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Prometabolites of 5-Diphospho-myo-inositol Pentakisphosphate


Pavlovic, Igor; Thakor, Divyeshsinh T; Bigler, Laurent; Wilson, Miranda S C; Laha, Debabrata; Schaaf, Gabriel; Saiardi, Adolfo; Jessen, Henning J (2015). Prometabolites of 5-Diphospho-myo-inositol Pentakisphosphate. Angewandte Chemie Internationale Edition, 54(33):9622-9626.

Abstract

Diphospho-myo-inositol phosphates (PP-InsPy) are an important class of cellular messengers. Thus far, no method for the transport of PP-InsPy into living cells is available. Owing to their high negative charge density, PP-InsPy 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-InsPy 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-InsP5 in mammalian cell/tissue homogenates within a few minutes and can be used to release 5-PP-InsP5 inside cells. These molecules will serve as a platform for the development of fundamental tools required to study PP-InsPy physiology.

Abstract

Diphospho-myo-inositol phosphates (PP-InsPy) are an important class of cellular messengers. Thus far, no method for the transport of PP-InsPy into living cells is available. Owing to their high negative charge density, PP-InsPy 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-InsPy 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-InsP5 in mammalian cell/tissue homogenates within a few minutes and can be used to release 5-PP-InsP5 inside cells. These molecules will serve as a platform for the development of fundamental tools required to study PP-InsPy physiology.

Citations

4 citations in Web of Science®
5 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:27 May 2015
Deposited On:26 Jan 2016 11:36
Last Modified:05 Apr 2016 19:54
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1433-7851
Publisher DOI:https://doi.org/10.1002/anie.201503094

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