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キーワード:
drug metabolism; nucleoside/nucleotide analogue; proteomics; purine; small molecule; yeast genetics; yeast metabolism
要旨:
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.
