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.

Identity and functions of inorganic and inositol polyphosphates in plants

“…Mammals possess three IP6K and two PPIP5K isoforms. Genetic deletion of single isoforms from each enzyme family in mice or human cell lines affects multiple processes, including cell growth, apoptosis, glycolysis, insulin production and even hearing loss (Chakraborty, 2018). In the green lineage, PPIP5K homologs have been characterized in Arabidopsis and in Chlamydomonas reinhardtii (Laha et al, 2015;Couso et al, 2016).…”

Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases

“…These biomolecules were named 'inositol pyrophosphates' (IPPs) to differentiate them from the monoester-based IPs [1][2][3][4][5][6][7]. The complex nomenclature of IPPs has been discussed previously [8][9][10][11][12][13]. Four major types of IPPs are characterized in mammalian cells; 5-diphosphoinositol (1,3,4,6)-tetrakisphosphate (5PP-IP4), 1-diphosphoinositol (2,3,4,5,6) pentakisphosphate (1PP-IP5 or 1-IP7), 5-diphosphoinositol (1,2,3,4,6) pentakisphosphate (5PP-IP5 or 5-IP7) and 1,5-bisdiphosphoinositol (2,3,4,6) tetrakisphosphate (1,5PP2-IP4 or 1,5-IP8), of which 5-IP7 is most characterized ( [12] and references therein).…”

“…Further studies will reveal whether inhibition of this pathway has similar pleiotropic benefits on metabolic health of humans. 2 of 28 human colon cancer cell line HCT116, 10-20% of total IP7 can be converted to 1,5-IP8 [12,19]. Figure 1 presents the major inositol pyrophosphate synthetic pathway in mammals.…”

“…IP6Ks may or may not interact with target proteins to facilitate 5-IP7-mediated effects. IP6Ks also regulate certain protein targets by direct protein-protein interaction, which is not dependent on their catalytic activity [12]. In addition to the classic lipid-IP3 pathway (phosphatidylinositol 4,5-bisphosphate, PIP2 is cleaved to diacylglycerol and inositol 1,4,5-trisphosphate IP3.…”

A pyro-phosphodegron controls MYC polyubiquitination to regulate cell survival

“…Inositol pyrophosphates are derivatives of myo-inositol characterized by the presence of one or more diphosphates in addition to monophosphates around the inositol ring (1). These small molecules are found in all eukaryotic cells, and are involved in the regulation of many cellular processes, including energy and phosphate metabolism, DNA repair, ribosome biogenesis, vesicle trafficking and insulin secretion (1)(2)(3)(4)(5). In mammals, the most abundant inositol pyrophosphate is 5-diphosphoinositol pentakisphosphate (5-PP-IP5 or 5-IP7), which is synthesized from inositol hexakisphosphate (IP6) by IP6 kinases.…”