Inositol pyrophosphates: Between signalling and metabolism

Medical Research Council (MRC) Cell Biology Unit and Laboratory for Molecular Cell Biology, Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, U.K.
Biochemical Journal (Impact Factor: 4.4). 06/2013; 452(3):369-379. DOI: 10.1042/BJ20130118
Source: PubMed


The present review will explore the insights gained into inositol pyrophosphates in the 20 years since their discovery in 1993. These molecules are defined by the presence of the characteristic 'high energy' pyrophosphate moiety and can be found ubiquitously in eukaryotic cells. The enzymes that synthesize them are similarly well distributed and can be found encoded in any eukaryote genome. Rapid progress has been made in characterizing inositol pyrophosphate metabolism and they have been linked to a surprisingly diverse range of cellular functions. Two decades of work is now beginning to present a view of inositol pyrophosphates as fundamental, conserved and highly important agents in the regulation of cellular homoeostasis. In particular it is emerging that energy metabolism, and thus ATP production, is closely regulated by these molecules. Much of the early work on these molecules was performed in the yeast Saccharomyces cerevisiae and the social amoeba Dictyostelium discoideum, but the development of mouse knockouts for IP6K1 and IP6K2 [IP6K is IP6 (inositol hexakisphosphate) kinase] in the last 5 years has provided very welcome tools to better understand the physiological roles of inositol pyrophosphates. Another recent innovation has been the use of gel electrophoresis to detect and purify inositol pyrophosphates. Despite the advances that have been made, many aspects of inositol pyrophosphate biology remain far from clear. By evaluating the literature, the present review hopes to promote further research in this absorbing area of biology.

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    • "This PTM is highly labile in acidic conditions and thus has not been detected by available MS techniques. The molecules responsible for this PTM, inositol pyrophosphates, are characterized by the presence of highly energetic pyrophosphate moieties and are able to regulate diverse functions by affecting cellular metabolism (Chakraborty et al., 2011; Wilson et al., 2013). Inositol pyrophosphates also regulate the metabolism of inorganic polyphosphate (polyP; Lonetti et al., 2011). "
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    ABSTRACT: The complexity of higher organisms is not simply a reflection of the number of genes. A network of additional regulatory features, including protein post-translational modifications (PTMs), provides functional complexity otherwise inaccessible to a single gene product. Virtually all proteins are targets of PTMs. Here we characterize "polyphosphorylation" as the covalent attachment of inorganic polyphosphate (polyP) to target proteins. We found that nuclear signal recognition 1 (Nsr1) and its interacting partner, topoisomerase 1 (Top1), are polyphosphorylated. This modification occurs on lysine (K) residues within a conserved N-terminal polyacidic serine (S) and K-rich (PASK) cluster. We show that polyphosphorylation negatively regulates Nsr1/Top1 interaction and impairs Top1 enzymatic activity. Physiological modulation of cellular levels of polyP regulates Top1 activity by modifying its polyphosphorylation status. We propose that polyphosphorylation adds an additional layer of regulation to nuclear signaling, where many PASK-containing proteins are known to play important roles. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular Cell 03/2015; 58(1). DOI:10.1016/j.molcel.2015.02.010 · 14.02 Impact Factor
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    • "A unique group of InsP signaling molecules containing diphosphate or triphosphate chains (i.e. PPx-InsPs) are emerging as critical players in various signaling processes in eukaryotes, and are synthesized from higher InsP precursors (Figure 1) (Saiardi, 2012; Shears et al., 2013; Wilson et al., 2013). PPx- InsPs are thought of as 'energy-rich' molecules because pyrophosphate moieties have a free energy of hydrolysis comparable to that of ATP (Hand and Honek, 2007). "
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    ABSTRACT: Inositol pyrophosphates are unique cellular signaling molecules with recently discovered roles in energy sensing and metabolism. Studies in eukaryotes have revealed that these compounds turn over rapidly, and thus only small amounts accumulate. Inositol pyrophosphates have not been the subject of investigation in plants even though seeds produce large amounts of their precursor, myo-inositol hexakisphosphate (InsP6). Here, we report that Arabidopsis and maize InsP6 transporter mutants have elevated levels of inositol pyrophosphates in their seed, providing unequivocal identification of their presence in plant tissues. We also show that plant seeds store a little over 1% of their inositol phosphate pool as InsP7 and InsP8. Many tissues, including, seed, seedlings, roots and leaves accumulate InsP7 and InsP8, thus synthesis is not confined to tissues with high InsP6. We identified two highly similar Arabidopsis genes, AtVip1 and AtVip2, which are orthologous to the yeast and mammalian VIP kinases. Both AtVip1 and AtVip2 encode proteins capable of restoring InsP7 synthesis in yeast mutants, thus AtVip1 and AtVip2 can function as bonafide InsP6 kinases. AtVip1 and AtVip2 are differentially expressed in plant tissues, suggesting non-redundant or non-overlapping functions in plants. These results contribute to our knowledge of inositol phosphate metabolism and will lay a foundation for understanding the role of InsP7 and InsP8 in plants.This article is protected by copyright. All rights reserved.
    The Plant Journal 09/2014; 80(4). DOI:10.1111/tpj.12669 · 5.97 Impact Factor
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    • "D. discoideum has also been instrumental in the discovery of inositol pyrophosphates (also known as diphosphoinositol phosphates) (For reviews see [6], [7]) molecules containing highly energetic pyrophosphate moiety(ies) recently implicated into the regulation of cellular homeostasis [8], [9], [10]. Inositol pyrophosphates were identified in 1993 in D. discoideum [11] and in mammalian cell [12]. "
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    ABSTRACT: The social amoeba Dictyostelium discoideum was instrumental in the discovery and early characterization of inositol pyrophosphates, a class of molecules possessing highly-energetic pyrophosphate bonds. Inositol pyrophosphates regulate diverse biological processes and are attracting attention due to their ability to control energy metabolism and insulin signalling. However, inositol pyrophosphate research has been hampered by the lack of simple experimental procedures to study them. The recent development of polyacrylamide gel electrophoresis (PAGE) and simple staining to resolve and detect inositol pyrophosphate species has opened new investigative possibilities. This technology is now commonly applied to study in vitro enzymatic reactions. Here we employ PAGE technology to characterize the D. discoideum inositol pyrophosphate metabolism. Surprisingly, only three major bands are detectable after resolving acidic extract on PAGE. We have demonstrated that these three bands correspond to inositol hexakisphosphate (IP6 or Phytic acid) and its derivative inositol pyrophosphates, IP7 and IP8. Biochemical analyses and genetic evidence were used to establish the genuine inositol phosphate nature of these bands. We also identified IP9 in D. discoideum cells, a molecule so far detected only from in vitro biochemical reactions. Furthermore, we discovered that this amoeba possesses three different inositol pentakisphosphates (IP5) isomers, which are largely metabolised to inositol pyrophosphates. Comparison of PAGE with traditional Sax-HPLC revealed an underestimation of the cellular abundance of inositol pyrophosphates by traditional methods. In fact our study revealed much higher levels of inositol pyrophosphates in D. discoideum in the vegetative state than previously detected. A three-fold increase in IP8 was observed during development of D. discoideum a value lower that previously reported. Analysis of inositol pyrophosphate metabolism using ip6k null amoeba revealed the absence of developmentally-induced synthesis of inositol pyrophosphates, suggesting that the alternative class of enzyme responsible for pyrophosphate synthesis, PP-IP5K, doesn't' play a major role in the IP8 developmental increase.
    PLoS ONE 01/2014; 9(1):e85533. DOI:10.1371/journal.pone.0085533 · 3.23 Impact Factor
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