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.

Fig. 1.

The axis of symmetry across the inositol ring. The apparent simplicity of the myo-inositol molecule is deceptive. Here it is depicted both in its thermodynamically preferred “chair” form (left) and in a Haworth projection (right). The latter is not so technically discriminating, but it does have the advantage of more obviously illustrating the plane of symmetry that runs across the 2/5 axis (the broken line), thereby dividing the molecule into two chiral halves. The hydrogen atoms are omitted, for clarity. Agranoff's turtle (Agranoff, 1978) provides a popular memory aid for the carbon numbering (see also Irvine and Schell, 2001); the logic underlying the numbering system is described elsewhere (IUPAC-IUB Commission on Biochemical Nomenclature, 1969).

Fig. 2.

Synthesis of Ins(1,3,4,5,6)P₅ from Ins(1,4,5)P₃ in mammals. In the abbreviations of the chemical structures, “Ins” indicates the myo-inositol skeleton. The number of monophosphates around the inositol ring is denoted as a suffix after the “P.” The figure shows two pathways (ITPK1-dependent and -independent) by which mammalian cells convert Ins(1,4,5)P₃ to Ins(1,3,4,5,6)P₅. It is unclear which of the two routes of Ins(1,3,4,5,6)P₅ synthesis is quantitatively the more important. IP3K, Ins(1,4,5)P₃ kinase; IPMK, inositol polyphosphate multikinase (also known as Ipk2 in yeast); 5-PASE, Ins(1,4,5)P₃/Ins(1,3,4,5)P₄ 5-phosphatase; ITPK1, inositol trisphosphate kinase. There is phylogenetic variability in the isomeric nature of the InsP₄ produced by Ins(1,4,5)P₃ phosphorylation by IMPK: it is mainly Ins(1,3,4,5)P₄ in mammals, mainly Ins(1,4,5,6)P₄ in yeasts, and IPK2 from D. melanogaster synthesizes almost equal amounts of both InsP₄ isomers (Seeds et al., 2004). Note that yeasts and D. melanogaster do not encode ITPK1 in their genomes (Seeds et al., 2004). Finally, plants (Brearley and Hanke, 1996) and slime molds (Stephens and Irvine, 1990) can synthesize Ins(1,3,4,5,6)P₅ by alternate metabolic pathways that do not use Ins(1,4,5)P₃.

Fig. 3.

Synthesis of PP-InsP₄, PP-InsP₅, and (PP)₂-InsP₄ in yeasts and mammals. This figure focuses on the best-characterized diphosphoinositol polyphosphates. Other members of this class of compounds do exist, but are less well understood (see text for details). The positions of the diphosphate groups have been determined in the following publications: Albert et al. (1997), Draskovic et al. (2008), and Lin et al. (2009). The “1/3” designation indicates that it is not yet known whether the diphosphate is present at either position 1 or 3 (or both!); the choice of position 1 in the figure is arbitrary. The 5- and 1/3-isomers of PP-InsP₅ are sometimes referred to as 5-IP₇ and 1/3-IP₇, respectively. The 1/3,5-(PP)₂-InsP₄ is often termed “IP₈” in the literature (see text). In addition to 5-PP-InsP₄, some 1/3-PP-InsP₄ is also formed from Ins(1,3,4,5,6)P₅ by IP6K (Draskovic et al., 2008).