DOUILLET, Delphine C.; PINSON, Benoît; CESCHIN, Johanna; HÜRLIMANN, Hans C.; SAINT-MARC, Christelle; LAPORTE, Damien; CLAVEROL, Stéphane; KONRAD, Manfred; BONNEU, Marc; DAIGNAN-FORNIER, Bertrand

doi:10.1074/jbc.RA118.004964

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DOUILLET, Delphine C.

PINSON, Benoît

CESCHIN, Johanna

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Journal of Biological Chemistry. 2019, vol. 294, n° 3, p. 805-815

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5-Aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR, or acadesine) is a precursor of the monophosphate derivative 5-amino-4-imidazole carboxamide ribonucleoside 5′-phosphate (ZMP), an intermediate in de novo purine biosynthesis. AICAR proved to have promising anti-proliferative properties, although 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 succinyl-ZMP, ZDP, or ZTP (di- and triphosphate 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 succinyl-ZMP 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.< Réduire

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purine

yeast genetics

yeast metabolism

nucleoside/nucleotide analogue

proteomics

drug metabolism

small molecule

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

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