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Synthetic tools for studying the chemical biology of InsP8.

Riley AM, Wang H, Shears SB, L Potter BV - Chem. Commun. (Camb.) (2015)

Bottom Line: To synthesise stabilised mimics of InsP8, the most phosphorylated inositol phosphate signalling molecule in Nature, we replaced its two diphosphate (PP) groups with either phosphonoacetate (PA) or methylenebisphosphonate (PCP) groups.Utility of the PA and PCP analogues was verified by structural and biochemical analyses of their interactions with enzymes of InsP8 metabolism.

View Article: PubMed Central - PubMed

Affiliation: Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.

ABSTRACT
To synthesise stabilised mimics of InsP8, the most phosphorylated inositol phosphate signalling molecule in Nature, we replaced its two diphosphate (PP) groups with either phosphonoacetate (PA) or methylenebisphosphonate (PCP) groups. Utility of the PA and PCP analogues was verified by structural and biochemical analyses of their interactions with enzymes of InsP8 metabolism.

Show MeSH
(a) Biosynthesis of diphosphoinositol polyphosphates from myo-inositol hexakisphosphate (InsP6). IP6K, inositol hexakisphosphate 5-kinase; PPIP5K, diphosphoinositol pentakisphosphate kinase; DIPP, diphosphoinositol polyphosphate phosphohydrolase; (b) structures of synthetic α-phosphonoacetic acid ester (PA) analogue 1 and methylenebisphosphonate (PCP) analogue 2.
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fig1: (a) Biosynthesis of diphosphoinositol polyphosphates from myo-inositol hexakisphosphate (InsP6). IP6K, inositol hexakisphosphate 5-kinase; PPIP5K, diphosphoinositol pentakisphosphate kinase; DIPP, diphosphoinositol polyphosphate phosphohydrolase; (b) structures of synthetic α-phosphonoacetic acid ester (PA) analogue 1 and methylenebisphosphonate (PCP) analogue 2.

Mentions: The most studied of the PP-InsPs are 5-InsP7, 1-InsP7 and InsP8 (Fig. 1), which are formed from InsP6 by InsP6 kinases (IP6Ks) and diphosphoinositol pentakisphosphate kinases (PPIP5Ks).9 The diphosphate groups that are produced by IP6K and PPIP5K are hydrolysed by a family of PP-InsP diphosphohydrolases (DIPPs), leaving monophosphate groups and liberating inorganic orthophosphate (Pi).10


Synthetic tools for studying the chemical biology of InsP8.

Riley AM, Wang H, Shears SB, L Potter BV - Chem. Commun. (Camb.) (2015)

(a) Biosynthesis of diphosphoinositol polyphosphates from myo-inositol hexakisphosphate (InsP6). IP6K, inositol hexakisphosphate 5-kinase; PPIP5K, diphosphoinositol pentakisphosphate kinase; DIPP, diphosphoinositol polyphosphate phosphohydrolase; (b) structures of synthetic α-phosphonoacetic acid ester (PA) analogue 1 and methylenebisphosphonate (PCP) analogue 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4643724&req=5

fig1: (a) Biosynthesis of diphosphoinositol polyphosphates from myo-inositol hexakisphosphate (InsP6). IP6K, inositol hexakisphosphate 5-kinase; PPIP5K, diphosphoinositol pentakisphosphate kinase; DIPP, diphosphoinositol polyphosphate phosphohydrolase; (b) structures of synthetic α-phosphonoacetic acid ester (PA) analogue 1 and methylenebisphosphonate (PCP) analogue 2.
Mentions: The most studied of the PP-InsPs are 5-InsP7, 1-InsP7 and InsP8 (Fig. 1), which are formed from InsP6 by InsP6 kinases (IP6Ks) and diphosphoinositol pentakisphosphate kinases (PPIP5Ks).9 The diphosphate groups that are produced by IP6K and PPIP5K are hydrolysed by a family of PP-InsP diphosphohydrolases (DIPPs), leaving monophosphate groups and liberating inorganic orthophosphate (Pi).10

Bottom Line: To synthesise stabilised mimics of InsP8, the most phosphorylated inositol phosphate signalling molecule in Nature, we replaced its two diphosphate (PP) groups with either phosphonoacetate (PA) or methylenebisphosphonate (PCP) groups.Utility of the PA and PCP analogues was verified by structural and biochemical analyses of their interactions with enzymes of InsP8 metabolism.

View Article: PubMed Central - PubMed

Affiliation: Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.

ABSTRACT
To synthesise stabilised mimics of InsP8, the most phosphorylated inositol phosphate signalling molecule in Nature, we replaced its two diphosphate (PP) groups with either phosphonoacetate (PA) or methylenebisphosphonate (PCP) groups. Utility of the PA and PCP analogues was verified by structural and biochemical analyses of their interactions with enzymes of InsP8 metabolism.

Show MeSH