Regulation of metabolism by 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.