The inositol pyrophosphate pathway in health and diseases

Abstract

Inositol pyrophosphates (IPPs) are present in organisms ranging from plants, slime moulds and fungi to mammals. Distinct classes of kinases generate different forms of energetic diphosphate-containing IPPs from inositol phosphates (IPs). Conversely, polyphosphate phosphohydrolase enzymes dephosphorylate IPPs to regenerate the respective IPs. IPPs and/or their metabolizing enzymes regulate various cell biological processes by modulating many proteins via diverse mechanisms. In the last decade, extensive research has been conducted in mammalian systems, particularly in knockout mouse models of relevant enzymes. Results obtained from these studies suggest impacts of the IPP pathway on organ development, especially of brain and testis. Conversely, deletion of specific enzymes in the pathway protects mice from various diseases such as diet-induced obesity (DIO), type-2 diabetes (T2D), fatty liver, bacterial infection, thromboembolism, cancer metastasis and aging. Furthermore, pharmacological inhibition of the same class of enzymes in mice validates the therapeutic importance of this pathway in cardio-metabolic diseases. This review critically analyses these findings and summarizes the significance of the IPP pathway in mammalian health and diseases. It also evaluates benefits and risks of targeting this pathway in disease therapies. Finally, future directions of mammalian IPP research are discussed.

Keywords: DIPP; IP6K; PPIP5K; TNP; aging; cancer; cardiovascular disease; development; diabetes; inositol pyrophosphate; obesity.

Fig. 1.

Generation of inositol phosphate IP5 from the lipid phosphoinositide phosphatidylinositol (4,5)-bisphosphate (PIP2) in mammals. Only major enzymes are denoted. DAG, diacylglycerol; INPP5, inositol polyphosphate 5-phosphatase; IP3K, IP3 3-kinase; IPMK, inositol polyphosphate multikinase; ITPK1, inositol tetrakisphosphate 1-kinase; PLC, phospholipase C.

Fig. 2.

Synthesis of inositol phosphate IP6 and inositol pyrophosphates. Inositol hexakisphosphate kinases (IP6Ks) convert IP5, IP6 and 1-IP7 to generate 5PP-IP4, 5-IP7 and 1,5-IP8 respectively. Diphosphoinositol pentakisphosphate kinases (PPIP5Ks) primarily convert 5-IP7 to 1,5-IP8. PPIP5Ks also generate 1-IP7 from IP6, albeit to a lesser extent (dotted arrow). Diphosphoinositol polyphosphate phosphohydrolases (DIPPs) hydrolyse inositol pyrophosphates to regenerate the respective inositol phosphates. At a lower ATP/ADP ratio, IP6Ks dephosphorylate IP6 to IP5*. Only well-characterized enzymes are depicted.

Fig. 3

A–C. Schematic presentation of the human inositol hexakisphosphate kinase (IP6K) isoforms. In addition to the highly conserved catalytic domain (cyan: catalytic), various other regions display substantial similarities (cyan). Conversely, certain (white) regions are isoform-specific. IP6Ks interact with various protein targets in an isoform-selective manner. A few representative protein-interactors are shown for IP6K1 and IP6K2, for which the target binding sites were mapped. Some isoform-specific interactions are partly explained by substantial dissimilarity in the binding regions. IP6Ks also bind to certain targets [perilipin-1 (PLIN1) for IP6K1 and TNF receptor-associated factor-2 (TRAF2) for IP6K2] via phosphorylation of isoform-specific residues. Details of these and other interactions are presented in Sections IV–VI. AMPK, AMP-activated protein kinase; CK2, casein kinase 2; HSP90, heat shock protein 90; p53, tumour suppressor protein 53; PKA/C, protein kinase A/C; Tti1, telomere length regulation protein 2 (Tel2)-interacting proteins 1.

Fig. 4.

Domain analyses of human diphosphoinositol pentaphosphate kinases PPIP5K1 and PPIP5K2 (redrawn from Shears et al., 2016). PPIP5Ks contain a kinase and a phosphatase domain, which share 86 and 77% homology between the isoforms. This group also contains an intrinsically disordered domain (IDR), essential for protein– protein interaction, which shares 3% identity. PPIP5K2 contains a penta-arginine (CPA) domain that serves as a nuclear-localization signal (NLS). Phosphorylation of the serine 1006 residue, adjacent to the NLS regulates the nuclear localization of PPIP5K2.

Fig. 5.

Isoform-specific post-translational modifications regulate inositol hexakisphosphate kinase (IP6K) stability or interaction with other proteins. Moreover, isoform-selective interactions with certain proteins regulate the catalytic activity of IP6K. (A) Protein kinase A/C (PKA/PKC)-mediated phosphorylation of IP6K1 mediates its interaction with the lipolytic modulator perilipin 1 (PLIN1). (B) Casein kinase-2 (CK2) phosphorylation facilitates degradation of IP6K2. (C) DNA damage binding protein-1 (DDB1) inhibits IP6K1 catalytic activity. (D) Heat shock protein 90 (HSP90) binds to inhibit the catalytic activity of IP6K2.

Fig. 6.

Mechanisms by which inositol pyrophosphate biosynthetic enzymes regulate protein targets. The model is based primarily on inositol hexakisphosphate kinases (IP6Ks). IP6Ks generate inositol phosphate IP7 from IP6. IP7 modulates protein (yellow) targets by direct binding. This activity also diminishes the effects of IP6 on its protein (blue) targets. Moreover, IP7 donates its β-phosphate (grey) to the serine residue of a protein (green), which is already phosphorylated (pink) by a priming protein kinase. This event is called pyrophosphorylation. IP6 is released by the process, which may enhance its interaction with protein targets. In addition, IP6Ks bind to certain protein targets (cyan), to alter their conformations and functions. This does not require catalytic activity of IP6Ks. The catalytic activity-mediated functions of IP6K may also require protein interaction. Diphosphoinositol pentakisphosphate kinase (PPIP5K) may display similar activities. See Section V for further details.

Fig. 7.

The inositol pyrophosphate (IPP) metabolic pathway regulates various cellular processes in mammals.

Fig. 8.

Summary of benefits and potential risks of perturbation of the inositol pyrophosphate (IPP) pathway. Studies using IP6K1-, IP6K2- and IP6K3-knockout mouse models and pan-pharmacological inhibition reveal that disruption of the pathway is beneficial in several diseases (highlighted in green). However, the knockout mice also display isoform-specific aberrations (highlighted in pink). Thus, although the IPP pathway is a novel and encouraging therapeutic target, precautions must be taken during drug development to minimize potential risks. Development of isoform-selective inhibitors would be beneficial. 4-NQO, 4-nitroquinoline-1-oxide; BM-MSC, bone marrow-derived mesenchymal stem cell; I/R, ischaemia/reperfusion; MI, myocardial infarction; MSC, mesenchymal stem cell.