4.6 Article

Identification of Yeast and Human 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAr) Transporters

Journal

JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 24, Pages 16844-16854

Publisher

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.551192

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Funding

  1. Association de la Recherche contre le Cancer [SFI-2012-120-5915]
  2. Ligue contre le Cancer du Perigord

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5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAr) is the precursor of the active monophosphate form (AICAR), a small molecule with potent anti-proliferative and low energy mimetic properties. The molecular bases for AICAR toxicity at the cellular level are poorly understood. Here, we report the isolation and characterization of several yeast AICAr-hypersensitive mutants. Identification of the cognate genes allowed us to establish that thiamine transporters Thi7 and Thi72 can efficiently take up AICAr under conditions where they are overexpressed. We establish that, under standard growth conditions, Nrt1, the nicotinamide riboside carrier, is the major AICAr transporter in yeast. A study of AICAR accumulation in human cells revealed substantial disparities among cell lines and confirmed that AICAr enters cells via purine nucleoside transporters. Together, our results point to significant differences between yeast and human cells for both AICAr uptake and AICAR accumulation.

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