Identification of yeast and human 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAr) transporters.
5-Aminoimidazole-4-carboxamide-1-β-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.
From the Université de Bordeaux IBGC UMR 5095 1, F-33077 Bordeaux, France and the Centre National de la Recherche Scientifique IBGC UMR 5095 1, F-33077 Bordeaux, France.
Johanna
J
Ceschin
From the Université de Bordeaux IBGC UMR 5095 1, F-33077 Bordeaux, France and the Centre National de la Recherche Scientifique IBGC UMR 5095 1, F-33077 Bordeaux, France.
Christelle
C
Saint-Marc
From the Université de Bordeaux IBGC UMR 5095 1, F-33077 Bordeaux, France and the Centre National de la Recherche Scientifique IBGC UMR 5095 1, F-33077 Bordeaux, France.
Jean
J
Laporte
From the Université de Bordeaux IBGC UMR 5095 1, F-33077 Bordeaux, France and the Centre National de la Recherche Scientifique IBGC UMR 5095 1, F-33077 Bordeaux, France.
Adrien
A
Labriet
From the Université de Bordeaux IBGC UMR 5095 1, F-33077 Bordeaux, France and the Centre National de la Recherche Scientifique IBGC UMR 5095 1, F-33077 Bordeaux, France.
Chloé
C
Philippe
From the Université de Bordeaux IBGC UMR 5095 1, F-33077 Bordeaux, France and the Centre National de la Recherche Scientifique IBGC UMR 5095 1, F-33077 Bordeaux, France.
Michel
M
Moenner
From the Université de Bordeaux IBGC UMR 5095 1, F-33077 Bordeaux, France and the Centre National de la Recherche Scientifique IBGC UMR 5095 1, F-33077 Bordeaux, France.
Bertrand
B
Daignan-Fornier
From the Université de Bordeaux IBGC UMR 5095 1, F-33077 Bordeaux, France and the Centre National de la Recherche Scientifique IBGC UMR 5095 1, F-33077 Bordeaux, France benoit.pinson@ibgc.cnrs.fr.
Benoît
B
Pinson
D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D033703:Nucleoside Transport Proteins / Q000235:genetics / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013831:Thiamine / Q000378:metabolism
D026901:Membrane Transport Proteins; C528866:Nrt1 protein, S cerevisiae; D033703:Nucleoside Transport Proteins; D012265:Ribonucleotides; D029701:Saccharomyces cerevisiae Proteins; C000592466:Thi7 protein, S cerevisiae; C000592467:Thi72 protein, S cerevisiae; D000620:Aminoimidazole Carboxamide; C031143:AICA ribonucleotide; D013831:Thiamine
AMP-activated Kinase (AMPK); Nicotinamide; Nucleoside/Nucleotide Transport; Thiamine; Transporter