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.
Highlights
Myo-inositol, a six-carbon glucose isomer with one axial and five equatorial hydroxyl groups, is a key nutrient in the human [1,2]
When IP6K1 is deleted in adipocytes, mice exhibit enhanced thermogenic energy expenditure, which is protective against high-fat-diet-induced obesity at ambient, but not thermoneutral, temperatures [59,60]
Recent whole-genome sequencing in familial keratoconus patients identified mutations in PPIP5K2 that were responsible for 1-IP7/IP8 synthesis [69]
Summary
Myo-inositol (inositol), a six-carbon glucose isomer with one axial and five equatorial hydroxyl groups, is a key nutrient in the human [1,2]. Inositol can be produced from the isomerization of glucose-6-phosphate by inositol 3-phosphate synthase to inositol 3-phosphate, which is dephosphorylated by inositol monophosphatase 1 to yield free myo-inositol. Inositol is primarily found as a structural component of phosphatidylinositols that helps maintain cellular membranes [1]. Inositol polyphosphates (IPs) such as inositol 1,4,5-trisphosphate (IP3), contain more than one phosphate. An example of bioactive inositol activity is IP3-mediated cytosolic calcium release [6,7]. Phospholipase C is activated by growth factor stimulation and cleaves the phosphatidylinositol 4,5-bisphosphate (PIP2), producing IP3 and the lipid-anchored diacylglycerol. IP3 released from the membrane to the cytosol subsequently binds to and opens the IP3 receptor, an IP3-gated calcium channel that regulates cytosolic calcium levels.
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