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J Biol Chem. 2019 Jan 18;294(3):805-815. doi: 10.1074/jbc.RA118.004964. Epub 2018 Nov 26.

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

Author information

1
From the Université de Bordeaux, IBGC UMR 5095, F-33077 Bordeaux, France.
2
the Centre National de la Recherche Scientifique, IBGC UMR 5095, F-33077 Bordeaux, France.
3
the University of Bordeaux, Bordeaux INP, Plateforme Proteome, F-33076 Bordeaux, France, and.
4
the Max-Planck-Institute for Biophysical Chemistry, D-37077 Goettingen, Germany.
5
From the Université de Bordeaux, IBGC UMR 5095, F-33077 Bordeaux, France, b.daignan-fornier@ibgc.cnrs.fr.

Abstract

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.

KEYWORDS:

drug metabolism; nucleoside/nucleotide analogue; proteomics; purine; small molecule; yeast genetics; yeast metabolism

PMID:
30478173
PMCID:
PMC6341394
[Available on 2020-01-18]
DOI:
10.1074/jbc.RA118.004964
[Indexed for MEDLINE]

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