic guanosine 3′, 5′-monophosphate (cGMP) from guanosine 5′-triphosphate (GTP), which goes on to mediate the diverse physiological functions noted above.[6] sGC is a heterodimeric hemoprotein; most commonly found as the α1/β1 isoform. The N-terminus of the β1 subunit contains a Heme-Nitric oxide/OXygen binding (H-NOX) domain, a conserved gas-sensing domain found in prokaryotes and eukaryotes.[7–9] The C-termini of the α1 and β1 subunits together form the catalytic domain that is responsible for the Mg2+-dependent conversion of GTP to cGMP. NO activates sGC by binding to the ferrous heme in the H-NOX domain leading to the cleavage of the Fe2+-His bond.[9–11] Ferrous heme is essential for NO-mediated sGC function; NO is a poor ligand for ferric sGC and does not activate the enzyme.[12, 13] sGC is highly resistant to oxidation by molecular oxygen (O2); the inability to form a ferrous-oxy complex certainly contributes to this stability. However, reactive oxygen species can oxidize sGC heme under conditions of oxidative stress, leading to a decreased sensitivity to NO in the diseased tissue.[14–16] This desensitization to NO, results in tolerance to treatments involving NO-donors.[17–19] While the extent of sGC oxidation in vivo is not known, oxidation of sGC under pathological conditions is thought to be an important contributor to the development of cardiovascular disorders and the decrease in effectiveness of treatments involving NO-donors.[17–19] Therefore, sGC has emerged as a promising pharmacological target for the treatment of cardiovascular and pulmonary disorders.[17, 19, 20]Since the emergence of sGC as a therapeutic target for cardiovascular disease, two classes of molecules have been developed: sGC stimulators and sGC activators. sGC stimulators, such as YC-1, the first sGC stimulator discovered, and BAY 41–2272, act directly on native, ferrous sGC.[21–24] In contrast, recently discovered sGC activators, such as BAY 58–2667 (cinaciguat, Figure 1A) and HMR-1766, have effects on both oxidized (ferric) and/or hemefree sGC.[25, 26] Cinaciguat, one such activator, can cause a 200-fold increase in the activity of oxidized and/or apo sGC.[25] Previous studies have shown that cinaciguat binds to the ferrous, ferric and apo states of sGC, but only activates the oxidized or apo forms of the
登录
查看更多内容
影响因子：
11.4
作者：
Ma, Xiaolei;Sayed, Nazish;van den Akker, Focco
通讯作者：
van den Akker, Focco
影响因子：
15.9
作者：
Stasch, Johannes-Peter;Schmidt, Peter M.;Schmidt, Harald H. H. W.
通讯作者：
Schmidt, Harald H. H. W.
影响因子：
37.8
作者：
Stasch JP;Pacher P;Evgenov OV
通讯作者：
Evgenov OV
DOI：
10.1016/0304-4165(82)90008-3
发表时间：
1982-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
IGNARRO, LJ;DEGNAN, JN;WOLIN, MS
通讯作者：
WOLIN, MS
影响因子：
7.3
作者：
Roy, B.;Mo, E.;Garthwaite, J.
通讯作者：
Garthwaite, J.