Inositol Pyrophosphates: Signaling Molecules with Pleiotropic Actions in Mammals

Abstract

Inositol pyrophosphates (PP-IPs) such as 5-diphosphoinositol pentakisphosphate (5-IP7) are inositol metabolites containing high-energy phosphoanhydride bonds. Biosynthesis of PP-IPs is mediated by IP6 kinases (IP6Ks) and PPIP5 kinases (PPIP5Ks), which transfer phosphate to inositol hexakisphosphate (IP6). Pleiotropic actions of PP-IPs are involved in many key biological processes, including growth, vesicular remodeling, and energy homeostasis. PP-IPs function to regulate their target proteins through allosteric interactions or protein pyrophosphorylation. This review summarizes the current understanding of how PP-IPs control mammalian cellular signaling networks in physiology and disease.

Transcriptional interference at tandem lncRNA and protein-coding genes: an emerging theme in regulation of cellular nutrient homeostasis

“…Inositol pyrophosphates (IPPs) IP7 and IP8 are signaling molecules implicated in a broad range of physiological processes in eukaryal cells ( 47 ). There are two cellular forms of IP7 that differ according to whether the pyrophosphate moiety is at the 1 or 5 position of the inositol ring; IP8 is pyrophosphorylated at both ring positions (Figure 6 ).…”

Metabolism and Functions of Inositol Pyrophosphates: Insights Gained from the Application of Synthetic Analogues

“…A number of studies have explored the biological activities of the PP-InsPs by pharmacological and/or genetic intervention in the metabolic pathway described by Figure 1 (see [ 6 , 8 ] for recent, authoritative reviews). However, the blockage of IP6K activity by itself cannot distinguish the actions of 5-InsP 7 from those of InsP 8 , since the synthesis of both is reduced.…”

“…This is a situation in which metabolically stable PP-InsP analogs can be helpful, particularly with regards to biochemical and cellular assays, in which the natural PP-InsPs have a short half-life due to their inherently fast turnover rate [ 20 , 21 ]. Another application for such research tools is to distinguish between the two molecular mechanisms by which protein function can be modulated by the PP-InsPs: allosteric regulation upon ligand binding, versus covalent regulation by non-enzymic phosphotransfer [ 1 , 6 , 7 , 8 , 22 ]. The latter cannot be mimicked by metabolically stable PP-InsP analogs.…”

“…The inositol pyrophosphates (PP-InsPs), particularly 1-InsP 7 , 5-InsP 7 , and 1,5-InsP 8 ( Appendix A ; Figure 1 ) are highly ‘energetic’ and diffusible signaling molecules that play important roles in many cellular processes throughout the eukaryotic kingdoms, particularly with regards to phosphate and bioenergetic homeostasis, both of which can have profound metabolic and physiological consequences [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. Indeed, it is hard to overstate the significance of dovetailing any signal transduction cascade with metabolic circuitry.…”

Signalling Properties of Inositol Polyphosphates

“…This review covers some examples of the processes regulated by IPs and mentions some of the potential pharmacological opportunities arising from modulation of IPs levels. The many roles of PP-IPs have been covered elsewhere in this special issue [ 11 ].…”