| Inositol pyrophosphates (PP-IPs) are a class of energy-rich signalling molecules found in all eukaryotic cells. These are derivatives of inositol that contain one or more diphosphate (or pyrophosphate) groups in addition to monophosphates. The more abundant and best studied PP-IPs are diphosphoinositol pentakisphosphate (IP 7 ) and bis-diphosphoinositol tetrakisphosphate (IP 8 ). These molecules can influence protein function by two mechanisms: binding and pyrophosphorylation. The former involves the specific interaction of a particular inositol pyrophosphate with a binding site on a protein, while the latter is a unique attribute of inositol pyrophosphates, wherein the β-phosphate moiety is transferred from a PP-IP to a pre-phosphorylated serine residue in a protein to generate pyrophosphoserine. Both these events can result in changes in the target protein's activity, localisation or its interaction with other partners. As a consequence of their ubiquitous presence in all eukaryotic organisms and all cell types examined till date, and their ability to modify protein function, PP-IPs have been found to participate in a wide range of metabolic, developmental, and signalling pathways.This review highlights many of the known functions of PP-IPs in the context of their temporal and spatial distribution in eukaryotic cells. The pathway of synthesis of inositol polyphosphates has been characterized in yeast, slime moulds, plants and animals. The simplest anabolic pathway, characterized in the yeast Saccharomyces cerevisiae (Fig. 1) (Fig. 1). Interestingly, the PPIP5Ks also possess a phosphatase domain which selectively cleaves the 1-position β-phosphate of 1-IP 7 and IP 8 , thus targeting the products of the kinase domain.35, 36 A recent study identified another yeast phosphatase, Siw14, that specifically targets the 5-position β-phosphate of PP-IPs 37 (Fig. 1). As PP-IPs are found in all eukaryotic organisms, they display many conserved and divergent 2, 131 Siw14, an inositol pyrophosphate phosphatase in yeast, preferentially cleaves the C5 β-phosphate on PP-IPs. 37 The yeast enzymes are depicted in purple, and mammalian enzymes are depicted in green and are bracketed. The undetermined inositol pyrophosphate structure is represented with an interrogation mark. Myoinositol contains five equatorial (parallel to the axis) and one axial (perpendicular to the axis) hydroxyl groups. Carbon atoms on the myo-inositol ring are numbered on the structures of PI(4,5)P 2 and IP 6 .

Inositol hexakisphosphate kinases (IP6Ks) are enzymes that catalyse the synthesis of the inositol pyrophosphate 5-IP7 which is involved in the regulation of many physiological processes in mammals. The IP6K paralog IP6K1 is expressed at high levels in the mammalian testis, and its deletion leads to sterility in male mice. Here, we show that the loss of IP6K1 in mice causes a delay in the first wave of spermatogenesis. Testes from juvenile Ip6k1 knockout mice show downregulation of transcripts that are involved in cell adhesion and formation of the testis-specific inter-Sertoli cell impermeable junction complex known as the blood-testis barrier (BTB). We demonstrate that loss of IP6K1 in the mouse testis causes BTB disruption associated with transcriptional misregulation of the tight junction protein claudin 3, and subcellular mislocalization of the gap junction protein connexin 43. In addition to BTB disruption, we also observe loss of germ cell adhesion in the seminiferous epithelium of Ip6k1 knockout mice, ultimately resulting in premature sloughing of round spermatids into the epididymis. Mechanistically, we show that loss of IP6K1 in the testis enhances cofilin activity due to increased AKT/ERK and integrin signalling, resulting in destabilization of the actin-based cytoskeleton in Sertoli cells and germ cell loss.