Inorganic polyphosphate in eukaryotes - synthesis, detection, metabolism and physiology

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Inorganic polyphosphate (polyP) is biopolymer of tens to hundreds of phosphate residues linked by a high-energy phosphoanhydride bonds. The metabolism and functions of this prebiotic ubiquitous polymer are quite well understood in prokaryotes and yeast. Although present in multicellular eukaryotes at much lower levels, polyP has been linked to important physiological phenomena such as blood clotting and bone calcification in mammals. While some studies have implicated polyP in different cellular functions including mitochondrial homeostasis, TOR signaling, chaperone function, and neuronal signaling, the overall understanding of polyP biology in high eukaryotes remains poor. The main reasons for this are the lack of specific and sensitive methods for the detection and quantification of polyP, and that the enzyme(s) responsible for polyP synthesis in metazoans is still unknown. Also, the chemical synthesis of polyP and analogues, which can help identify the enzymes involved in polyP turnover, and probe other cellular functions of polyP, is underdeveloped. In this joint project proposal to DBT and DFG for funding Indo-German Fundamental Research Projects in the Life Sciences, we bring together our complementary expertise in Biochemistry (Rashna Bhandari), Chemical Synthesis (Henning Jessen) and Drosophila genetics (Manish Jaiswal) to address the shortcomings in our understanding of polyP biology in multicellular eukaryotes. We will work together to achieve the following objectives:a) Develop sensitive and specific assays to detect polyP in biological samplesb) Chemically synthesize polyP and analogues and achieve the cellular delivery of such compoundsc) Investigate cross-talk between inositol pyrophosphates and polyP in mitochondrial energy metabolismd) Identify the pathway of polyP synthesis in higher eukaryotese) Study organism-level phenotypic effects of polyP depletionIn its entirety, this proposal will help us to unravel the enigmas of polyP synthesis and function in higher eukaryotes and will significantly drive the field by providing novel analytical, biochemical and biological approaches.