Thiophosphate analogs of coenzyme A and its precursors

• Verfasst von: Löcherer, Christian [VerfasserIn]
• Verfasst von: Tosun, Elif [VerfasserIn]
• Verfasst von: Backes, Hannah [VerfasserIn]
• Verfasst von: Jäschke, Andres [VerfasserIn]
• Titel: Thiophosphate analogs of coenzyme A and its precursors
• Titelzusatz: synthesis, stability, and biomimetic potential
• Verf.angabe: Christian Löcherer, Elif Tosun, Hannah Backes and Andres Jäschke
• E-Jahr: 2022
• Jahr: 1 August 2022
• Umfang: 9 S.
• Fussnoten: Gesehen am 13.09.2022
• Titel Quelle: Enthalten in: Biomolecules
• Ort Quelle: Basel : MDPI, 2011
• Jahr Quelle: 2022
• Band/Heft Quelle: 12(2022), 8, Artikel-ID 1065, Seite 1-9
• ISSN Quelle: 2218-273X
• DOI: doi:10.3390/biom12081065
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: CoA
• Sach-SW: CoA biosynthesis
• Sach-SW: CoA deficiency
• Sach-SW: CoA degradation
• Sach-SW: HoPan
• Sach-SW: NBIA
• Sach-SW: Nudt7
• Sach-SW: phosphorothioate
• Sach-SW: PKAN
• Sach-SW: PPanSH
• K10plus-PPN: 1816489336

Abstract

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.