PMID- 26283791
OWN - NLM
STAT- MEDLINE
DCOM- 20151217
LR  - 20210205
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 290
IP  - 39
DP  - 2015 Sep 25
TI  - Disruption of Nucleotide Homeostasis by the Antiproliferative Drug 
      5-Aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside Monophosphate (AICAR).
PG  - 23947-59
LID - 10.1074/jbc.M115.656017 [doi]
AB  - 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside monophosphate (AICAR) is a 
      natural metabolite with potent anti-proliferative and low energy mimetic 
      properties. At high concentration, AICAR is toxic for yeast and mammalian cells, 
      but the molecular basis of this toxicity is poorly understood. Here, we report 
      the identification of yeast purine salvage pathway mutants that are synthetically 
      lethal with AICAR accumulation. Genetic suppression revealed that this synthetic 
      lethality is in part due to low expression of adenine phosphoribosyl transferase 
      under high AICAR conditions. In addition, metabolite profiling points to the 
      AICAR/NTP balance as crucial for optimal utilization of glucose as a carbon 
      source. Indeed, we found that AICAR toxicity in yeast and human cells is 
      alleviated when glucose is replaced by an alternative carbon source. Together, 
      our metabolic analyses unveil the AICAR/NTP balance as a major factor of AICAR 
      antiproliferative effects.
CI  - (c) 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Ceschin, Johanna
AU  - Ceschin J
AD  - From the Universite de Bordeaux and the Centre National de la Recherche 
      Scientifique, Institut de Biochimie et Genetique Cellulaires UMR 5095, 
      Saint-Saens, F-33077 Bordeaux, France.
FAU - Hurlimann, Hans Caspar
AU  - Hurlimann HC
AD  - From the Universite de Bordeaux and the Centre National de la Recherche 
      Scientifique, Institut de Biochimie et Genetique Cellulaires UMR 5095, 
      Saint-Saens, F-33077 Bordeaux, France.
FAU - Saint-Marc, Christelle
AU  - Saint-Marc C
AD  - From the Universite de Bordeaux and the Centre National de la Recherche 
      Scientifique, Institut de Biochimie et Genetique Cellulaires UMR 5095, 
      Saint-Saens, F-33077 Bordeaux, France.
FAU - Albrecht, Delphine
AU  - Albrecht D
AD  - From the Universite de Bordeaux and the Centre National de la Recherche 
      Scientifique, Institut de Biochimie et Genetique Cellulaires UMR 5095, 
      Saint-Saens, F-33077 Bordeaux, France.
FAU - Violo, Typhaine
AU  - Violo T
AD  - From the Universite de Bordeaux and the Centre National de la Recherche 
      Scientifique, Institut de Biochimie et Genetique Cellulaires UMR 5095, 
      Saint-Saens, F-33077 Bordeaux, France.
FAU - Moenner, Michel
AU  - Moenner M
AD  - From the Universite de Bordeaux and the Centre National de la Recherche 
      Scientifique, Institut de Biochimie et Genetique Cellulaires UMR 5095, 
      Saint-Saens, F-33077 Bordeaux, France.
FAU - Daignan-Fornier, Bertrand
AU  - Daignan-Fornier B
AD  - From the Universite de Bordeaux and the Centre National de la Recherche 
      Scientifique, Institut de Biochimie et Genetique Cellulaires UMR 5095, 
      Saint-Saens, F-33077 Bordeaux, France b.daignan-fornier@ibgc.cnrs.fr.
FAU - Pinson, Benoit
AU  - Pinson B
AD  - From the Universite de Bordeaux and the Centre National de la Recherche 
      Scientifique, Institut de Biochimie et Genetique Cellulaires UMR 5095, 
      Saint-Saens, F-33077 Bordeaux, France.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150817
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Nucleotides)
RN  - 0 (Ribonucleotides)
RN  - 0 (Saccharomyces cerevisiae Proteins)
RN  - 360-97-4 (Aminoimidazole Carboxamide)
RN  - EC 2.4.2.7 (Adenine Phosphoribosyltransferase)
RN  - F0X88YW0YK (AICA ribonucleotide)
SB  - IM
MH  - Adenine Phosphoribosyltransferase/*antagonists & inhibitors/genetics/metabolism
MH  - Aminoimidazole Carboxamide/*analogs & derivatives/pharmacology
MH  - Cell Line
MH  - Cell Proliferation/*drug effects/genetics
MH  - Humans
MH  - Nucleotides/genetics/*metabolism
MH  - Ribonucleotides/*pharmacology
MH  - Saccharomyces cerevisiae/*metabolism
MH  - Saccharomyces cerevisiae Proteins/*antagonists & inhibitors/genetics/metabolism
PMC - PMC4583016
OTO - NOTNLM
OT  - nucleoside/nucleotide analog
OT  - nucleoside/nucleotide metabolism
OT  - purine
OT  - yeast genetics
OT  - yeast metabolism
EDAT- 2015/08/19 06:00
MHDA- 2015/12/19 06:00
PMCR- 2016/09/25
CRDT- 2015/08/19 06:00
PHST- 2015/03/31 00:00 [received]
PHST- 2015/08/19 06:00 [entrez]
PHST- 2015/08/19 06:00 [pubmed]
PHST- 2015/12/19 06:00 [medline]
PHST- 2016/09/25 00:00 [pmc-release]
AID - S0021-9258(20)44730-1 [pii]
AID - M115.656017 [pii]
AID - 10.1074/jbc.M115.656017 [doi]
PST - ppublish
SO  - J Biol Chem. 2015 Sep 25;290(39):23947-59. doi: 10.1074/jbc.M115.656017. Epub 
      2015 Aug 17.