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Thiophosphate analogs of coenzyme A and its precursors: synthesis, stability, and biomimetic potential

Coenzyme A (CoA) is ubiquitous and essential for key cellular processes in any living organism. Primary degradation of CoA occurs by enzyme-mediated pyrophosphate hydrolysis intracellularly and extracellularly to form adenosine 3’,5’-diphosphate and 4’-phosphopantetheine (PPanSH). The latter can be...

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Bibliographic Details
Main Authors: Löcherer, Christian (Author) , Tosun, Elif (Author) , Backes, Hannah (Author) , Jäschke, Andres (Author)
Format: Article (Journal)
Language:English
Published: 1 August 2022
In: Biomolecules
Year: 2022, Volume: 12, Issue: 8, Pages: 1-9
ISSN:2218-273X
DOI:10.3390/biom12081065
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/biom12081065
Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/2218-273X/12/8/1065
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Author Notes:Christian Löcherer, Elif Tosun, Hannah Backes and Andres Jäschke
Description
Summary:Coenzyme A (CoA) is ubiquitous and essential for key cellular processes in any living organism. Primary degradation of CoA occurs by enzyme-mediated pyrophosphate hydrolysis intracellularly and extracellularly to form adenosine 3’,5’-diphosphate and 4’-phosphopantetheine (PPanSH). The latter can be recycled for intracellular synthesis of CoA. Impairments in the CoA biosynthetic pathway are linked to a severe form of neurodegeneration with brain iron accumulation for which no disease-modifying therapy is available. Currently, exogenous administration of PPanSH is examined as a therapeutic intervention. Here, we describe biosynthetic access to thiophosphate analogs of PPanSH, 3′-dephospho-CoA, and CoA. The stabilizing effect of thiophosphate modifications toward degradation by extracellular and peroxisomal enzymes was studied in vitro. Experiments in a CoA-deficient cell model suggest a biomimetic potential of the PPanSH thiophosphate analog PSPanSH (C1). According to our findings, the administration of PSPanSH may provide an alternative approach to support intracellular CoA-dependent pathways.
Item Description:Gesehen am 13.09.2022
Physical Description:Online Resource
ISSN:2218-273X
DOI:10.3390/biom12081065

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