Inositol pyrophosphate kinases in health and disease

Inositol phosphates (InsPs) are intracellular signaling molecules that are essential for life. Inositol pyrophosphates, a subset of inositol phosphates, are the end products of inositol phosphate metabolism. In mammalian cells, up to 90% of inositol pyrophosphates are 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5PP-InsP₅), which is generated by inositol hexakisphosphate kinases (IP6Ks). 5PP-InsP₅ can be further phosphorylated by diphosphoinositol pentakisphosphate kinases (PPIP5Ks) to generate 1,5-bisdiphosphoinositol 2,3,4,6-tetrakisphosphate (InsP₈). Unlike freely diffusible molecules, 5PP-InsP₅ and InsP₈ act locally at the sites where they are synthesized. Thus, individual IP6K and PPIP5K enzymes perform specific functions. Preclinical and clinical studies suggest that these molecules contribute to early life development, but mediate age-related diseases beyond adulthood. In this review, we summarize the functions and mechanisms of action of every individual IP6K and PPIP5K in both physiological processes and diseases and discuss the potential applications of these inositol pyrophosphate kinases as druggable targets for disease treatment.