Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 54, Issue 33, Pages 9622-9626Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201503094
Keywords
Inositol pyrophosphates; metabolism; protecting groups; second messengers
Categories
Funding
- SNSF [PP00P2_157607]
- MRC [MC_UU_1201814]
- DFG [SCHA 1274/2-1]
- MRC [MC_UU_12018/4, MC_U122680443] Funding Source: UKRI
- Medical Research Council [MC_U122680443, MC_UU_12018/4] Funding Source: researchfish
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Diphospho-myo-inositol phosphates (PP-InsP(y)) are an important class of cellular messengers. Thus far, no method for the transport of PP-InsP(y) into living cells is available. Owing to their high negative charge density, PP-InsP(y) will not cross the cell membrane. A strategy to circumvent this issue involves the generation of precursors in which the negative charges are masked with biolabile groups. A PP-InsP(y) prometabolite would require twelve to thirteen biolabile groups, which need to be cleaved by cellular enzymes to release the parent molecules. Such densely modified prometabolites of phosphate esters and anhydrides have never been reported to date. This study discloses the synthesis of such agents and an analysis of their metabolism in tissue homogenates by gel electrophoresis. The acetoxybenzyl-protected system is capable of releasing 5-PP-InsP(5) in mammalian cell/tissue homogenates within a few minutes and can be used to release 5-PP-InsP(5) inside cells. These molecules will serve as a platform for the development of fundamental tools required to study PP-InsP(y) physiology.
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