Metabolomics and proteomics identify the toxic form and the associated cellular binding targets of the anti-proliferative drug AICAR - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Journal of Biological Chemistry Année : 2019

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

Résumé

5-Aminoimidazole-4-carboxamide 1-␤-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-␤ 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 over-expression of KAP123 for 15 of them. These results reveal nuclear protein trafficking as a function affected by AICAR.
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Dates et versions

hal-02346549 , version 1 (05-11-2019)

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Delphine C Douillet, Benoit Pinson, Johanna Ceschin, Hans C Hürlimann, Christelle Saint-Marc, et al.. Metabolomics and proteomics identify the toxic form and the associated cellular binding targets of the anti-proliferative drug AICAR. Journal of Biological Chemistry, 2019, 294 (3), pp.805-815. ⟨10.1074/jbc.RA118.004964⟩. ⟨hal-02346549⟩

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