Identification of an Evolutionarily Conserved Family of Inorganic Polyphosphate Endopolyphosphatases

Abstract

Inorganic polyphosphate (poly-P) consists of just a chain of phosphate groups linked by high energy bonds. It is found in every organism and is implicated in a wide variety of cellular processes (e.g. phosphate storage, blood coagulation, and pathogenicity). Its metabolism has been studied mainly in bacteria while remaining largely uncharacterized in eukaryotes. It has recently been suggested that poly-P metabolism is connected to that of highly phosphorylated inositol species (inositol pyrophosphates). Inositol pyrophosphates are molecules in which phosphate groups outnumber carbon atoms. Like poly-P they contain high energy bonds and play important roles in cell signaling. Here, we show that budding yeast mutants unable to produce inositol pyrophosphates have undetectable levels of poly-P. Our results suggest a prominent metabolic parallel between these two highly phosphorylated molecules. More importantly, we demonstrate that DDP1, encoding diadenosine and diphosphoinositol phosphohydrolase, possesses a robust poly-P endopolyphosphohydrolase activity. In addition, we prove that this is an evolutionarily conserved feature because mammalian Nudix hydrolase family members, the three Ddp1 homologues in human cells (DIPP1, DIPP2, and DIPP3), are also capable of degrading poly-P.

Developmental accumulation of inorganic polyphosphate affects germination and energetic metabolism in Dictyostelium discoideum

“…In yeast, the level of polyP is metabolically connected to the level of inositol pyrophosphates (17). These molecules (InsP 7 and InsP 8 ) are notable for their ability to control cellular ATP synthesis (32,33).…”

“…Both exo-and endo polyphosphatases have also been identified in yeast (16,17). Furthermore, the yeast model has revealed a metabolic link between polyP and the phosphate-rich inositol pyrophosphates.…”

“…Furthermore, the yeast model has revealed a metabolic link between polyP and the phosphate-rich inositol pyrophosphates. In yeast, the levels of inositol pyrophosphates closely correlate with the level of polyP, and yeast strains lacking inositol pyrophosphates possess almost no polyP (17).…”

The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances inmyo‐Inositol Chemistry)

“…However, 232 has a 136-fold lower K i value but 218 is approximately two-fold lower compared to its natural parent 1PP-InsP 5 (167) and in line with the substrate preference for 1PP-InsP 5 . [237] Removing the 2-phosphate to give 233 provides a further four-fold enhancement of inhibition compared to 232 demonstrating that removal of a negative charge increases inhibition of hDIPP1. 231 Has similar inhibition properties to 232 in the low nanomolar region and may be a useful candidate to produce a lipophilic analogue for in vivo studies, in a similar way as 253.…”

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

“…The de-phosphorylation of inositol pyrophosphates to IP 6 or IP 5 is catalyzed by the enzyme diphosphoinositol polyphosphate phosphohydrolase (DIPP) (Safrany and Shears 1998;Safrany et al 1999;Caffrey et al 2000;Kilari et al 2013) (Figure 1). Compared to 5-IP 7 , 1-IP 7 seems to be a better substrate for DIPP (Lonetti et al 2011;Kilari et al 2013). This bias may be the reason mammalian cells produce higher levels of 5-IP 7 than 1-IP 7 .…”