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  Metabolomics and proteomics identify the toxic form and the associated cellular binding targets of the anti-proliferative drug AICAR.

Doulliet, D. C., Pinson, B., Ceschin, J., Hürlimann, H. C., Saint-Marc, C., Laporte, D., et al. (2019). Metabolomics and proteomics identify the toxic form and the associated cellular binding targets of the anti-proliferative drug AICAR. Journal of Biological Chemistry, 294, 805-815. doi:10.1074/jbc.RA118.004964.

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 Urheber:
Doulliet, D. C., Autor
Pinson, B., Autor
Ceschin, J., Autor
Hürlimann, H. C., Autor
Saint-Marc, C., Autor
Laporte, D., Autor
Claverol, S., Autor
Konrad, M.1, Autor           
Bonneu, M., Autor
Daignan-Fornier, B., Autor
Affiliations:
1Research Group of Enzyme Biochemistry, MPI for biophysical chemistry, Max Planck Society, ou_578612              

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Schlagwörter: drug metabolism; nucleoside/nucleotide analogue; proteomics; purine; small molecule; yeast genetics; yeast metabolism
 Zusammenfassung: AICAR (Acadesine; 5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside) is a precursor of the monophosphate derivative ZMP, an intermediate in de novo purine biosynthesis. AICAR proved promising anti-proliferative properties, though the molecular basis of its toxicity is poorly understood. To exert cytotoxicity, AICAR needs to be metabolized, but the AICAR-derived toxic metabolite was not identified. Here, we show that ZMP is the major toxic derivative of AICAR in yeast and establish that its metabolization to SZMP (succinyl-ZMP), ZDP or ZTP (di- and tri-phosphate derivatives of AICAR) strongly reduced its toxicity. Affinity chromatography identified 74 ZMP-binding proteins, including 41 that were found neither as AMP-, nor as AICAR- or SZMP-binders. Overexpression of karyopherin-β Kap123, one of the ZMP-specific binders, partially rescued AICAR-toxicity. Quantitative proteomic analyses revealed 57 proteins significantly less abundant on nuclei-enriched fractions from AICAR-fed cells, this effect being compensated by overexpression of KAP123 for 15 of them. These results reveal nuclear protein trafficking as a function affected by AICAR.

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Sprache(n): eng - English
 Datum: 2018-11-262019-01-18
 Publikationsstatus: Erschienen
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 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: DOI: 10.1074/jbc.RA118.004964
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Titel: Journal of Biological Chemistry
Genre der Quelle: Zeitschrift
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Seiten: - Band / Heft: 294 Artikelnummer: - Start- / Endseite: 805 - 815 Identifikator: -