If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Synonyms: diphosphorylated inositol polyphosphates biosynthesis
|Superclasses:||Biosynthesis → Secondary Metabolites Biosynthesis → Sugar Derivatives Biosynthesis → Cyclitols Biosynthesis|
Expected Taxonomic Range: Eukaryota
In the early 1990s, two groups working independently discovered a novel subgroup of the inositol phosphate signaling family in which diphosphate groups are added to D-myo-inositol 1,3,4,5,6-pentakisphosphate and 1D-myo-inositol 1,2,3,4,5,6-hexakisphosphate [Stephens93, Menniti93], forming compounds that are now known as "inositol pyrophosphates" or "diphosphoinositol polyphosphates" [Bennett06]. These molecules have been reported to be involved in the regulation of vesicle trafficking [Saiardi02], transcription [El03b], chemotaxis [Luo03], telomere maintenance [York05, Saiardi05], apoptosis [Nagata05a, Morrison01], and DNA repair [Luo02], and to mediate environmental stress responses [Dubois02, Pesesse04, Safrany04, Choi05b].
The concentration of the molecules appear to be tightly regulated with an extremely rapid turnover [Burton09a]. By inhibiting the enzymes that remove the pyrophosphate groups (encoded by NUDT3, NUDT4, NUDT10 and NUDT11) it was possible to calculate that their cellular pools were normally turning over at least 10 times every 40 min [Glennon93].
The pathway that leads to the biosynthesis of inositol pyrophosphates has been illucidated. Two main classes of enzymes are involved in yeast and mammals: 5-kinases (encoded in mammals by IP6K1, IP6K2 and IP6K3, and in yeast by KcsI) [Saiardi99, Saiardi01a] and 1/3 kinases (encoded in mammals by PPIP5K1 and PPIP5K2 and in yeast by Vip1) [Mulugu07, Lin09c].
All of these enzymes can phosphorylate 1D-myo-inositol 1,2,3,4,5,6-hexakisphosphate, generating either 1D-myoinositol 5-diphosphate 1,2,3,4,6-pentakisphosphate (in the case of IP6K) or a mixture of 1D-myo-inositol 1-diphosphate 2,3,4,5,6-pentakisphosphate and 1D-myo-inositol 3-diphosphate 1,2,4,5,6-pentakisphosphate (in the case of PPIP5K). These compounds, which contain a single pyrophosphate, are also known simply as InsP7. In addition, each enzyme class can continue to phosphorylate the product of the other enzyme class, resulting in a mixture of 1D-myo-inositol 1,5-bis(diphosphate) 2,3,4,6-tetrakisphosphate and 3,5-bisdiphosphoinositol-1D-myo-inositol 2,3,4,6-tetrakisphosphate, also known as InsP8 [Lin09c].
Another inositol pyrophosphate that is found in cells is a diphospho-1D-myo-inositol tetrakisphosphate, whose exact stereomeric structure has not been defined yet. This compound is synthesized from D-myo-inositol 1,3,4,5,6-pentakisphosphate by the three IP6K [Saiardi00a], as well as the inositol 1,3,4,6-tetrakisphosphate 5-kinase (IPMK) [Saiardi01].
Superpathways: superpathway of inositol phosphate compounds
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Lin09c: Lin H, Fridy PC, Ribeiro AA, Choi JH, Barma DK, Vogel G, Falck JR, Shears SB, York JD, Mayr GW (2009). "Structural analysis and detection of biological inositol pyrophosphates reveal that the family of VIP/diphosphoinositol pentakisphosphate kinases are 1/3-kinases." J Biol Chem 284(3);1863-72. PMID: 18981179
Luo02: Luo HR, Saiardi A, Yu H, Nagata E, Ye K, Snyder SH (2002). "Inositol pyrophosphates are required for DNA hyperrecombination in protein kinase c1 mutant yeast." Biochemistry 41(8);2509-15. PMID: 11851397
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