Diphosphoinositol Polyphosphates: Metabolic Messengers?

Abstract

The diphosphoinositol polyphosphates ("inositol pyrophosphates") are a specialized subgroup of the inositol phosphate signaling family. This review proposes that many of the current data concerning the metabolic turnover and biological effects of the diphosphoinositol polyphosphates are linked by a common theme: these polyphosphates act as metabolic messengers. This review will also discuss the latest proposals concerning possible molecular mechanisms of action of this intriguing class of molecules.The discovery of cyclic AMP Sutherland and Rall, 1958) introduced us to the concept of a "second messenger" (Robison et al., 1968): a diffusible molecule (or ion) that, in response to an extracellular stimulus, is rapidly generated at (or released from) a particular subcellular site and then regulates particular effector proteins within the cell so as to elicit a cellular response. Of course, evolution has a remarkable tendency to repeat a good idea, so many different second messengers are now known. The inositol phosphate family represents the convergence of several "good signaling ideas," most notably in their use of a recurring theme in the cell-signaling genre: phosphate groups. Phosphates have two especially prominent features that facilitate specificity of interactions between cell signaling entities. First, the bulky nature of the phosphate group imposes geometric constraints on ligand-protein and protein-protein interactions. Second, the phosphate's negative charge at physiological pH bestows specificity on its interactions with target proteins through multiple ionic and hydrogen bonds. The negative charges on the phosphate group also make soluble, phosphorylated molecules lipid-impermeant, so that they can be retained inside cells.Inositol offers several additional assets for a signaling molecule. It is chemically stable, it is small (hence it diffuses through cytosol quickly), and it is only a short synthetic offshoot from the glycolytic pathway (Sherman et al., 1977). There is also a functionally significant plane of symmetry across the 2/5-axis of the inositol ring (Fig. 1). That symmetry permits one inositol phosphate to imitate another's threedimensional phosphate recognition pattern when the orientation of the inositol ring changes in relation to the protein's ligand-binding site (Wilcox et al., 1994), although in addition the binding site itself has to be somewhat flexible . This phenomenon provides a molecular explanation for the metabolic promiscuity of certain inositol phosphate kinases (for review, see Shears, 2004), and it also facilitates functionally important metabolic interactions between differ-

VIH2 Regulates the Synthesis of Inositol Pyrophosphate InsP8 and Jasmonate-Dependent Defenses in Arabidopsis

“…Inositol pyrophosphates have gained recent attention as signaling molecules in amoeba, yeast, and mammalian cells (Mulugu et al, 2007;Shears, 2009;Chakraborty et al, 2011;Szijgyarto et al, 2011;Wundenberg and Mayr, 2012;Pöhlmann et al, 2014). Here, we describe the presence of InsP 7 and InsP 8 in the model plant Arabidopsis and show that VIH2 is a functional inositol pyrophosphate synthetase responsible for InsP 8 production, playing a critical role in jasmonate-regulated defenses.…”

“…In these organisms, inositol pyrophosphates regulate many cellular processes, including stress responses, membrane trafficking, telomere maintenance, ribosome biogenesis, cytoskeletal dynamics, insulin signaling, apoptosis, phosphate homeostasis, and neutrophil activation (Barker et al, 2009;Burton et al, 2009;Shears, 2009;Chakraborty et al, 2011;Wundenberg and Mayr, 2012). Two distinct classes of inositol pyrophosphate synthetases have been described: inositol hexakisphosphate kinases (also termed IP6Ks or Kcs1-like proteins) and diphosphoinositol pentakisphosphate kinases (PPIP5K or IP7K/Vip1-like proteins).…”

Synergism between Inositol Polyphosphates and TOR Kinase Signaling in Nutrient Sensing, Growth Control, and Lipid Metabolism in Chlamydomonas

“…In fungi, the roles of InsPs have been dissected using mutants that block different steps in the biosynthetic pathway. InsP 7 and InsP 8 are produced by VIP1 and/ or KCS1 kinases whose animal homologs are PP-InsP5K and InsP6K, respectively, and play diverse roles in cell physiology, including signaling phosphate starvation, telomere length control, DNA repair, autophagy, environmental stress responses, cytoskeletal dynamics, and ribosome biogenesis (Bennett et al, 2006;Shears, 2009;Tsui and York, 2010;Wundenberg and Mayr, 2012;Wilson et al, 2013;Thota and Bhandari, 2015;Livermore et al, 2016).…”

Inositol pyrophosphates as multifaceted metabolites in the regulation of mammalian signaling networks

“…The steady-state cellular concentration of IP 7 in mammals varies from 0.5 to 5 μM (Stephens et al 1993;Barker et al 2004;Lin et al 2009), and the level of IP 8 is typically less than half of the concentration of IP 7 (Glennon and Shears 1993;Albert et al 1997). Due to their structural stability, high turnover rate, and high-energy phosphate bonds, PP-IPs have been referred to variously as 'metabolic messengers' (Shears 2009), 'regulators of cell homeostasis' (Wundenberg and Mayr 2012), and 'mammalian cell signals' (Chakraborty et al 2011). …”