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The inositol pyrophosphates I[P.sub.7] and I[P.sub.8] contain highly energetic pyrophosphate bonds. Although implicated in various biologic functions, their molecular sites of action have not been clarified. Using radiolabeled I[P.sub.7], we detected phosphorylation of multiple eukaryotic proteins. We also observed phosphorylation of endogenous proteins by endogenous I[P.sub.7] in yeast. Phosphorylation by I[P.sub.7] is nonenzymatic and may represent a novel intracellular signaling mechanism., Inositol phosphates serve diverse biologic functions, with the best characterized, inositol 1,4,5-trisphosphate (I[P.sub.3]), mediating the release of intracellular calcium stores. In mammals, inositol pyrophosphates, such as diphosphoinositol pentakisphosphate (5PP-I[P.sub.5], or [...]

The article presents a study which showed that HIV is evolutionarily constrained to maintain an immature lattice stability that ensures IP6 packaging without preventing maturation. Topics discussed include interdependence of IP6 binding and immature lattice stability, effects of treatment with the MI PF96, and IP6 incorporation as the key feature linking immature lattice stability to virion maturation and infectivity.

Phosphorus is a macronutrient taken up by cells as inorganic phosphate (Pi). How cells sense cellular Pi levels is poorly characterized. Here, we report that SPX domains--which are found in eukaryotic phosphate transporters, signaling proteins, and inorganic polyphosphate polymerases--provide a basic binding surface for inositol polyphosphate signaling molecules (InsPs), the concentrations of which change in response to Pi availability. Substitutions of critical binding surface residues impair InsP binding in vitro, inorganic polyphosphate synthesis in yeast, and Pi transport in Arabidopsis. In plants, InsPs trigger the association of SPX proteins with transcription factors to regulate Pi starvation responses. We propose that InsPs communicate cytosolic Pi levels to SPX domains and enable them to interact with a multitude of proteins to regulate Pi uptake, transport, and storage in fungi, plants, and animals. [ABSTRACT FROM AUTHOR]

With its high-energy phosphate bonds, adenosine triphosphate (ATP) is the main intracellular energy carrier. It also functions in most signaling pathways, as a phosphate donor or a precursor for cyclic adenosine monophosphate. We show here that inositol pyrophosphates participate in the control of intracelullar ATP concentration. Yeasts devoid of inositol pyrophosphates have dysfunctional mitochondria but, paradoxically, contain four times as much ATP because of increased glycolysis. We demonstrate that inositol pyrophosphates control the activity of the major glycolytic transcription factor GCR1. Thus, inositol pyrophosphates regulate ATP concentration by altering the glycolytic/mitochondrial metabolic ratio. Metabolic reprogramming through inositol pyrophosphates is an evolutionary conserved mechanism that is also preserved in mammalian systems. [ABSTRACT FROM AUTHOR]

Inositol pyrophosphates are recognized components of cellular processes that regulate vesicle trafficking, telomere length, and apoptosis. We observed that pancreatic β cells maintain high basal concentrations of the pyrophosphate diphosphoinositol pentakisphosphate (InsP7 or IP7). Inositol hexakisphosphate kinases (IP6Ks) that can generate IP7 were overexpressed. This overexpression stimulated exocytosis of insulin-containing granules from the readily releasable pool. Exogenously applied IP7 dose-dependently enhanced exocytosis at physiological concentrations. We determined that IP6K1 and IP6K2 were present in β cells. RNA silencing of IP6K1, but not IP6K2, inhibited exocytosis, which suggests that IP6K1 is the critical endogenous kinase. Maintenance of high concentrations of IP7 in the pancreatic β cell may enhance the immediate exocytotic capacity and consequently allow rapid adjustment of insulin secretion in response to increased demand. [ABSTRACT FROM AUTHOR]

Inositol 3,4,5,6-tetrakisphosphate [Ins(3,4,5,6)P4] is an inhibitor of the conductance of the Ca(2+)-activated chloride channels in the plasma membrane. These ion channels are required for salt and fluid secretion from epithelial cells, for cell volume homeostasis, and for electrical excitability in neurons and smooth muscle. The enzyme ITPK1 (inositol 1,3,4-triphosphate 5/6 kinase) is the source of Ins(3,4,5,6)P4. It can phosphorylate both Ins(1,3,4)P3 at the 5 or 6 positions and Ins(3,4,5,6)P4 at the 1 position and can also dephosphorylate Ins(1,3,4,5,6)P5 to Ins(3,4,5,6)P4. A study now shows that these various enzyme activities manifested by ITPK1 provide a molecular mechanism that allows the receptor-activated changes in phospholipase C activity and consequent increases in the concentration of Ins(1,3,4)P3 to regulate the abundance of Ins(3,4,5,6)P4. ITPK1 sequesters a tightly bound nucleotide that can accept a phosphate from, or donate a phosphate directly to, an inositol polyphosphate without the nucleotide being released in the bulk medium. This phenomenon of "intersubstrate" transfer is found only in the human enzyme, which can use Ins(1,3,4)P3 to promote increased cellular concentrations of Ins(3,4,5,6)P4.