title: Physiological and toxic effects of purine intermediate 5-amino-4-imidazolecarboxamide ribonucleotide (AICAR) in yeast.
abstract: 5-Amino-4-imidazolecarboxamide ribonucleotide 5'-phosphate (AICAR) is a monophosphate metabolic intermediate of the de novo purine synthesis pathway that has highly promising metabolic and antiproliferative properties. Yeast mutants unable to metabolize AICAR are auxotroph for histidine. A screening for suppressors of this phenotype identified recessive and dominant mutants that result in lowering the intracellular AICAR concentration. The recessive mutants affect the adenosine kinase, which is shown here to catalyze the phosphorylation of AICAR riboside in yeast. The dominant mutants strongly enhance the capacity of the alkaline phosphatase Pho13 to dephosphorylate 5-amino-4-imidazole N-succinocarboxamide ribonucleotide 5'-phosphate(SAICAR) into its non-toxic riboside form. By combining these mutants with transcriptomics and metabolomics analyses, we establish that in yeast responses to AICAR and SAICAR are clearly linked to the concentration of the monophosphate forms, whereas the derived nucleoside moieties have no effect even at high intracellular concentration. Finally, we show that AICAR/SAICAR concentrations vary under physiological conditions known to modulate transcription of the purine and phosphate pathway genes.
authors.affiliation: Institut de Biochimie et Génétique Cellulaires (IBGC) Unité Mixte de Recherche (UMR) 5095, Université Ségalen, Bordeaux F-33077, France; IBGC UMR 5095, CNRS, Bordeaux F-33077, France.
authors.forename: Hans C
authors.initials: HC
authors.lastname: Hürlimann
authors.affiliation: Institut de Biochimie et Génétique Cellulaires (IBGC) Unité Mixte de Recherche (UMR) 5095, Université Ségalen, Bordeaux F-33077, France; IBGC UMR 5095, CNRS, Bordeaux F-33077, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Laloo
authors.affiliation: Institut de Biochimie et Génétique Cellulaires (IBGC) Unité Mixte de Recherche (UMR) 5095, Université Ségalen, Bordeaux F-33077, France; IBGC UMR 5095, CNRS, Bordeaux F-33077, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Simon-Kayser
authors.affiliation: Institut de Biochimie et Génétique Cellulaires (IBGC) Unité Mixte de Recherche (UMR) 5095, Université Ségalen, Bordeaux F-33077, France; IBGC UMR 5095, CNRS, Bordeaux F-33077, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Saint-Marc
authors.affiliation: Institut de Biologie de l'ENS, IBENS, École normale supérieure (ENS), Paris F-75005, France; INSERM, U1024, Paris F-75005, France; UMR 8197, CNRS, Paris F-75005, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Coulpier
authors.affiliation: Institut de Biologie de l'ENS, IBENS, École normale supérieure (ENS), Paris F-75005, France; INSERM, U1024, Paris F-75005, France; UMR 8197, CNRS, Paris F-75005, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lemoine
authors.affiliation: Institut de Biochimie et Génétique Cellulaires (IBGC) Unité Mixte de Recherche (UMR) 5095, Université Ségalen, Bordeaux F-33077, France; IBGC UMR 5095, CNRS, Bordeaux F-33077, France. Electronic address: b.daignan-fornier@ibgc.cnrs.fr.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Daignan-Fornier
authors.affiliation: Institut de Biochimie et Génétique Cellulaires (IBGC) Unité Mixte de Recherche (UMR) 5095, Université Ségalen, Bordeaux F-33077, France; IBGC UMR 5095, CNRS, Bordeaux F-33077, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Pinson
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives*; D002384:Catalysis; D002853:Chromatography, Liquid / Q000379:methods; D005656:Fungal Proteins / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D005799:Genes, Dominant; D005800:Genes, Fungal; D005808:Genes, Recessive; D008956:Models, Chemical; D009154:Mutation; D011687:Purines / Q000737:chemistry*; D012265:Ribonucleotides / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D013045:Species Specificity; D014158:Transcription, Genetic
chemical_list: D005656:Fungal Proteins; D011687:Purines; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D000469:Alkaline Phosphatase; C031143:AICA ribonucleotide