Modelling carbon core metabolism in Bacillus subtilis - exploring the contribution of protein complexes in core carbon and nitrogen metabolism

模拟枯草芽孢杆菌的碳核心代谢 - 探索蛋白质复合物在核心碳和氮代谢中的贡献

• 批准号: BB/I004572/1
• 负责人: Richard Lewis
• 金额: $ 82.34万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI004572%2F1
• 关键词: Modelling; carbon; core; metabolism; Bacillus

In this proposal, we aim to combine data obtained by direct experimentation with mathematical models that seek to predict the behaviour of central carbon metabolism in a model bacterium. This interplay between biologists and mathematicians, using a systems level approach, provides a potentially powerful tool for characterising biological processes. The system that we seek to understand is that of central carbon metabolism - the means by which nutrients are converted into energy - in the model Gram+ bacterium called Bacillus subtilis. B. subtilis has been particularly well studied and thus acts as a highly amenable model organism for studies of bacterial physiology. In our consortium, which brings together biologists from complementary disciplines and mathematicians, we will focus on the way in which carbon is assimilated by this organism and the interplay between carbon and nitrogen metabolism. In recent years it has become clear that many key aspects of physiology are regulated not by discrete enzymes, but by multi-component complexes. Central to this research proposal is the way in which many of the key enzymes in carbon/nitrogen assimilation may function as complexes. We seek to identify and validate these complexes in metabolism. These macromolecular complexes are likely to confer special properties to the enzymatic reactions that are catalysed by these essential proteins. For instance, maintaining two enzymes that catalyse consecutive steps in the biochemical pathway of carbon/nitrogen metabolism in a tightly-associated complex may increase the rate at which substrate A is converted to product C via intermediate B through the process of substrate channeling. Although it may seem intuitive that this ought to be the case, it has not been demonstrated unequivocally. Moreover, these essential protein:protein complexes may change composition depending on the energy status of the cell, a possibility that has yet to be explored. Consequently, by a series of experiments designed to identify key complexes, we will assess the impact on the life cycle of the organism by targeted disruption by mutagenesis of interface regions. By feeding strands of data from a variety of sources into a computer model that aims to describe the metabolic pathway on a mathematical basis, we can use the model to form a hypothesis about the likely effect of changes to the system, and then go back to the laboratory to test these predictions. Central to our aims is the description of key biochemical parameters that define the interactions between proteins for the completion of the computer model in the most robust form, and also to determine the 3-dimensional structures of key complexes so that we can place a cellular phenomenon on an atomic scale.

在这个提议中，我们的目标是将通过直接实验获得的联合收割机数据与寻求预测模型细菌中中心碳代谢行为的数学模型相结合。生物学家和数学家之间的这种相互作用，使用系统水平的方法，提供了一个潜在的强大的工具，表征生物过程。我们试图理解的系统是中心碳代谢-营养物质转化为能量的方式-在称为枯草芽孢杆菌的革兰氏阳性菌模型中。B。枯草芽孢杆菌已经被特别好地研究，因此作为细菌生理学研究的高度顺从的模式生物。在我们的联盟中，来自互补学科的生物学家和数学家聚集在一起，我们将重点关注这种生物体吸收碳的方式以及碳和氮代谢之间的相互作用。近年来，已经清楚的是，生理学的许多关键方面不是由离散的酶调节，而是由多组分复合物调节。这项研究建议的核心是碳/氮同化中的许多关键酶可能作为复合物发挥作用的方式。我们试图在代谢中识别和验证这些复合物。这些大分子复合物可能赋予这些必需蛋白质催化的酶促反应特殊性质。例如，将催化碳/氮代谢的生物化学途径中的连续步骤的两种酶保持在紧密结合的复合物中，可以增加底物A通过底物通道化过程经由中间体B转化为产物C的速率。虽然这似乎是直觉，应该是这样的，但它并没有得到明确的证明。此外，这些必需的蛋白质：蛋白质复合物可能会根据细胞的能量状态改变组成，这种可能性尚未被探索。因此，通过一系列旨在识别关键复合物的实验，我们将评估通过界面区域诱变的靶向破坏对生物体生命周期的影响。通过将来自各种来源的数据输入计算机模型，该模型旨在以数学为基础描述代谢途径，我们可以使用该模型来形成关于系统变化可能影响的假设，然后回到实验室来测试这些预测。我们的目标的核心是描述关键的生化参数，这些参数定义了蛋白质之间的相互作用，以最稳健的形式完成计算机模型，并确定关键复合物的三维结构，以便我们可以将细胞现象置于原子尺度上。

项目成果

The YmdB Phosphodiesterase Is a Global Regulator of Late Adaptive Responses in Bacillus subtilis

• DOI: 10.1128/jb.00826-13
• 发表时间: 2014-01-01
• 期刊: JOURNAL OF BACTERIOLOGY
• 影响因子: 3.2
• 作者: Diethmaier, Christine;Newman, Joseph A.;Stuelke, Joerg
• 通讯作者: Stuelke, Joerg

Simulations of stressosome activation emphasize allosteric interactions between RsbR and RsbT.

• DOI: 10.1186/1752-0509-7-3
• 发表时间: 2013-01-15
• 期刊: BMC systems biology
• 作者: Liebal UW;Millat T;Marles-Wright J;Lewis RJ;Wolkenhauer O
• 通讯作者: Wolkenhauer O

Exploring the role of SlrR and SlrA in the SinR epigenetic switch.

• DOI: 10.4161/cib.25658
• 发表时间: 2013-11-01
• 期刊: Communicative & integrative biology
• 作者: Newman JA;Lewis RJ
• 通讯作者: Lewis RJ