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Biological roles and mechanisms of nitric oxide reactions with iron-sulfur cluster transcriptional regulators

一氧化氮与铁硫簇转录调节因子反应的生物学作用和机制

基本信息

批准号：
BB/J003247/1
负责人：
Nicolas Le Brun
金额：
$ 44.93万
依托单位：
University of East Anglia
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FJ003247%2F1
关键词：
Biological roles mechanisms nitric oxide

项目摘要

Nitric oxide is a poisonous molecule that is generated by soil bacteria and in our bodies as a defence against pathogenic organisms trying to establish infection. One of the major ways by which nitric oxide exerts its toxic effects is through reaction with a widespread group of proteins that contain a type of cofactor made from both iron and sulfur (called an iron-sulfur cluster). Members of this group play crucial roles in a very wide range of cellular processes. To avoid nitric oxide toxicity, disease-causing (as well as benign) bacteria have evolved protective systems that function to detoxify nitric oxide by removing it through chemical reaction. The fact that iron-sulfur cofactors are particularly sensitive to nitric oxide has been exploited in Nature, through the evolution of a number of regulatory proteins that themselves contain an iron-sulfur cluster and which function as biological switches, turning on the cellular nitric oxide detoxification response in the presence of nitric oxide. Despite the importance and widespread nature of the reaction of iron-sulfur clusters with NO, very little is known about this reaction process. This application is focussed on understanding how NO-responsive iron-sulfur cluster-containing regulators function. Here, we propose to investigate two such regulators (called WhiD and NsrR). One (WhiD) is a member of a family of proteins that are found only in a small number of bacteria (including Mycobacteria tuberculosis, the causative agent of tuberculosis, one of the world's major killers, and Streptomyces coelicolor, the source of many of the antibiotics currently in use in the clinic). Members of this protein family are known to play key roles in these bacteria in cell developmental processes associated with stress response, and are crucial for the ability of M. tuberculosis to survive in the inhospitable environment of a human host for years, in a dormant state that is highly resistant to antibiotics. The other (NsrR), is a member of a widely distributed but largely unstudied family of regulators. It functions as a primary NO sensor by controlling the cellular response to NO toxicity. Recent work in our laboratories has revealed important new insight into the nature of these regulatory proteins, including, for the first time, detailed mechanistic information about the reaction of a protein-bound iron-sulfur cluster with nitric oxide, leading to the formation of previously unreported products. We now propose to exploit these recent advances to explore, using a wide range of methods, the biochemistry of the reaction of NO with these proteins. This will reveal unprecedented mechanistic insight into how NO-sensing regulatory proteins function, and provide information that will be of general importance for all iron-sulfur protein NO reactions.

一氧化氮是一种有毒分子，由土壤细菌产生，并在我们体内作为防御病原体试图建立感染的防御。一氧化氮发挥其毒性作用的主要途径之一是通过与一组广泛存在的蛋白质发生反应，这些蛋白质含有一种由铁和硫组成的辅助因子（称为铁硫簇）。这个群体的成员在非常广泛的细胞过程中起着至关重要的作用。为了避免一氧化氮中毒，致病（以及良性）细菌已经进化出保护系统，通过化学反应去除一氧化氮来解毒。铁硫辅助因子对一氧化氮特别敏感的事实已经在《自然》杂志上被利用，通过一些调节蛋白的进化，这些蛋白本身含有铁硫簇，并作为生物开关，在一氧化氮存在的情况下开启细胞一氧化氮解毒反应。尽管铁硫簇与NO反应的重要性和广泛性，但对这一反应过程知之甚少。该应用程序的重点是了解no响应的含铁硫簇调节剂的功能。在这里，我们建议调查两个这样的监管机构（称为WhiD和NsrR）。其中一种（WhiD）是仅在少数细菌（包括结核分枝杆菌，结核病的病原体，世界主要杀手之一）中发现的一个蛋白质家族的成员，以及目前临床上使用的许多抗生素的来源——色链霉菌。已知该蛋白家族的成员在这些细菌与应激反应相关的细胞发育过程中发挥关键作用，并且对于结核分枝杆菌在人类宿主的恶劣环境中存活多年，处于对抗生素具有高度抗性的休眠状态的能力至关重要。另一个（NsrR）是一个分布广泛但基本上未被研究过的监管家族的成员。它通过控制细胞对NO毒性的反应而发挥主要NO传感器的作用。我们实验室最近的工作揭示了对这些调节蛋白性质的重要新见解，包括首次提供了蛋白质结合铁硫簇与一氧化氮反应的详细机制信息，导致以前未报道的产物的形成。我们现在建议利用这些最新的进展来探索，使用广泛的方法，NO与这些蛋白质反应的生物化学。这将揭示前所未有的NO感应调节蛋白如何发挥作用的机制，并提供对所有铁硫蛋白NO反应具有普遍重要性的信息。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Differentiated, Promoter-specific Response of [4Fe-4S] NsrR DNA Binding to Reaction with Nitric Oxide.

DOI：
10.1074/jbc.m115.693192
发表时间：
2016-04-15
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Crack JC;Svistunenko DA;Munnoch J;Thomson AJ;Hutchings MI;Le Brun NE
通讯作者：
Le Brun NE

Probing the mechanism of the dedicated NO sensor [4Fe-4S] NsrR: the effect of cluster ligand environment

DOI：
10.1016/j.jinorgbio.2023.112457
发表时间：
2024-01-03
期刊：
JOURNAL OF INORGANIC BIOCHEMISTRY
影响因子：
3.9
作者：
Dodd，Erin L.;Le Brun，Nick E.
通讯作者：
Le Brun，Nick E.

NsrR from Streptomyces coelicolor is a nitric oxide-sensing [4Fe-4S] cluster protein with a specialized regulatory function.

DOI：
10.1074/jbc.m115.643072
发表时间：
2015-05-15
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Crack JC;Munnoch J;Dodd EL;Knowles F;Al Bassam MM;Kamali S;Holland AA;Cramer SP;Hamilton CJ;Johnson MK;Thomson AJ;Hutchings MI;Le Brun NE
通讯作者：
Le Brun NE

Biochemical properties of Paracoccus denitrificans FnrP: reactions with molecular oxygen and nitric oxide.