Regulation of metabolism by inositol pyrophosphates

肌醇焦磷酸调节代谢

• 批准号: MR/T028904/1
• 负责人: Adolfo Saiardi
• 金额: $ 210.96万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT028904%2F1
• 关键词: Regulation; metabolism; inositol; pyrophosphates

To function, our bodies need food and water. The nutrients in food are cleaved into small parts, and absorbed by the intestines. These small molecules give our bodies the building blocks to grow, develop, and make energy. This process is called metabolism, and is fine-tuned by regulatory processes. The dysregulation of metabolism is the underlining cause of diabetes and obesity, two highly debilitating human diseases often referred as 'metabolic disorders'. Metabolism is regulated at different levels, from that of the body as a whole, to the mechanisms by which individual cells control their metabolism. Deregulation of cellular metabolism is a common feature of human malignancies; cancerous cells are distinguishable from normal cells due to their altered metabolism, a characteristic used by diagnostic methods such as PET scanning. Due to the fundamental importance of metabolism, cells possess various mechanisms to fine-tune it to their physiological needs. While there has been progress in our understanding of cell metabolism, many aspects of cellular metabolic control are still unclear. Here we propose to look at this regulation from a new angle. Inositol pyrophosphates, a type of small molecule, regulate various aspects of cell activity. We propose that the many cellular features regulated by inositol pyrophosphates are underpinned by their ability to control cellular metabolism. Our idea arises from evidence suggesting that inositol pyrophosphates regulate two key parts of metabolic control: the level of the cell's energy currency, ATP; and the homeostasis of an important nutrient, phosphate, that is not only a constituent of ATP but also plays a role in the structure of DNA, our genetic material. We plan to define inositol pyrophosphates' mode operandi, dissecting how they become synthesized. More importantly, we aim to identify their ability to regulate the metabolic fluxes affecting ATP production and cellular health. Ultimately, our objective is to understand how inositol pyrophosphates are able to fine-tune cell physiology and thus affect homeostatic regulation. Dysregulation of homeostatic control could be thought of as the underlying cause of all human illness, thus our project has potentially far-reaching implications. Since scientific breakthroughs often follow methods development; we will also develop novel experimental approaches to achieve our ambitious objectives.

我们的身体需要食物和水才能正常工作。食物中的营养物质被分解成小部分，并被肠道吸收。这些小分子为我们的身体提供了生长、发育和制造能量的基础。这个过程被称为新陈代谢，并通过调节过程进行微调。代谢失调是糖尿病和肥胖症的主要原因，这两种高度衰弱的人类疾病通常被称为“代谢紊乱”。代谢在不同的水平上受到调节，从整个身体的水平到单个细胞控制其代谢的机制。细胞代谢失调是人类恶性肿瘤的共同特征;癌细胞由于其代谢改变而与正常细胞区分开，这是PET扫描等诊断方法所使用的特征。由于新陈代谢的根本重要性，细胞具有各种机制来微调它以满足其生理需求。虽然我们对细胞代谢的理解已经取得了进展，但细胞代谢控制的许多方面仍然不清楚。在这里，我们建议从一个新的角度来看待这一规定。肌醇焦磷酸是一种小分子，调节细胞活性的各个方面。我们认为，肌醇焦磷酸调节的许多细胞功能是由它们控制细胞代谢的能力所支撑的。我们的想法来自于有证据表明肌醇焦磷酸盐调节代谢控制的两个关键部分：细胞能量货币ATP的水平;以及重要营养素磷酸盐的稳态，磷酸盐不仅是ATP的组成部分，而且在我们的遗传物质DNA的结构中发挥作用。我们计划定义肌醇焦磷酸盐的工作模式，剖析它们是如何合成的。更重要的是，我们的目标是确定它们调节影响ATP产生和细胞健康的代谢通量的能力。最终，我们的目标是了解肌醇焦磷酸是如何能够微调细胞生理学，从而影响稳态调节。体内平衡控制的失调可以被认为是所有人类疾病的根本原因，因此我们的项目具有潜在的深远影响。由于科学突破往往伴随着方法的发展，我们还将开发新的实验方法来实现我们的宏伟目标。

项目成果

Evolutionary perspective on mammalian inorganic polyphosphate (polyP) biology.

• DOI: 10.1042/bst20230483
• 发表时间: 2023-10-31
• 期刊: Biochemical Society transactions
• 影响因子: 3.9

Cytoplasmic cleavage of IMPA1 3' UTR is necessary for maintaining axon integrity.

• DOI: 10.1016/j.celrep.2021.108778
• 发表时间: 2021-02-23
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Andreassi C;Luisier R;Crerar H;Darsinou M;Blokzijl-Franke S;Lenn T;Luscombe NM;Cuda G;Gaspari M;Saiardi A;Riccio A
• 通讯作者: Riccio A

Stable isotope phosphate labelling of diverse metabolites is enabled by a family of 18O-phosphoramidites

18O-亚磷酰胺家族可实现多种代谢物的稳定同位素磷酸盐标记

• DOI: 10.26434/chemrxiv-2021-0r9g7
• 发表时间: 2021
• 作者: Haas T

The inositol pyrophosphate metabolism of Dictyostelium discoideum does not regulate inorganic polyphosphate (polyP) synthesis.

• DOI: 10.1016/j.jbior.2021.100835
• 发表时间: 2022-01
• 期刊: Advances in biological regulation
• 作者: Desfougères Y;Portela-Torres P;Qiu D;Livermore TM;Harmel RK;Borghi F;Jessen HJ;Fiedler D;Saiardi A
• 通讯作者: Saiardi A

Phytocannabinoid-dependent mTORC1 regulation is dependent upon inositol polyphosphate multikinase activity.

• DOI: 10.1111/bph.15351
• 发表时间: 2021-03
• 期刊: British journal of pharmacology
• 影响因子: 7.3