A Novel Inositol Pyrophosphate Phosphatase in Saccharomyces cerevisiae: Siw14 PROTEIN SELECTIVELY CLEAVES THE β-PHOSPHATE FROM 5-DIPHOSPHOINOSITOL PENTAKISPHOSPHATE (5PP-IP5)

J Biol Chem. 2016 Mar 25;291(13):6772-83. doi: 10.1074/jbc.M116.714907. Epub 2016 Jan 31.


Inositol pyrophosphates are high energy signaling molecules involved in cellular processes, such as energetic metabolism, telomere maintenance, stress responses, and vesicle trafficking, and can mediate protein phosphorylation. Although the inositol kinases underlying inositol pyrophosphate biosynthesis are well characterized, the phosphatases that selectively regulate their cellular pools are not fully described. The diphosphoinositol phosphate phosphohydrolase enzymes of the Nudix protein family have been demonstrated to dephosphorylate inositol pyrophosphates; however, theSaccharomyces cerevisiaehomolog Ddp1 prefers inorganic polyphosphate over inositol pyrophosphates. We identified a novel phosphatase of the recently discovered atypical dual specificity phosphatase family as a physiological inositol pyrophosphate phosphatase. Purified recombinant Siw14 hydrolyzes the β-phosphate from 5-diphosphoinositol pentakisphosphate (5PP-IP5or IP7)in vitro. In vivo,siw14Δ yeast mutants possess increased IP7levels, whereas heterologousSIW14overexpression eliminates IP7from cells. IP7levels increased proportionately whensiw14Δ was combined withddp1Δ orvip1Δ, indicating independent activity by the enzymes encoded by these genes. We conclude that Siw14 is a physiological phosphatase that modulates inositol pyrophosphate metabolism by dephosphorylating the IP7isoform 5PP-IP5to IP6.

Keywords: IP7; Saccharomyces cerevisiae; Siw14; Vip1; dual-specificity phosphoprotein phosphatase; inositol phosphate; phosphatase; phosphatidylinositol; second messenger.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cloning, Molecular
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Deletion
  • Gene Expression Regulation, Fungal*
  • Genetic Complementation Test
  • Inositol Phosphates / metabolism*
  • Kinetics
  • Phosphotransferases (Phosphate Group Acceptor) / genetics
  • Phosphotransferases (Phosphate Group Acceptor) / metabolism
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism*
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Signal Transduction
  • Substrate Specificity


  • Inositol Phosphates
  • Recombinant Proteins
  • Saccharomyces cerevisiae Proteins
  • 1-diphosphoinositol pentakisphosphate
  • Phosphotransferases (Phosphate Group Acceptor)
  • inositol hexakisphosphate kinase
  • Protein Tyrosine Phosphatases
  • Siw14 protein, S cerevisiae