Inositol pyrophosphates: why so many phosphates?

Abstract

The inositol pyrophosphates (PP-InsPs) are a specialized group of "energetic" signaling molecules found in yeasts, plants and animals. PP-InsPs boast the most crowded three dimensional phosphate arrays found in Nature; multiple phosphates and diphosphates are crammed around the six-carbon, inositol ring. Yet, phosphate esters are also a major energy currency in cells. So the synthesis of PP-InsPs, and the maintenance of their levels in the face of a high rate of ongoing turnover, all requires significant bioenergetic input. What are the particular properties of PP-InsPs that repay this investment of cellular energy? Potential answers to that question are discussed here, against the backdrop of a recent hypothesis that signaling by PP-InsPs is evolutionarily ancient. The latter idea is extended herein, with the proposal that the primordial origins of PP-InsPs is reflected in the apparent lack of isomeric specificity of certain of their actions. Nevertheless, there are other aspects of signaling by these polyphosphates that are more selective for a particular PP-InsP isomer. Consideration of the nature of both specific and non-specific effects of PP-InsPs can help rationalize why such molecules possess so many phosphates.

Keywords: Analogs; Cell-signaling; Diphosphoinositol polyphosphates; Inositol pyrophosphates; Kinase; Phosphorylation; Structure.

Fig. 1. Synthesis of the PP-InsPs

The figure describes the metabolic reactions that account for the synthesis of the PP-InsPs in both yeasts and mammalian cells. The positions of the diphosphate groups were determined in the following publications: (Albert et al., 1997; Draskovic et al., 2008; Wang et al., 2012). PPIP5K (E.C. 2.7.1.158), inositol pentakisphosphate kinase; IP6K (E.C.2.7.4.21), inositol hexakisphosphate kinase, PPIP5K (E.C.2.7.4.24), diphosphoinositol pentakisphophate kinase. This figure is adapted from (Shears et al., 2013). For the brave-hearted who wish to gain insight into the unassailable logic behind the universal numbering system for the six carbon atoms of Ins, start here: (Nomenclature Committee of the International Union of Biochemistry., 1989).

Fig. 2. The possible significance of stimulus-dependent, PtdIns(3,4,5) P₃-driven compartmentalization of PPIP5K1 at the plasma membrane

Electrostatic effects of InsP₆ and 5-InsP₇ are proposed to attenuate the ability of proteins with PH domains to bind to PtdIns(3,4,5)P₃ in the plasma membrane (Gokhale et al., 2013). However, previous work (Gokhale et al., 2011; Gokhale et al., 2013) has demonstrated PI3K-mediated recruitment of PPIP5K1 to the plasma membrane (courtesy of its own PtdIns(3,4,5)P₃-binding domain). It is hypothesized that this translocation causes a local depletion of subplasmalemmal levels of InsP₆ and 5-InsP₇ through their phosphorylation to 1-InsP₇ and InsP₈ respectively, relieving the impediment to PH domain translocation (Gokhale et al., 2013). See text for details.