Functions, Mechanisms, and therapeutic applications of the inositol pyrophosphates 5PP-InsP 5 and InsP 8 in mammalian cells

Water-soluble myo -inositol phosphates have long been characterized as second messengers. The signaling properties of these compounds are determined by the number and arrangement of phosphate groups on the myo -inositol backbone. Recently, higher inositol phosphates with pyrophosphate groups were recognized as signaling molecules. 5-Diphosphoinositol 1,2,3,4,6-pentakisphosphate (5PP-InsP 5 ) is the most abundant isoform, constituting more than 90% of intracellular inositol pyrophosphates. 5PP-InsP 5 can be further phosphorylated to 1,5-bisdiphosphoinositol 2,3,4,6-tetrakisphosphate (InsP 8 ). These two molecules, 5PP-InsP 5 and InsP 8 , are present in various subcellular compartments, where they participate in regulating diverse cellular processes such as cell death, energy homeostasis, and cytoskeletal dynamics. The synthesis and metabolism of inositol pyrophosphates are subjected to tight regulation, allowing for their highly specific functions. Blocking the 5PP-InsP 5 /InsP 8 signaling pathway by inhibiting the biosynthesis of 5PP-InsP 5 demonstrates therapeutic benefits in preclinical studies, and thus holds promise as a therapeutic approach for certain diseases treatment, such as metabolic disorders. Graphical Abstract