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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| Format: | Article |
| Language: | English |
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MDPI AG
2022-08-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/12/8/1065 |
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| author | Christian Löcherer Elif Tosun Hannah Backes Andres Jäschke |
| author_facet | Christian Löcherer Elif Tosun Hannah Backes Andres Jäschke |
| author_sort | Christian Löcherer |
| collection | DOAJ |
| description | 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 P<sub>S</sub>PanSH (C1). According to our findings, the administration of P<sub>S</sub>PanSH may provide an alternative approach to support intracellular CoA-dependent pathways. |
| first_indexed | 2024-03-09T10:00:21Z |
| format | Article |
| id | doaj.art-4ed60d941da742dbabbab4ca3a34f14b |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T10:00:21Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-4ed60d941da742dbabbab4ca3a34f14b2023-12-01T23:28:54ZengMDPI AGBiomolecules2218-273X2022-08-01128106510.3390/biom12081065Thiophosphate Analogs of Coenzyme A and Its Precursors—Synthesis, Stability, and Biomimetic PotentialChristian Löcherer0Elif Tosun1Hannah Backes2Andres Jäschke3Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, GermanyInstitute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, GermanyInstitute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, GermanyInstitute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, GermanyCoenzyme 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 P<sub>S</sub>PanSH (C1). According to our findings, the administration of P<sub>S</sub>PanSH may provide an alternative approach to support intracellular CoA-dependent pathways.https://www.mdpi.com/2218-273X/12/8/1065CoAPPanSHphosphorothioateCoA biosynthesisCoA degradationNudt7 |
| spellingShingle | Christian Löcherer Elif Tosun Hannah Backes Andres Jäschke Thiophosphate Analogs of Coenzyme A and Its Precursors—Synthesis, Stability, and Biomimetic Potential Biomolecules CoA PPanSH phosphorothioate CoA biosynthesis CoA degradation Nudt7 |
| title | Thiophosphate Analogs of Coenzyme A and Its Precursors—Synthesis, Stability, and Biomimetic Potential |
| title_full | Thiophosphate Analogs of Coenzyme A and Its Precursors—Synthesis, Stability, and Biomimetic Potential |
| title_fullStr | Thiophosphate Analogs of Coenzyme A and Its Precursors—Synthesis, Stability, and Biomimetic Potential |
| title_full_unstemmed | Thiophosphate Analogs of Coenzyme A and Its Precursors—Synthesis, Stability, and Biomimetic Potential |
| title_short | Thiophosphate Analogs of Coenzyme A and Its Precursors—Synthesis, Stability, and Biomimetic Potential |
| title_sort | thiophosphate analogs of coenzyme a and its precursors synthesis stability and biomimetic potential |
| topic | CoA PPanSH phosphorothioate CoA biosynthesis CoA degradation Nudt7 |
| url | https://www.mdpi.com/2218-273X/12/8/1065 |
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