Regulation of metabolism by inositol pyrophosphates

Lead Research Organisation: University College London
Department Name: Lab for Molecular Cell Bio MRC-UCL


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.

Technical Summary

Cell metabolism is at the very core of any physiological process in health or disease. Understanding metabolic control is, therefore, of fundamental importance. Our work on inositol pyrophosphates (PP-IPs) has positioned this class of cellular messengers at the interface between cell metabolism and cell signalling. The evidence that PP-IPs are involved in the pathogenesis of metabolic disorders such as obesity and diabetes has increased the interest in PP-IPs as regulators of metabolism. However, despite their clear relevance, many aspects of the PP-IPs modus operandi remain poorly understood. The proposed program intends to fill these lacunae by defining several aspects of PP-IPs biology, from regulation to mechanism of action, helping to pinpoint how these molecules regulate cell metabolism. Our comprehensive program aims to define the metabolic inositol fluxes leading to PP-IPs synthesis, as well as characterising the regulation of the PP-IPs synthesizing enzymes. These studies will be accompanied by analysing how PP-IPs regulate mammalian cellular phosphate homeostasis, since the nutrient phosphate is involved in virtually every biochemical reaction, and thus understanding its homeostatic control is fundamental to comprehending metabolism. To appreciate PP-IPs signalling and metabolic control we should understand the molecular mechanisms of action. Therefore, we aim to dissect the post-translational protein modifications directly and indirectly controlled by PP-IPs. Since transformative science can only be achieved by developing novel experimental approaches, we also aim to enable visualisation of inositol phosphates by Raman spectromicroscopy, and their detection by easy-to-perform LC-MS methods. These novel techniques will help us achieve our main objective of elucidating how PP-IPs control metabolism.

Planned Impact

The program of work by addressing, using an unconventional angle, the fundamental question: how metabolism is regulated? Will potentially have huge impact. Linking PP-IPs to metabolism control could be a game-changing prospect for scientists of different research fields interested in cellular homeostasis and its dysregulation in disease states. While our research is not directly translational, any discovery that sheds light on cellular metabolic control is potentially of translational interest. Our work could provide different ideas and approaches to ameliorating and preventing important metabolic disorders such diabetes, obesity, cancer. We will exploit these opportunity by disseminating our ideas to, and ideally to collaborate with, physicians and physiologists. The unique knowhow and expertise the program will generate will benefit the wider scientific community. The development of new analytical methods and IPs visualization by Raman spectromicroscopy will influence how researchers study this class of molecules. We will share freely these technologies affecting, as we have done in the past, on the scientific output of different researchers.
However, besides scientific knowledge our project can positively influence several aspects of UK socioeconomic development. For example, by training highly skilled peoples. The personnel involved in the project will not only receive state-of-the-art research skills but will also grow professionally utilizing the many opportunity that the LMCB and UCL are offering. Thus after their training they will be ready to contribute to UK's economic progress.
Our attempts to disseminate our scientific discovery outside the traditional scientific publication route will increase public science awareness, fundamental aspect to build a future pro-science society. The public engagement activities planned aim to share our knowledge with non-scientists to increase science's standing and explain the importance of scientific discovery in the wider society. Our project aiming to understand basic metabolism, ultimately providing an opportunity to explore and explain the underlying causes of metabolic disorders such as diabetes and obesity that are affecting a growing number of people. Thus we foresee 'engaging' public engagement activities.


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Description Cities Partnership Program London-Paris
Amount £4,000 (GBP)
Organisation University College London 
Sector Academic/University
Country United Kingdom
Start 03/2021 
End 10/2021
Description UCL-IISc Joint Seed Call 2021-2022
Amount £4,000 (GBP)
Organisation University College London 
Sector Academic/University
Country United Kingdom
Start 02/2022 
End 01/2023
Description WS23-015 FEBS Workshop 2023 Polyphosphate: The Actual Biology of an Ancient Polymer (9-12 May 2023, Cádiz, Spain).
Amount € 21,000 (EUR)
Funding ID WS23-015 
Organisation Federation of European Biochemical Societies (FEBS) 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2023 
End 06/2023
Title Development of a LC-MS metod to distinguish myo-inositol chiro-inositol and scyllo-inositol 
Description We developed an HPLC-Mass Spectrometry method to analyze sugars extracted from cells. This new protocol allows the simultaneous detection of glucose, fructose, and several isomers of inositol. 
Type Of Material Technology assay or reagent 
Year Produced 2024 
Provided To Others? No  
Impact This new analytical assay is permitting to perform experiments previously impossible to perform. 
Description Developing inositol phosphate chemical tools 
Organisation University of Zurich
Country Switzerland 
Sector Academic/University 
PI Contribution Developing inositol phosphate chemical tools
Collaborator Contribution organic synthesis
Impact One publication Pavlovic I, Thakor DT, Bigler L, Wilson MS, Laha D, Schaaf G, Saiardi A, Jessen HJ. Prometabolites of 5-Diphospho-myo-inositol Pentakisphosphate. Angew Chem Int Ed Engl. 2015 Aug 10;54(33):9622-6. PMID: 26014370.
Start Year 2013
Description Inositol pyrophosphate signaling in the yeast S. pombe 
Organisation Heinrich Heine University Düsseldorf
Country Germany 
Sector Academic/University 
PI Contribution Transfer of my inositol pyrophosphate and inorganic polyphosphate (polyP) theoretical and practical know-how. Biochemical analysis of Schizosaccharomyces pombe inositol kinases mutant strains.
Collaborator Contribution Initiated the project identifying by genetic studies key roles for inositol phosphate kinases of Schizosaccharomyces pombe, Is providing stains, expertise, tools and genetic analyses.
Impact This collaboration is just started, thus there are not output to be listed. However, a important publication has been just been accepted (Mol Cell Biol. 2018 Feb 12. pii: MCB.00047-18. doi: 10.1128/MCB.00047-18.) in wich we describe the importance of the phosphatase domain of PP-IP5K to regulate the level of inositol pyrophosphates. This collaboration is multidisciplinary, involving a yeast geneticist and a biochemist.
Start Year 2017
Description Roles of Inositol Phosphates in Viral Biology 
Organisation Medical Research Council (MRC)
Department MRC Laboratory of Molecular Biology (LMB)
Country United Kingdom 
Sector Academic/University 
PI Contribution Our inositol phosphate analysis technologies allow us to analyse the inositol phosphate levels in HIV virion. We are also theoretically contributing to this collaborative project by transferring our unique inositol metabolic pathways know-own.
Collaborator Contribution The partner is a HIV structural biologist and bring in this collaboration the HIV biology expertise
Impact This collaboration is multidisciplinary, involving a structural biologist/ immunologist and a biochemist. This collaboration generated a published paper and a second manuscript just submitted. IP6 is an HIV pocket factor that prevents capsid collapse and promotes DNA synthesis. Mallery DL, et al. Elife. 2018 May 31;7. pii: e35335.
Start Year 2017
Description Study polyphosphate metabolism in green algae Chlamydomonas reinhardtii 
Organisation University of Leeds
Country United Kingdom 
Sector Academic/University 
PI Contribution Transfer my polyphosphate tools/reagents and theoretical and practical polyphosphate expertise to the collaborator laboratory
Collaborator Contribution Provide green algae to analyze
Impact no yet
Start Year 2022
Description caratterising Lipid Signalin in marchantia polymorpha 
Organisation Autonomous University of Madrid
Country Spain 
Sector Academic/University 
PI Contribution We are biochemically characterizing a plant lipid phosphatase acting on soluble inositol phosphates.
Collaborator Contribution My collaborator identified this lipid phosphatase in a genetic screening aimed to characterize auxin signaling.
Impact no yet
Start Year 2023
Description plant inositol pyrophosphate 
Organisation Eberhard Karls University of Tübingen
Country Germany 
Sector Academic/University 
PI Contribution analysis of inositol phosphate levels excenge of reagent and tecnologies
Collaborator Contribution developing the research line and generating plant mutant lines
Impact One publication VIH2 Regulates the Synthesis of Inositol Pyrophosphate InsP8 and Jasmonate-Dependent Defenses in Arabidopsis. Laha D, Johnen P, Azevedo C, Dynowski M, Weiß M, Capolicchio S, Mao H, Iven T, Steenbergen M, Freyer M, Gaugler P, de Campos MK, Zheng N, Feussner I, Jessen HJ, Van Wees SC, Saiardi A, Schaaf G. Plant Cell. 2015 Apr;27(4):1082-97.
Start Year 2013