Metabolomics and proteomics identify the toxic form and the associated cellular binding targets of the anti-proliferative drug AICAR
| dc.rights.license | open | en_US |
| dc.contributor.author | DOUILLET, Delphine C. | |
| dc.contributor.author | PINSON, Benoît | |
| dc.contributor.author | CESCHIN, Johanna | |
| dc.contributor.author | HÜRLIMANN, Hans C. | |
| dc.contributor.author | SAINT-MARC, Christelle | |
| dc.contributor.author | LAPORTE, Damien | |
| dc.contributor.author | CLAVEROL, Stéphane | |
| dc.contributor.author | KONRAD, Manfred | |
| dc.contributor.author | BONNEU, Marc | |
| dc.contributor.author | DAIGNAN-FORNIER, Bertrand | |
| dc.date.accessioned | 2019 | |
| dc.date.available | 2019 | |
| dc.date.issued | 2019 | |
| dc.identifier.issn | 1083-351X | en_US |
| dc.identifier.uri | https://oskar-bordeaux.fr/handle/20.500.12278/3810 | |
| dc.description.abstractEn | 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. | |
| dc.language.iso | EN | en_US |
| dc.subject.en | purine | |
| dc.subject.en | yeast genetics | |
| dc.subject.en | yeast metabolism | |
| dc.subject.en | nucleoside/nucleotide analogue | |
| dc.subject.en | proteomics | |
| dc.subject.en | drug metabolism | |
| dc.subject.en | small molecule | |
| dc.title.en | Metabolomics and proteomics identify the toxic form and the associated cellular binding targets of the anti-proliferative drug AICAR | |
| dc.title.alternative | J. Biol. Chem. | en_US |
| dc.type | Article de revue | en_US |
| dc.identifier.doi | 10.1074/jbc.RA118.004964 | |
| dc.subject.hal | Chimie/Matériaux | en_US |
| bordeaux.journal | Journal of Biological Chemistry | en_US |
| bordeaux.page | 805-815 | en_US |
| bordeaux.volume | 294 | en_US |
| bordeaux.hal.laboratories | Institut de Chimie & de Biologie des Membranes & des Nano-objets (CBMN) - UMR 5248 | |
| bordeaux.issue | 3 | en_US |
| bordeaux.institution | Université de Bordeaux | en_US |
| bordeaux.peerReviewed | oui | en_US |
| bordeaux.inpress | non | en_US |
| hal.identifier | hal-03181365 | |
| hal.version | 1 | |
| hal.date.transferred | 2021-03-25T14:33:41Z | |
| hal.export | true | |
| bordeaux.COinS | ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Journal%20of%20Biological%20Chemistry&rft.date=2019&rft.volume=294&rft.issue=3&rft.spage=805-815&rft.epage=805-815&rft.eissn=1083-351X&rft.issn=1083-351X&rft.au=DOUILLET,%20Delphine%20C.&PINSON,%20Beno%C3%AEt&CESCHIN,%20Johanna&H%C3%9CRLIMANN,%20Hans%20C.&SAINT-MARC,%20Christelle&rft.genre=article |
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