Autoregulation and Autoinhibition of the Main NO Synthase Isoforms (Brief Review).

IF 1.1 Q4 MEDICINE, RESEARCH & EXPERIMENTAL
Sovremennye Tehnologii v Medicine Pub Date : 2023-01-01 Epub Date: 2023-05-28 DOI:10.17691/stm2023.15.3.06
N A Popova, S K Soodaeva, I A Klimanov, V M Misharin, A A Temnov
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引用次数: 0

Abstract

Nitric oxide (II) (NO) is the most important mediator of a wide range of physiological and pathophysiological processes. It is synthesized by NO synthases (NOSs), which have three main isoforms differing from each other in terms of activation and inhibition features, levels of NO production, subcellular localization, etc. At the same time, all isoforms are structurally very similar, and these differences are determined by NOS autoregulatory elements. The article presents an analysis of the autoregulatory and autoinhibitory mechanisms of the NOS reductase domain that determine differences in the productivity of isoforms, as well as their dependence on the concentration of Ca2+ ions. The main regulatory elements in NOS that modulate the electron transfer from flavin to heme include calmodulin (CaM), an autoinhibitory insert (AI), and the C-terminal tail (C-tail). Hydrophobic interactions of CaM with the surface of the NOS oxidase domain are assumed to facilitate electron transfer from flavin mononucleotide (FMN). CaM binding causes a change in the inter-domain distances, a shift of AI and the C-tail, and, as a result, a decrease in their inhibitory effect. CaM also shifts the conformational equilibrium of the reductase domain towards more open conformations, reduces the lifetime of conformations, their stereometric distribution, and accelerates the flow of electrons through the reductase domain. The AI element, apparently, induces a conformational change that hinders electron transfer within the reductase domain, similar to the hinge domain in cytochrome P450. Together with CaM, the C-tail regulates the electron flow between flavins, the distance and relative orientation of isoalloxane rings, and also modulates the electron flow from FMN to the terminal acceptor. Together with the C-tail, AI also predetermines the dependence of neuronal and endothelial forms of NOS on the concentration of Ca2+ ions, and the C-tail length affects differences in the productivity of NO synthesis. The inhibitory effect of the C-tail is likely to be reduced by CaM binding due to the C-tail shift due to the electrostatic repulsive forces of the negatively charged phosphate and aspartate residues. The autoregulatory elements of NOS require further study, since the mechanisms of their interaction are complex and multidirectional, and hence provide a wide range of characteristics of the observed isoforms.

一氧化氮合酶主要异构体的自调节和自抑制(综述)
一氧化氮(II) (NO)是广泛的生理和病理生理过程中最重要的介质。它是由NO合成酶(NOSs)合成的,NOSs主要有三种亚型,在激活和抑制特征、NO产生水平、亚细胞定位等方面各不相同。同时,所有同种异构体在结构上非常相似,这些差异是由NOS自调节元件决定的。本文分析了NOS还原酶结构域的自调节和自抑制机制,这些机制决定了异构体生产力的差异,以及它们对ca2 +离子浓度的依赖。NOS中调节黄素向血红素电子转移的主要调控元件包括钙调素(CaM)、自抑制插入物(AI)和c端尾(C-tail)。CaM与NOS氧化酶结构域表面的疏水相互作用被认为促进了黄素单核苷酸(FMN)的电子转移。CaM结合引起域间距离的改变,导致AI和c尾的移位,从而降低了它们的抑制作用。CaM还使还原酶结构域的构象平衡向更开放的构象转移,减少了构象的寿命,减少了它们的立体分布,并加速了电子在还原酶结构域的流动。显然,AI元素诱导了一种构象变化,阻碍了还原酶结构域内的电子转移,类似于细胞色素P450中的铰链结构域。C-tail与CaM一起调节黄素之间的电子流、异四氧烷环的距离和相对取向,并调节从FMN到末端受体的电子流。与c尾一起,AI还预先决定了神经元和内皮形式的NOS对ca2 +离子浓度的依赖性,c尾长度影响NO合成效率的差异。由于带负电荷的磷酸基和天冬氨酸残基的静电斥力,c尾发生位移,CaM结合可能会降低c尾的抑制作用。NOS的自调节元件需要进一步研究,因为它们相互作用的机制是复杂和多向的,因此提供了观察到的同工型的广泛特征。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Sovremennye Tehnologii v Medicine
Sovremennye Tehnologii v Medicine MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
1.80
自引率
0.00%
发文量
38
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