Investigating metabolite-RNase communication.

研究代谢物-RNase 通讯。

• 批准号: BB/J016179/1
• 负责人: Anastasia Callaghan
• 金额: $ 42.99万
• 依托单位: University of Portsmouth
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ016179%2F1
• 关键词: Investigating; metabolite; RNase; communication.

Within living cells a whole series of chemical reactions occur in order to provide the energy the cell needs to sustain life. This series of reactions is collectively known as a cell's metabolism. Understanding how metabolism is controlled within a cell is fundamentally important and is directly applicable to medical, environmental and biotechnological advances. At the present time, some aspects of how metabolism is controlled are understood, but we have recently discovered a whole new control mechanism of key importance.It is already known that messenger molecules (RNA) within a cell play a role in controlling metabolism and that in turn, destroyer molecules (RNA degraders) in the cell keep the number of RNA molecules in check. Our studies have identified that one of the chemicals involved in metabolism, known as a metabolite, interacts with an RNA degrader and affects its ability to destroy RNA. Our work therefore indicates that a full feedback system exists within a cell, with metabolites altering the ability of RNA degraders to destroy RNA, which in turn affects cellular metabolism, which impacts metabolites, which then interact with RNA degraders and so the loop continues.The aim of the proposed work is to investigate the newly identified interactions between metabolism and RNA-degraders in detail. Specifically, our objectives are to answer a number of key questions. What changes occur to the population of messenger molecules within the cell when this mechanism takes place and are some messenger molecules targeted earlier than others? By monitoring the population of messenger molecules can it be seen whether the mechanism changes once the RNA-degraders form larger complex structures with other RNA degraders? If we specifically change the metabolite-recognition site on the RNA-degrader, what happens to the population of messenger molecules and what can this tell us about the mechanism? Is this mechanism of communication between metabolism and RNA-degraders found in all types of cells from simple bacteria to complex animal cells? To answer these questions our research will use a comprehensive state-of-the-art toolset of proven practical and computational biological research techniques. Understanding these additional details about the communication between metabolism and RNA-degraders allows us to take the next step towards realising the full impact of our recent discovery. In the longer term, such knowledge could allow scientists to artificially control metabolism within living cells. For example, simple bacterial cells play an important role in many industrial applications and this artificial metabolic control could optimise their use. This may potentially increase efficiency by reducing energy costs, increasing yields and reducing starting material requirements, all of economic and environmental value. Examples include exploitation within the pharmaceutical industry (e.g. more efficient drug production), the food industry (e.g. improvements in food production) and particularly in relation to environmental concerns (e.g. aiding biofuel production and bioremediation projects). In a similar manner, the artificial control of metabolism within animal cells has the potential to offer far reaching therapeutic benefits.

在活细胞内，为了提供细胞维持生命所需的能量，会发生一系列的化学反应。这一系列反应统称为细胞的新陈代谢。了解新陈代谢是如何在细胞内控制的是非常重要的，并直接适用于医学、环境和生物技术的进步。目前，关于新陈代谢如何控制的某些方面已经被了解，但我们最近发现了一种全新的关键控制机制。众所周知，细胞内的信使分子(RNA)在控制新陈代谢中发挥作用，反过来，细胞中的破坏者分子(RNA降解物)控制RNA分子的数量。我们的研究已经确定，参与新陈代谢的一种化学物质，称为代谢物，与RNA降解物相互作用，并影响其摧毁RNA的能力。因此，我们的工作表明，细胞内存在一个完整的反馈系统，代谢产物改变了RNA降解者破坏RNA的能力，进而影响细胞代谢，进而影响代谢产物，然后代谢产物与RNA降解物相互作用，从而继续循环。拟议工作的目的是详细研究新发现的代谢与RNA降解物之间的相互作用。具体地说，我们的目标是回答一些关键问题。当这种机制发生时，细胞内信使分子的数量发生了什么变化，一些信使分子比其他信使分子更早被靶向？通过监测信使分子的数量，是否可以看到一旦RNA降解者与其他RNA降解者形成更大的复杂结构，机制是否会改变？如果我们特别改变了RNA降解物上的代谢物识别位置，信使分子的数量会发生什么变化，这能告诉我们关于机制的什么信息？从简单的细菌到复杂的动物细胞，所有类型的细胞都存在代谢和RNA降解物之间的这种交流机制吗？为了回答这些问题，我们的研究将使用经过验证的实用和计算生物学研究技术的综合最先进的工具包。了解这些关于新陈代谢和RNA降解物之间的交流的额外细节，可以让我们迈出下一步，实现我们最近发现的全部影响。从长远来看，这种知识可以让科学家人工控制活细胞内的新陈代谢。例如，简单的细菌细胞在许多工业应用中扮演着重要的角色，这种人工代谢控制可以优化它们的使用。这可能会通过降低能源成本、增加产量和减少起始材料需求来潜在地提高效率，所有这些都具有经济和环境价值。例子包括制药业(例如更高效的药品生产)、食品业(例如食品生产的改进)内的开发，特别是与环境问题有关的开发(例如协助生物燃料生产和生物修复项目)。以类似的方式，人工控制动物细胞内的新陈代谢有可能提供深远的治疗益处。

项目成果

Identification of Novel Inhibitors of Escherichia coli DNA Ligase (LigA).

• DOI: 10.3390/molecules26092508
• 发表时间: 2021-04-25
• 期刊: Molecules (Basel, Switzerland)
• 作者: Alomari A;Gowland R;Southwood C;Barrow J;Bentley Z;Calvin-Nelson J;Kaminski A;LeFevre M;Callaghan AJ;Vincent HA;Gowers DM
• 通讯作者: Gowers DM

The first small-molecule inhibitors of members of the ribonuclease E family.

• DOI: 10.1038/srep08028
• 发表时间: 2015-01-26
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Kime L;Vincent HA;Gendoo DM;Jourdan SS;Fishwick CW;Callaghan AJ;McDowall KJ
• 通讯作者: McDowall KJ

Inhibition of homologous phosphorolytic ribonucleases by citrate may represent an evolutionarily conserved communicative link between RNA degradation and central metabolism.

• DOI: 10.1093/nar/gkx114
• 发表时间: 2017-05-05
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Stone CM;Butt LE;Bufton JC;Lourenco DC;Gowers DM;Pickford AR;Cox PA;Vincent HA;Callaghan AJ
• 通讯作者: Callaghan AJ