Next Article in Journal
A Historical Overview of Natural Products in Drug Discovery
Next Article in Special Issue
1H Nuclear Magnetic Resonance (NMR) Metabolomic Study of Chronic Organophosphate Exposure in Rats
Previous Article in Journal
Stoichiometry Based Steady-State Hepatic Flux Analysis: Computational and Experimental Aspects
Previous Article in Special Issue
The Effect of LC-MS Data Preprocessing Methods on the Selection of Plasma Biomarkers in Fed vs. Fasted Rats
Article Menu

Export Article

Metabolites 2012, 2(2), 292-302; doi:10.3390/metabo2020292

5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl 5'-Monophosphate (AICAR), a Highly Conserved Purine Intermediate with Multiple Effects
Université Bordeaux, CNRS, IBGC, UMR 5095, F-33000 Bordeaux, France
Author to whom correspondence should be addressed.
Received: 29 February 2012; in revised form: 15 March 2012 / Accepted: 16 March 2012 / Published: 23 March 2012


: AICAR (5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl 5'-monophosphate) is a natural metabolic intermediate of purine biosynthesis that is present in all organisms. In yeast, AICAR plays important regulatory roles under physiological conditions, notably through its direct interactions with transcription factors. In humans, AICAR accumulates in several metabolic diseases, but its contribution to the symptoms has not yet been elucidated. Further, AICAR has highly promising properties which have been recently revealed. Indeed, it enhances endurance of sedentary mice. In addition, it has antiproliferative effects notably by specifically inducing apoptosis of aneuploid cells. Some of the effects of AICAR are due to its ability to stimulate the AMP-activated protein kinase but some others are not. It is consequently clear that AICAR affects multiple targets although only few of them have been identified so far. This review proposes an overview of the field and suggests future directions.
AICAR; AMPK; metabolism; signal transduction; purine; ATIC

1. Introduction

AICAR (5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl 5'-monophosphate), also known as ZMP (the “Z” referring to imidaZole [1]), is an intermediate in the inosine monophosphate (IMP) conserved pathway which is responsible for de novo purine biosynthesis in all organisms. The recent attention paid to AICAR is testified by more than one thousand publications referenced in databases such as PubMed, 90% of which having been published during the last 10 years. This massive and sustained interest for this small molecule is due to its multiple biological effects, which will be presented in this review.

2. Metabolism of AICAR

AICAR is an intermediate metabolite in the purine de novo synthesis pathway (Figure 1), it is synthesized from succinyl-AICAR (SAICAR) by adenylosuccinate lyase (ASL), an enzyme inhibited by AICAR through a feedback regulation [2]. As a consequence, massive accumulation of AICAR is associated with SAICAR accumulation in micro-organisms such as yeast [3] and in a specific human pathology [4]. In the de novo purine synthesis pathway, AICAR is further metabolized to IMP by successive action of AICAR-Transformylase and IMP Cyclohydrolase, two enzymatic activities which are generally carried on a single protein named ATIC. In micro-organisms, AICAR is also synthesized as a by-product of the histidine biosynthesis pathway (Figure 1).

Figure 1. Schematic representation of the de novo purine and histidine pathways in yeast. AICAR: 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl 5'-monophosphate. AICAr: riboside form of AICAR (also named acadesine). AMP: Adenosine 5'-monophosphate; GMP: Guanosine 5'-monophosphate; IMP: Inosine 5'-monophosphate. PRFAICAR: 5-(5-Phospho-D-ribosylaminoformimino)-1-(5-phosphoribosyl)-imidazole-4-carboxamide. SAICAR: succinyl-AICAR. SAICAr: succinyl-AICAr. ZMP: AICAR monophosphate. ZTP: AICAR triphosphate. Enzyme names are given in blue. Question marks indicate enzymatic activities catalyzed by unidentified enzymes.
Figure 1. Schematic representation of the de novo purine and histidine pathways in yeast. AICAR: 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl 5'-monophosphate. AICAr: riboside form of AICAR (also named acadesine). AMP: Adenosine 5'-monophosphate; GMP: Guanosine 5'-monophosphate; IMP: Inosine 5'-monophosphate. PRFAICAR: 5-(5-Phospho-D-ribosylaminoformimino)-1-(5-phosphoribosyl)-imidazole-4-carboxamide. SAICAR: succinyl-AICAR. SAICAr: succinyl-AICAr. ZMP: AICAR monophosphate. ZTP: AICAR triphosphate. Enzyme names are given in blue. Question marks indicate enzymatic activities catalyzed by unidentified enzymes.
Metabolites 02 00292 g001 1024

Under conditions where AICAR accumulates, riboside and triphosphate derivatives are often found in cellular extracts or body fluids. A patient lacking ATIC activity showed accumulation of large amounts of AICAR riboside (also known as acadesine or AICAr) in urines and mono- di- and tri-phosphate forms of AICAR in erythrocytes [4]. The enzyme(s) dephosphorylating AICAR monophosphate to its riboside form is not identified yet, but it is clear that adenosine kinase can reverse the reaction and phosphorylate AICAR riboside to the monophosphate form [5]. Synthesis of ZTP (triphosphate form of AICAR) was found to occur directly from AICAR through the catalytic action of PRPP-synthetase [6]. Consequently, ZDP (diphosphate form of AICAR) detected in erythrocytes is likely to result from ZTP degradation and to appear upon intracellular degradation or during metabolite extraction, rather than be a ZTP synthesis intermediate. In the early eighties, ZTP was proposed to be an “alarmone” signaling folate deficiency in Salmonella typhimurium [1] but a later study did not confirm such a role for ZTP in Escherichia coli [7].

3. Roles of Physiologically Produced AICAR and Accumulation in Metabolic Diseases

A physiological role for AICAR has been found in yeast cells where it stimulates the interaction between two pairs of transcription factors (Bas1-Pho2 and Pho4-Pho2), thereby resulting in the transcriptional activation of specific sets of genes [3,8]. Importantly, most of the AICAR-responsive genes also respond to extracellular adenine, their expression being low when adenine is abundant in the growth medium [3,9,10,11,12,13,14]. AICAR concentration is linked to exogenous adenine through feedback regulation of the first step of the purine de novo pathway. This feedback regulation is thought to be mediated by ATP and ADP [2]. Consistently, in adenine replete conditions, ADP and ATP concentrations are higher [12], while AICAR concentration decreases [15]. Finally, fusion chimera between AICAR-stimulated transcription factors resulted in an adenine-independent transcriptional activation of the target genes [3,16]. These results led to a model accounting for the complex regulatory effects of AICAR in yeast and their connection to purine precursor availability in the growth medium (Figure 2). Beside these physiological effects associated to moderate AICAR accumulation, massive accumulation of AICAR can also lead to detrimental effects in yeast. Intracellular accumulation of AICAR in the millimolar range provokes histidine auxotrophy and, when combined to the fau1 mutation affecting 5,10-methenyltetrahydrofolate synthetase, leads to methionine auxotrophy. Higher concentrations, up to 10-15 mM, result in growth arrest [15]. In yeast, physiological and detrimental effects of AICAR are only associated to its phophorylated form(s), since accumulation of the riboside form at the same concentration has no effects either on transcription, amino-acids prototrophy nor on cellular growth [15].

In mammalian cells it is not known whether endogenous AICAR plays regulatory roles. It is however striking that most purine metabolism-associated diseases result in AICAR accumulation in the patient cells [17]. The most dramatic accumulation of AICAR was observed in the erythrocytes of an ATIC-deficient patient and was associated to dysmorphic features, severe neurological defects, and congenital blindness [4]. At this point it is not clear whether some or all of these symptoms are the direct result of very high AICAR concentrations or whether they are due to the increase of AICAR derivatives and/or to the severe ATP depletion associated with AICAR massive accumulation [4]. The consequences of AICAR accumulation in other purine metabolism-associated diseases is not established, but AICAR was proposed as the possible toxic metabolite in Lesch-Nyhan disease resulting from impaired hypoxanthine-guanine phosphoribosyl transferase [18].

Figure 2. Schematic representation of AICAR physiological effects in yeast. Intracellular ATP and AICAR concentrations were determined by liquid chromatography as described in [19] on exponentially BY4741 cells grown in SD medium containing 1% casaminoacid (Difco), tryptophan (0.2 mM) and containing (upper panel) or not (lower panel) adenine (0.3 mM). ADE and PHO genes refer to Bas1-Pho2 and Pho4-Pho2 target genes, respectively.
Figure 2. Schematic representation of AICAR physiological effects in yeast. Intracellular ATP and AICAR concentrations were determined by liquid chromatography as described in [19] on exponentially BY4741 cells grown in SD medium containing 1% casaminoacid (Difco), tryptophan (0.2 mM) and containing (upper panel) or not (lower panel) adenine (0.3 mM). ADE and PHO genes refer to Bas1-Pho2 and Pho4-Pho2 target genes, respectively.
Metabolites 02 00292 g002 1024

4. AICAR, a Potent Activator of AMP-Activated Protein Kinase

In the early 90s, AICAR in its monophosphate form was found to activate the human AMP-activated protein kinase (AMPK) activity in vitro [20]. The AICAR riboside precursor was then used to activate AMPK in isolated rat adipocytes [21]. Since then, AICAR has been used in hundreds of studies as an inducer of AMPK activity. A major advantage of AICAR compared to other AMPK-inducers is that AICAR addition at low concentration (< 500 µM) does not affect AMP, ADP or ATP levels [22]. However, more recently, effects of AICAR on ATP concentration were reported in rat hepatocytes [23,24]. This observation combined with the multiple AMPK-independent effects reported for AICAR (see below) should inspire cautious interpretation of the results (as discussed in [25]).

AICAR was found to directly interact with the gamma-subunit of AMPK. This interaction induces a conformational change and favors phosphorylation of the catalytic alpha subunit, which in turn becomes more active. Structural analysis of the AMPK-AICAR complex suggests that activation of this protein kinase by AICAR mimics activation by AMP [26]. Hence, the effect of AICAR on AMPK is presumed to be direct.

AICAR monophosphate is provided to the cells as a riboside precursor, which is taken up by adenosine transporter(s) [27]. In many studies, the authors use an inhibitor of adenosine kinase to show that AICAR monophosphate, and not its riboside precursor, is the active molecule (Figure 3) [28]. Among the effects attributed to AICAR monophosphate, many are AMPK-dependent as shown by si- or sh-RNA gene silencing of the gamma-subunits (see Figure 3). For instance the potent effect of AICAR on induction of apoptosis in aneuploid cells was abolished by shRNA on AMPK, however it was poorly mimicked by other AMPK inducers such as metformin or 2-deoxyglucose [29]. This example illustrates the complexity of AICAR effects and calls attention to the fact that a careful analysis is required to establish whether an AICAR effect is fully AMPK-dependent or not.

Figure 3. Schematic depiction of AICAR cellular targets and associated biological effects.CML: Chronic myeloid leukemia. CLL: Chronic lymphocytic leukemia. PKC: Protein kinase C. Ryr1: Ryanodine receptor 1. All targets and biological effects presented are described in [29,30,31,32,33,34,35,36].
Figure 3. Schematic depiction of AICAR cellular targets and associated biological effects.CML: Chronic myeloid leukemia. CLL: Chronic lymphocytic leukemia. PKC: Protein kinase C. Ryr1: Ryanodine receptor 1. All targets and biological effects presented are described in [29,30,31,32,33,34,35,36].
Metabolites 02 00292 g003 1024

5. AMPK-Independent Effects of AICAR: Other Protein Targets

It should be stressed that there is a growing number of examples where AICAR effects are totally or partially independent of AMPK (Figure 3) [37,38,39,40]. It appears more and more evident that AICAR is a multi-target molecule resulting in complex and combined effects, in line with the paradigm of “network pharmacology” recently proposed by A. Hopkins [41]. For such highly integrated effects, it is critical to apprehend the complexity of the drug effects by identifying its targets. This quest is complex because it requires to identify drug-interacting proteins and establish their role in the drug action in vivo.

The use of an AICAR-resin has allowed validating two yeast transcription factors as AICAR-binders [3]. More recently, affinity chromatography coupled to mass spectrometry allowed us to perform a large-scale identification of yeast and mouse AICAR-binders, many of which being conserved through species (our unpublished results).

The next step is to validate the binders as true AICAR targets in vivo. Interestingly, it was recently found that the yeast AMPK (Snf1) is activated by ADP but not by AMP [42], thereby accounting for the fact that AICAR apparently does not activate the yeast AMPK, as presumed from the transcriptome signature [3]. Yeast is therefore an appealing simple eukaryotic model to study AMPK-independent AICAR effects.

Aside from AMPK, AICAR modulates several enzymes such as glucokinase [43] or glycogen phosphorylase [44]. In a few cases, direct binding of AICAR to specific proteins has been reported, including phosphofructokinase (PFK) and fructose-1,6-biphosphatase (F1,6-BPase) which are inhibited in vitro by AICAR [45,46]. AICAR interaction with Hsp90 was also demonstrated and many client proteins of Hsp90 were found destabilized in vivo in the presence of AICAR [47]. Both PFK and Hsp90 contribute to important functions for tumor growth and could thus be involved in the anti-proliferative effects of AICAR, which was reported for several tumor cell lines (such as PC-3, MCF-7,C6 glioma, U87MG, K-562 and CEM) [48]. It is noteworthy that, while AICAR replaces AMP in AMPK [26], it competes with ATP in Hsp90 [47]. It will be interesting to determine whether all AICAR targets are nucleotide-binding proteins.

6. Effects of AICAR on Whole Organisms

There are few studies showing effects of AICAR on whole organisms and in most cases the protein effectors are not clearly identified, although AICAR was chosen in these studies for its AMPK-activating properties.

AICAR feeding of Caenorhabditis elegans resulted in decreased fat storage as would be predicted when AMPK is activated [49]. Drosphila melanogaster fed with AICAR were more resistant to anoxia/re-oxygenation injuries [50]. AICAR has been found to reduce myocardial ischemic injury in several models (rat, mice, rabbit, dog…) [51] and in humans [52]. Injection of AICAR to mice resulted in a hypoglycemic effect [53]. Strikingly, sedentary mice fed with AICAR showed increased endurance [54]. AICAR was renamed “the exercise pill” and subsequently suspected of human misusage as a doping agent. AICAR is not currently approved by FDA and has only been used in a very few investigations in humans [55,56,57].

7. Conclusion

AICAR is a highly promising pharmacophore showing various effects on multiple functions. In the future, AICAR or derivatives could represent key molecules for several diseases including heat induced sudden death, cytochrome c-oxidase deficiencies, cancer and other pathologies associated with muscle wasting. The systematic identification of AICAR targets is now required to understand the complex consequences resulting, most probably, from synthetic effects on several proteins. Importantly, AICAR has both activating and inhibiting effects and hence, determining the way AICAR affects each target will require individual characterization. This time consuming process will hopefully be made easier by the use of model organisms such as yeast or nematode.


We apologize to authors whose work has not been cited here owing to space limitations. We thank Eric Chevet for helpful comments on the manuscript. This work was supported by Association Française contre les Myopathies.

Conflict of Interest

The authors declare no conflict of interest

References and Notes

  1. Bochner, B.R.; Ames, B.N. ZTP (5-amino 4-imidazole carboxamide riboside 5'-triphosphate): a proposed alarmone for 10-formyl-tetrahydrofolate deficiency. Cell 1982, 29, 929–937. [Google Scholar] [CrossRef]
  2. Rebora, K.; Desmoucelles, C.; Borne, F.; Pinson, B.; Daignan-Fornier, B. Yeast AMP pathway genes respond to adenine through regulated synthesis of a metabolic intermediate. Mol. Cell Biol. 2001, 21, 7901–7912. [Google Scholar]
  3. Pinson, B.; Vaur, S.; Sagot, I.; Coulpier, F.; Lemoine, S.; Daignan-Fornier, B. Metabolic intermediates selectively stimulate transcription factor interaction and modulate phosphate and purine pathways. Genes Dev. 2009, 23, 1399–1407. [Google Scholar] [CrossRef]
  4. Marie, S.; Heron, B.; Bitoun, P.; Timmerman, T.; Van Den Berghe, G.; Vincent, M.F. AICA-ribosiduria: a novel, neurologically devastating inborn error of purine biosynthesis caused by mutation of ATIC. Am. J. Hum. Genet. 2004, 74, 1276–1281. [Google Scholar] [CrossRef]
  5. Sabina, R.L.; Patterson, D.; Holmes, E.W. 5-Amino-4-imidazolecarboxamide riboside (Z-riboside) metabolism in eukaryotic cells. J. Biol. Chem. 1985, 260, 6107–6114. [Google Scholar]
  6. Sabina, R.L.; Holmes, E.W.; Becker, M.A. The enzymatic synthesis of 5-amino-4-imidazolecarboxamide riboside triphosphate (ZTP). Science 1984, 223, 1193–1195. [Google Scholar]
  7. Rohlman, C.E.; Matthews, R.G. Role of purine biosynthetic intermediates in response to folate stress in Escherichia coli. J. Bacteriol. 1990, 172, 7200–7210. [Google Scholar]
  8. Rebora, K.; Laloo, B.; Daignan-Fornier, B. Revisiting purine-histidine cross-pathway regulation in Saccharomyces cerevisiae: a central role for a small molecule. Genetics 2005, 170, 61–70. [Google Scholar] [CrossRef]
  9. Daignan-Fornier, B.; Fink, G.R. Coregulation of purine and histidine biosynthesis by the transcriptional activators BAS1 and BAS2. Proc. Natl. Acad. Sci. USA 1992, 89, 6746–6750. [Google Scholar] [CrossRef]
  10. Denis, V.; Boucherie, H.; Monribot, C.; Daignan-Fornier, B. Role of the myb-like protein bas1p in Saccharomyces cerevisiae: a proteome analysis. Mol. Microbiol. 1998, 30, 557–566. [Google Scholar] [CrossRef]
  11. Denis, V.; Daignan-Fornier, B. Synthesis of glutamine, glycine and 10-formyl tetrahydrofolate is coregulated with purine biosynthesis in Saccharomyces cerevisiae. Mol. Gen. Genet. 1998, 259, 246–255. [Google Scholar] [CrossRef]
  12. Gauthier, S.; Coulpier, F.; Jourdren, L.; Merle, M.; Beck, S.; Konrad, M.; Daignan-Fornier, B.; Pinson, B. Co-regulation of yeast purine and phosphate pathways in response to adenylic nucleotide variations. Mol. Microbiol. 2008, 68, 1583–1594. [Google Scholar]
  13. Springer, C.; Kunzler, M.; Balmelli, T.; Braus, G.H. Amino acid and adenine cross-pathway regulation act through the same 5'-TGACTC-3' motif in the yeast HIS7 promoter. J. Biol. Chem. 1996, 271, 29637–29643. [Google Scholar]
  14. Tice-Baldwin, K.; Fink, G.R.; Arndt, K.T. BAS1 has a Myb motif and activates HIS4 transcription only in combination with BAS2. Science 1989, 246, 931–935. [Google Scholar]
  15. Hurlimann, H.C.; Laloo, B.; Simon-Kayser, B.; Saint-Marc, C.; Coulpier, F.; Lemoine, S.; Daignan-Fornier, B.; Pinson, B. Physiological and toxic effects of purine intermediate 5-amino-4-imidazolecarboxamide ribonucleotide (AICAR) in yeast. J. Biol. Chem. 2011, 286, 30994–31002. [Google Scholar]
  16. Pinson, B.; Kongsrud, T.L.; Ording, E.; Johansen, L.; Daignan-Fornier, B.; Gabrielsen, O.S. Signaling through regulated transcription factor interaction: mapping of a regulatory interaction domain in the Myb-related Bas1p. Nucleic. Acids Res. 2000, 28, 4665–4673. [Google Scholar]
  17. Sidi, Y.; Mitchell, B.S. Z-nucleotide accumulation in erythrocytes from Lesch-Nyhan patients. J. Clin. Invest. 1985, 76, 2416–2419. [Google Scholar]
  18. Lopez, J.M. Is ZMP the toxic metabolite in Lesch-Nyhan disease? Med. Hypotheses 2008, 71, 657–663. [Google Scholar] [CrossRef]
  19. Laporte, D.; Lebaudy, A.; Sahin, A.; Pinson, B.; Ceschin, J.; Daignan-Fornier, B.; Sagot, I. Metabolic status rather than cell cycle signals control quiescence entry and exit. J. Cell Biol. 2011, 192, 949–957. [Google Scholar]
  20. Sullivan, J.E.; Carey, F.; Carling, D.; Beri, R.K. Characterisation of 5'-AMP-activated protein kinase in human liver using specific peptide substrates and the effects of 5'-AMP analogues on enzyme activity. Biochem. Biophys. Res. Commun. 1994, 200, 1551–1556. [Google Scholar]
  21. Sullivan, J.E.; Brocklehurst, K.J.; Marley, A.E.; Carey, F.; Carling, D.; Beri, R.K. Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell-permeable activator of AMP-activated protein kinase. FEBS Lett. 1994, 353, 33–36. [Google Scholar] [CrossRef]
  22. Corton, J.M.; Gillespie, J.G.; Hawley, S.A.; Hardie, D.G. 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur. J. Biochem. 1995, 229, 558–565. [Google Scholar] [CrossRef]
  23. Guigas, B.; Bertrand, L.; Taleux, N.; Foretz, M.; Wiernsperger, N.; Vertommen, D.; Andreelli, F.; Viollet, B.; Hue, L. 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside and metformin inhibit hepatic glucose phosphorylation by an AMP-activated protein kinase-independent effect on glucokinase translocation. Diabetes 2006, 55, 865–874. [Google Scholar]
  24. Mukhtar, M.H.; Payne, V.A.; Arden, C.; Harbottle, A.; Khan, S.; Lange, A.J.; Agius, L. Inhibition of glucokinase translocation by AMP-activated protein kinase is associated with phosphorylation of both GKRP and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2008, 294, R766–774. [Google Scholar] [CrossRef]
  25. Viollet, B.; Guigas, B.; Leclerc, J.; Hebrard, S.; Lantier, L.; Mounier, R.; Andreelli, F.; Foretz, M. AMP-activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives. Acta. Physiol. (Oxf.) 2009, 196, 81–98. [Google Scholar] [CrossRef]
  26. Day, P.; Sharff, A.; Parra, L.; Cleasby, A.; Williams, M.; Horer, S.; Nar, H.; Redemann, N.; Tickle, I.; Yon, J. Structure of a CBS-domain pair from the regulatory gamma1 subunit of human AMPK in complex with AMP and ZMP. Acta. Crystallog.r D. Biol. Crystallogr. 2007, 63, 587–596. [Google Scholar]
  27. Fryer, L.G.; Parbu-Patel, A.; Carling, D. Protein kinase inhibitors block the stimulation of the AMP-activated protein kinase by 5-amino-4-imidazolecarboxamide riboside. FEBS Lett. 2002, 531, 189–192. [Google Scholar] [CrossRef]
  28. Ugarkar, B.G.; DaRe, J.M.; Kopcho, J.J.; Browne, C.E., 3rd; Schanzer, J.M.; Wiesner, J.B.; Erion, M.D. Adenosine kinase inhibitors. 1. Synthesis, enzyme inhibition, and antiseizure activity of 5-iodotubercidin analogues. J. Med. Chem. 2000, 43, 2883–2893. [Google Scholar]
  29. Tang, Y.C.; Williams, B.R.; Siegel, J.J.; Amon, A. Identification of aneuploidy-selective antiproliferation compounds. Cell 2011, 144, 499–512. [Google Scholar] [CrossRef]
  30. Mihaylova, M.M.; Shaw, R.J. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell. Biol. 2011, 13, 1016–1023. [Google Scholar] [CrossRef]
  31. Hardie, D.G. AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev. 2011, 25, 1895–1908. [Google Scholar] [CrossRef]
  32. Wong, A.K.; Howie, J.; Petrie, J.R.; Lang, C.C. AMP-activated protein kinase pathway: a potential therapeutic target in cardiometabolic disease. Clin. Sci. (Lond.) 2009, 116, 607–620. [Google Scholar] [CrossRef]
  33. Santidrian, A.F.; Gonzalez-Girones, D.M.; Iglesias-Serret, D.; Coll-Mulet, L.; Cosialls, A.M.; de Frias, M.; Campas, C.; Gonzalez-Barca, E.; Alonso, E.; Labi, V.; Viollet, B.; Benito, A.; Pons, G.; Villunger, A.; Gil, J. AICAR induces apoptosis independently of AMPK and p53 through up-regulation of the BH3-only proteins BIM and NOXA in chronic lymphocytic leukemia cells. Blood 2010, 116, 3023–3032. [Google Scholar]
  34. Lanner, J.T.; Georgiou, D.K.; Dagnino-Acosta, A.; Ainbinder, A.; Cheng, Q.; Joshi, A.D.; Chen, Z.; Yarotskyy, V.; Oakes, J.M.; Lee, C.S.; Monroe, T.O.; Santillan, A.; Dong, K.; Goodyear, L.; Ismailov, II; Rodney, G.G.; Dirksen, R.T.; Hamilton, S.L. AICAR prevents heat-induced sudden death in RyR1 mutant mice independent of AMPK activation. Nat. Med. 2012, 18, 244–251. [Google Scholar]
  35. Isebaert, S.F.; Swinnen, J.V.; McBride, W.H.; Begg, A.C.; Haustermans, K.M. 5-aminoimidazole-4-carboxamide riboside enhances effect of ionizing radiation in PC3 prostate cancer cells. Int. J. Radiat. Oncol. Biol. Phys. 2011, 81, 1515–1523. [Google Scholar]
  36. Robert, G.; Ben Sahra, I.; Puissant, A.; Colosetti, P.; Belhacene, N.; Gounon, P.; Hofman, P.; Bost, F.; Cassuto, J.P.; Auberger, P. Acadesine kills chronic myelogenous leukemia (CML) cells through PKC-dependent induction of autophagic cell death. PLoS One 2009, 4, e7889. [Google Scholar]
  37. Guigas, B.; Taleux, N.; Foretz, M.; Detaille, D.; Andreelli, F.; Viollet, B.; Hue, L. AMP-activated protein kinase-independent inhibition of hepatic mitochondrial oxidative phosphorylation by AICA riboside. Biochem. J. 2007, 404, 499–507. [Google Scholar]
  38. Jacobs, R.L.; Lingrell, S.; Dyck, J.R.; Vance, D.E. Inhibition of hepatic phosphatidylcholine synthesis by 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside is independent of AMP-activated protein kinase activation. J. Biol. Chem. 2007, 282, 4516–4523. [Google Scholar]
  39. Kuo, C.L.; Ho, F.M.; Chang, M.Y.; Prakash, E.; Lin, W.W. Inhibition of lipopolysaccharide-induced inducible nitric oxide synthase and cyclooxygenase-2 gene expression by 5-aminoimidazole-4-carboxamide riboside is independent of AMP-activated protein kinase. J. Cell Biochem. 2008, 103, 931–940. [Google Scholar] [CrossRef]
  40. Lopez, J.M.; Santidrian, A.F.; Campas, C.; Gil, J. 5-Aminoimidazole-4-carboxamide riboside induces apoptosis in Jurkat cells, but the AMP-activated protein kinase is not involved. Biochem. J. 2003, 370, 1027–1032. [Google Scholar] [CrossRef]
  41. Hopkins, A.L. Network pharmacology: the next paradigm in drug discovery. Nat. Chem. Biol. 2008, 4, 682–690. [Google Scholar] [CrossRef]
  42. Mayer, F.V.; Heath, R.; Underwood, E.; Sanders, M.J.; Carmena, D.; McCartney, R.R.; Leiper, F.C.; Xiao, B.; Jing, C.; Walker, P.A.; Haire, L.F.; Ogrodowicz, R.; Martin, S.R.; Schmidt, M.C.; Gamblin, S.J.; Carling, D. ADP regulates SNF1, the Saccharomyces cerevisiae homolog of AMP-activated protein kinase. Cell Metab. 2011, 14, 707–714. [Google Scholar]
  43. Vincent, M.F.; Bontemps, F.; Van den Berghe, G. Inhibition of glycolysis by 5-amino-4-imidazolecarboxamide riboside in isolated rat hepatocytes. Biochem. J. 1992, 281 ( Pt 1), 267–272. [Google Scholar]
  44. Shang, J.; Lehrman, M.A. Activation of glycogen phosphorylase with 5-aminoimidazole-4-carboxamide riboside (AICAR). Assessment of glycogen as a precursor of mannosyl residues in glycoconjugates. J. Biol. Chem. 2004, 279, 12076–12080. [Google Scholar]
  45. Javaux, F.; Vincent, M.F.; Wagner, D.R.; van den Berghe, G. Cell-type specificity of inhibition of glycolysis by 5-amino-4-imidazolecarboxamide riboside. Lack of effect in rabbit cardiomyocytes and human erythrocytes, and inhibition in FTO-2B rat hepatoma cells. Biochem. J. 1995, 305 ( Pt 3), 913–919. [Google Scholar]
  46. Vincent, M.F.; Marangos, P.J.; Gruber, H.E.; Van den Berghe, G. Inhibition by AICA riboside of gluconeogenesis in isolated rat hepatocytes. Diabetes 1991, 40, 1259–1266. [Google Scholar]
  47. Meli, M.; Pennati, M.; Curto, M.; Daidone, M.G.; Plescia, J.; Toba, S.; Altieri, D.C.; Zaffaroni, N.; Colombo, G. Small-molecule targeting of heat shock protein 90 chaperone function: rational identification of a new anticancer lead. J. Med. Chem. 2006, 49, 7721–7730. [Google Scholar]
  48. Rattan, R.; Giri, S.; Singh, A.K.; Singh, I. 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside inhibits cancer cell proliferation in vitro and in vivo via AMP-activated protein kinase. J. Biol. Chem. 2005, 280, 39582–39593. [Google Scholar]
  49. Lemieux, G.A.; Liu, J.; Mayer, N.; Bainton, R.J.; Ashrafi, K.; Werb, Z. A whole-organism screen identifies new regulators of fat storage. Nat. Chem. Biol. 2011, 7, 206–213. [Google Scholar]
  50. Vigne, P.; Tauc, M.; Frelin, C. Strong dietary restrictions protect Drosophila against anoxia/reoxygenation injuries. PLoS One 2009, 4, e5422. [Google Scholar]
  51. Mullane, K. Acadesine: the prototype adenosine regulating agent for reducing myocardial ischaemic injury. Cardiovasc. Res. 1993, 27, 43–47. [Google Scholar] [CrossRef]
  52. Leung, J.M.; Stanley, T., 3rd; Mathew, J.; Curling, P.; Barash, P.; Salmenpera, M.; Reves, J.G.; Hollenberg, M.; Mangano, D.T. An initial multicenter, randomized controlled trial on the safety and efficacy of acadesine in patients undergoing coronary artery bypass graft surgery. SPI Research Group. Anesth. Analg. 1994, 78, 420–434. [Google Scholar]
  53. Vincent, M.F.; Erion, M.D.; Gruber, H.E.; Van den Berghe, G. Hypoglycaemic effect of AICAriboside in mice. Diabetologia 1996, 39, 1148–1155. [Google Scholar] [CrossRef]
  54. Narkar, V.A.; Downes, M.; Yu, R.T.; Embler, E.; Wang, Y.X.; Banayo, E.; Mihaylova, M.M.; Nelson, M.C.; Zou, Y.; Juguilon, H.; Kang, H.; Shaw, R.J.; Evans, R.M. AMPK and PPARdelta agonists are exercise mimetics. Cell 2008, 134, 405–415. [Google Scholar]
  55. Bosselaar, M.; Smits, P.; van Loon, L.J.; Tack, C.J. Intravenous AICAR during hyperinsulinemia induces systemic hemodynamic changes but has no local metabolic effect. J. Clin. Pharmacol. 2011, 51, 1449–1458. [Google Scholar] [CrossRef]
  56. Babraj, J.A.; Mustard, K.; Sutherland, C.; Towler, M.C.; Chen, S.; Smith, K.; Green, K.; Leese, G.; Hardie, D.G.; Rennie, M.J.; Cuthbertson, D.J. Blunting of AICAR-induced human skeletal muscle glucose uptake in type 2 diabetes is dependent on age rather than diabetic status. Am. J. Physiol. Endocrinol. Metab. 2009, 296, E1042–1048. [Google Scholar]
  57. Cuthbertson, D.J.; Babraj, J.A.; Mustard, K.J.; Towler, M.C.; Green, K.A.; Wackerhage, H.; Leese, G.P.; Baar, K.; Thomason-Hughes, M.; Sutherland, C.; Hardie, D.G.; Rennie, M.J. 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside acutely stimulates skeletal muscle 2-deoxyglucose uptake in healthy men. Diabetes 2007, 56, 2078–2084. [Google Scholar]
Metabolites EISSN 2218-1989 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top