Mechanism of Nitric Oxide Synthase Regulation: Electron Transfer and Interdomain Interactions.
Mechanism of Nitric Oxide Synthase Regulation: Electron Transfer and Interdomain Interactions.
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DOI：
10.1016/j.ccr.2011.10.011
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发表时间：
2012-02-01
影响因子：
20.6
通讯作者：
Feng C
中科院分区：
文献类型：
--
作者：
Feng C
一氧化氮合酶(NOS)是一种黄色素蛋白，在低浓度时作为血管扩张和神经传递的关键信号分子，在较高浓度时又作为一种防御性细胞毒素，对一氧化氮(NO)的合成具有严格的调控作用。INOS、eNOS和nNOS三种亚型(诱导型、内皮型和神经型)通过结构域间相互作用严格调控结构域间电子转移(IET)过程来实现其关键的生物学功能。特别是，FMN-血红素IET在还原酶区域的电子传递与血红素区域的NO合成的耦合中是必不可少的，因为它传递了催化血红素位置的O2激活所需的电子。令人信服的证据表明，钙调蛋白(CaM)通过使FMN结构域从被屏蔽的电子接受(输入)状态转变到新的电子给予(输出)状态来激活eNOS和nNOS中NO的合成，并且CaM也是结构域正确排列所必需的。一氧化氮合酶酶学中另一个令人兴奋的最新发展是发现FMN结构域运动在调节催化血红素活性部位的反应性和结构方面的重要性(除了控制IET过程的主要作用外)。在没有全长NOS结构的情况下，光谱(如脉冲EPR、MCD、共振拉曼)、快速动力学(激光闪光光解和停流)和突变方法的综合方法是解开FMN/heme结构域间相互作用的分子细节的关键。这是为了研究FMN结构域的动态构象变化以及主要功能FMN结构域与血红素结构域之间的对接在调节NOS活性中的作用。本综述的重点是对由联合方法驱动的一氧化氮合酶调控机制的理解的最新进展。对FMN/Home域间相互作用和CaM结合作用的深入理解可能是设计新的选择性一氧化氮合酶亚型抑制剂的基础。
Nitric oxide synthase (NOS), a flavo-hemoprotein, tightly regulates nitric oxide (NO) synthesis and thereby its dual biological activities as a key signaling molecule for vasodilatation and neurotransmission at low concentrations, and also as a defensive cytotoxin at higher concentrations. Three NOS isoforms, iNOS, eNOS and nNOS (inducible, endothelial, and neuronal NOS), achieve their key biological functions by tight regulation of interdomain electron transfer (IET) process via interdomain interactions. In particular, the FMN–heme IET is essential in coupling electron transfer in the reductase domain with NO synthesis in the heme domain by delivery of electrons required for O2 activation at the catalytic heme site. Compelling evidence indicates that calmodulin (CaM) activates NO synthesis in eNOS and nNOS through a conformational change of the FMN domain from its shielded electron-accepting (input) state to a new electron-donating (output) state, and that CaM is also required for proper alignment of the domains. Another exciting recent development in NOS enzymology is the discovery of importance of the the FMN domain motions in modulating reactivity and structure of the catalytic heme active site (in addition to the primary role of controlling the IET processes). In the absence of a structure of full-length NOS, an integrated approach of spectroscopic (e.g. pulsed EPR, MCD, resonance Raman), rapid kinetics (laser flash photolysis and stopped flow) and mutagenesis methods is critical to unravel the molecular details of the interdomain FMN/heme interactions. This is to investigate the roles of dynamic conformational changes of the FMN domain and the docking between the primary functional FMN and heme domains in regulating NOS activity. The recent developments in understanding of mechanisms of the NOS regulation that are driven by the combined approach are the focuses of this review. An improved understanding of the role of interdomain FMN/heme interaction and CaM binding may serve as the basis for the design of new selective inhibitors of NOS isoforms.
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影响因子：
64.8
作者：
Chen, Chun-An;Wang, Tse-Yao;Varadharaj, Saradhadevi;Reyes, Levy A.;Hemann, Craig;Talukder, M. A. Hassan;Chen, Yeong-Renn;Druhan, Lawrence J.;Zweier, Jay L.
通讯作者：
Zweier, Jay L.
影响因子：
2.9
作者：
Adir, N;Axelrod, HL;Feher, G
通讯作者：
Feher, G
DOI：
10.1073/pnas.012470099
发表时间：
2002-01-08
影响因子：
11.1
作者：
Adak, S;Bilwes, AM;Stuehr, DJ
通讯作者：
Stuehr, DJ
影响因子：
4.8
作者：
Albakri, QA;Stuehr, DJ
通讯作者：
Stuehr, DJ
影响因子：
4.8
作者：
Craig, DH;Chapman, SK;Daff, S
通讯作者：
Daff, S