Inositol pyrophosphates as multifaceted metabolites in the regulation of mammalian signaling networks

Abstract

Inositol pyrophosphates (PP-IPs) such as 5-diphosphoinositol pentakisphosphate (5-IP 7 ) are inositol metabolites with high-energy phosphoanhydride bonds. The formation of PP-IPs is catalyzed by two groups of enzymes, the IP6 kinases and the PPIP5 kinases, which both phosphorylate inositol hexakisphosphate (IP 6 ). In mammals, PP-IPs are implicated in diverse biological phenomena including cellular growth, vesicular trafficking, apoptosis, and metabolic homeostasis. Mechanistically, all the diverse actions of PP-IPs proceed in one of two ways: the PP-IPs modulate the activity of their target proteins either through allosteric binding or protein pyrophosphorylation. In this review, we highlight recent advances in our understanding of the pleiotropic functions of the mammalian PP-IPs and the metabolic enzymes that produce them. We also discuss some future challenges in the exploration of areas where PP-IPs play important but unknown roles in physiology and disease.ARTICLE HISTORY

Inositol Pyrophosphates: Signaling Molecules with Pleiotropic Actions in Mammals

“…Among many IP species, pyrophosphorylated-IPs (PP-IPs) exhibit a unique structural feature in that they contain highly energetic phosphoanhydride bonds (pyrophosphates) at specific positions [10,11]. Their biosynthesis is catalyzed by two groups of IP kinases, the IP6 kinases (IP6Ks) [12,13] and the PPIP5 kinases (PPIP5Ks) [14,15], which phosphorylate IP6 and IP7.…”

“…In addition to IP7, cellular conditions such as osmolarity [14], temperature [26], and phosphate levels [27] are also known to increase IP8 levels. Because of their high-energy phosphate bonds and rapid cellular turnover in response to cellular stimuli, PP-IPs have been viewed as 'mammalian cell signals', 'regulators of cell homeostasis', and 'metabolic messengers' [9,11,[28][29][30].…”

“…It is challenging to characterize the mechanistic basis underlying the cellular and physiological changes regulated by PP-IPs. Similar to signaling molecules, PP-IPs modulate specific target proteins to control cellular signaling events via different molecular interactions [9,11,31]. Non-covalent interactions between these metabolites and proteins occur allosterically or stably.…”

“…Non-covalent interactions between these metabolites and proteins occur allosterically or stably. In common with other major signaling molecules, such as cyclic AMP [32], allosteric interactions between PP-IPs and their protein targets are the representative mode of PP-IP action [11,31].…”

“…An additional metabolite signaling action is the covalent modification of proteins; metabolites serve as substrates for protein modification (e.g., ATP and succinyl-CoA) and can induce chemical changes on proteins, to regulate functioning or biochemical fates, such as protein stability and subcellular localization. Furthermore, PP-IPs are known as the source for protein pyrophosphorylation [11,31,33,34] (Figure 2).…”