The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

ATIC  -  5-aminoimidazole-4-carboxamide...

Homo sapiens

Synonyms: AICAR, AICARFT, Bifunctional purine biosynthesis protein PURH, HEL-S-70p, IMPCHASE, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of ATIC

  • In addition, expected decreases in ATIC enzymatic function in ATIC-ALK-containing lymphomas may render these tumors more sensitive to antifolate drugs such as methotrexate [1].
  • ATIC 347GG was associated with gastrointestinal side effects (OR 3.0, P < 0.01), while TSER*2/*2 (OR 5.4, P < 0.01) and SHMT1 1420CC (OR 3.2, P < 0.01) were associated with alopecia [2].
  • Both recombinant molecules possessing AICAR transformylase activity were overproduced in Escherichia coli [3].
  • Regarding toxicity, only ATIC G allele carriers experienced a greater frequency of adverse events (OR 2.0 [95% confidence interval 1.1-3.7]) [4].
  • AICA-ribosiduria is a recently discovered inherited metabolic disease caused by a defect in final steps of purine de novo biosynthesis-5-amino-4-imidazolecarboxamide ribotide (AICAR)-transformylase/inosinemonophosphate (IMP)-cyclohydrolase (ATIC) [5].

Psychiatry related information on ATIC

  • CONCLUSION: The observed anti-inflammatory/anti-oxidant and neuroprotective functions of AICAR suggest it as a viable candidate for use in treatment of Alzheimer's disease [6].

High impact information on ATIC

  • Moreover, activation of AMPK by metformin or AICAR largely blocked the ability of ethanol to increase levels of mature SREBP-1 protein [7].
  • AICA-ribosiduria: a novel, neurologically devastating inborn error of purine biosynthesis caused by mutation of ATIC [8].
  • Incubation of her fibroblasts with AICA-riboside led to accumulation of AICAR, not observed in control cells, suggesting impairment of the final steps of purine biosynthesis, catalyzed by the bifunctional enzyme AICAR transformylase/IMP cyclohydrolase (ATIC) [8].
  • The active sites of the IMPCH and AICAR Tfase domains are approximately 50 A apart, with no structural evidence of a tunnel connecting the two active sites [9].
  • Incubation with AICAR diminished, but did not abolish, the effect of glucose on PPI transcription [10].

Chemical compound and disease context of ATIC


Biological context of ATIC

  • A pharmacogenetic index was calculated as the sum of homozygous variant genotypes (RFC-1 AA + ATIC 347GG + TSER *2/*2) carried by the patients [16].
  • This is the first evidence of a variant rearrangement involving the ATIC gene in IMT and the first cytogenetic description of an IMT originating from the urinary bladder [17].
  • Potent and selective inhibition of the AICAR transformylase active site, compared with other folate-dependent enzymes, should therefore be pursued by further design of sulfonyl-containing antifolates [18].
  • The cDNA encoding human 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase has been cloned from a placenta cDNA library, utilizing a PCR-derived probe [3].
  • ATIC encodes an enzyme involved in purine biosynthesis which, like other fusion partners of ALK, is constitutively expressed and appears to contain a dimerization domain [19].

Anatomical context of ATIC

  • Incubation of cardiac myocytes with AICAR increased the protein expression of the fatty acid transporter FABPpm after 90 min (+27%, P < 0.05) and this protein remained stably overexpressed until 180 min [20].
  • Importantly, exposure of type 2 diabetic skeletal muscle to a combination of insulin and AICAR increased glucose transport and cell-surface GLUT4 content to levels achieved in control subjects [21].
  • This phosphorylation correlates with a 65% increase in insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity in C2C12 myotubes preincubated with AICAR [22].
  • In this study, we investigated the prophylactic and therapeutic efficacy of an AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), in active and passive EAE induced by active immunization with PLP(139-151) or MOG(35-55) and in adoptive transfer of PLP(139-151)-sensitized T cells, respectively [23].
  • We used transcriptional profiling to search for AICAR-regulated genes in hepatocyte cell lines [24].

Associations of ATIC with chemical compounds

  • ATIC is a bifunctional enzyme (5-aminoimidazole-4-carboxamide ribonucleotide transformylase and IMP cyclohydrolase enzymatic activities) that catalyzes the penultimate and final enzymatic activities of the purine nucleotide synthesis pathway [25].
  • The kinetic mechanism of the human bifunctional enzyme ATIC (5-amino-4-imidazolecarboxamide ribonucleotide transformylase/inosine 5'-monophosphate cyclohydrolase). A surprising lack of substrate channeling [26].
  • IMPCHase and AICARFT activities are located within the NH2-terminal 223 and COOH-terminal 406 amino acids, respectively [27].
  • GST-AICAR transformylase can be purified to homogeneity by a single-step affinity procedure with glutathione Sepharose [3].
  • Identification of the AICAR transformylase active site and a proposed formyl transfer mechanism have already resulted from analysis of crystal structures of avian ATIC in complex with substrate and/or inhibitors [28].

Physical interactions of ATIC

  • Insulin and AICAR increased glucose transport and cell-surface GLUT4 content to a similar extent in control subjects [21].
  • Experimental tests show that AICAR binds the Hsp90 N-domain, destabilizes multiple Hsp90 client proteins in vivo, including survivin, and exhibits antiproliferative and proapoptotic activity in multiple tumor cell lines, while not affecting proliferation of normal human fibroblasts [29].
  • In addition, nuclear extracts from AICAR-treated mice bound to the consensus sequence of myocyte enhancer factor-2 (from -473 to -464) to a greater extent than from saline-injected mice [30].

Enzymatic interactions of ATIC


Regulatory relationships of ATIC

  • Activation of endogenous AMPK with the cell-permeant adenosine analog 5-amino-4-imidazolecarboxamide-1-beta-d-ribofuranoside (AICAR) inhibited forskolin-stimulated CFTR-dependent I(sc) in nonpermeabilized monolayers and monolayers with nystatin permeabilization of the basolateral membrane [32].
  • AICAR stimulates adiponectin and inhibits cytokines in adipose tissue [33].
  • AICAR suppresses IL-2 expression through inhibition of GSK-3 phosphorylation and NF-AT activation in Jurkat T cells [34].
  • The small interfering RNA for AMPKalpha1 attenuated metformin or AICAR-induced inhibition of NF-kappaB activation by TNF-alpha, suggesting a possible role of AMPK in the regulation of cell inflammation [35].
  • In contrast, insulin- and AICAR-stimulated responses on glucose transport and cell-surface GLUT4 content were impaired in subjects with type 2 diabetes [21].

Other interactions of ATIC

  • Other rearrangements involving the ALK gene have recently been shown to be associated with ALCL, among which the ATIC-ALK rearrangement resulting from the inv(2)(p23q35) translocation is probably the most recurrent [36].
  • RESULTS: There were no significant differences in MTX sensitivity among the genotypes of RFC1, ATIC and TYMS genes [37].
  • The compounds with three and four gamma-glutamyl residues were found to bind two orders of magnitude better than dmAMT itself to DHFR, TS, and AICARFT, with 50% inhibitory concentration values in the 200 to 300 nM range against all three enzymes [38].
  • When the AICAR-induced AMPK phosphorylation was blocked, neither FAT/CD36 nor FABPpm were overexpressed, nor were palmitate uptake and oxidation increased [20].
  • RESULTS: Patients carrying the AMPD1 34T allele, ATIC 347CC, or ITPA 94CC were more likely to have a good clinical response, as defined by a DAS of </=2.4 (OR [95% confidence interval] 2.1 [1.0-4.5], 2.5 [1.3-4.7], and 2.7 [1.1-8.1], respectively) [4].

Analytical, diagnostic and therapeutic context of ATIC

  • Subsequent FISH and RT-PCR analysis confirmed the ALK-ATIC chimeric fusion in tumor cells [17].
  • A 10-amino acid sequence within the COOH-terminal portion of human AICARFT/IMPCHase has some degree of homology to a previously noted "folate binding site." Site directed mutagenesis studies indicate that this sequence plays no role in enzymatic activity [27].
  • Northern-blot analysis of human AICAR transformylase mRNA showed the expression of a single 2.0 kb mRNA in all tissues examined [3].
  • The crystal structure of ATIC provides a framework to probe both catalytic mechanisms and to design specific inhibitors for use in cancer chemotherapy and inflammation [9].
  • We find that ATIC participates in a monomer/dimer equilibrium with a dissociation constant of 240 +/- 50 nM at 4 degrees C. To determine whether the presence of substrates affects the monomer/dimer equilibrium, further ultracentrifugation studies were performed [39].


  1. Inv(2)(p23q35) in anaplastic large-cell lymphoma induces constitutive anaplastic lymphoma kinase (ALK) tyrosine kinase activation by fusion to ATIC, an enzyme involved in purine nucleotide biosynthesis. Ma, Z., Cools, J., Marynen, P., Cui, X., Siebert, R., Gesk, S., Schlegelberger, B., Peeters, B., De Wolf-Peeters, C., Wlodarska, I., Morris, S.W. Blood (2000) [Pubmed]
  2. Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid arthritis. Weisman, M.H., Furst, D.E., Park, G.S., Kremer, J.M., Smith, K.M., Wallace, D.J., Caldwell, J.R., Dervieux, T. Arthritis Rheum. (2006) [Pubmed]
  3. Characterization of molecularly cloned human 5-aminoimidazole-4-carboxamide ribonucleotide transformylase. Sugita, T., Aya, H., Ueno, M., Ishizuka, T., Kawashima, K. J. Biochem. (1997) [Pubmed]
  4. Relationship between genetic variants in the adenosine pathway and outcome of methotrexate treatment in patients with recent-onset rheumatoid arthritis. Wessels, J.A., Kooloos, W.M., Jonge, R.D., De Vries-Bouwstra, J.K., Allaart, C.F., Linssen, A., Collee, G., Sonnaville, P.D., Lindemans, J., Huizinga, T.W., Guchelaar, H.J. Arthritis Rheum. (2006) [Pubmed]
  5. Diagnosing AICA-ribosiduria by capillary electrophoresis. Hornik, P., Vyskocilov??, P., Friedeck??, D., Adam, T. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. (2006) [Pubmed]
  6. 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) attenuates the expression of LPS- and Abeta peptide-induced inflammatory mediators in astroglia. Ayasolla, K.R., Singh, A.K., Singh, I. Journal of neuroinflammation [electronic resource]. (2005) [Pubmed]
  7. The role of AMP-activated protein kinase in the action of ethanol in the liver. You, M., Matsumoto, M., Pacold, C.M., Cho, W.K., Crabb, D.W. Gastroenterology (2004) [Pubmed]
  8. AICA-ribosiduria: a novel, neurologically devastating inborn error of purine biosynthesis caused by mutation of ATIC. Marie, S., Heron, B., Bitoun, P., Timmerman, T., Van Den Berghe, G., Vincent, M.F. Am. J. Hum. Genet. (2004) [Pubmed]
  9. Crystal structure of a bifunctional transformylase and cyclohydrolase enzyme in purine biosynthesis. Greasley, S.E., Horton, P., Ramcharan, J., Beardsley, G.P., Benkovic, S.J., Wilson, I.A. Nat. Struct. Biol. (2001) [Pubmed]
  10. Role of AMP-activated protein kinase in the regulation by glucose of islet beta cell gene expression. da Silva Xavier, G., Leclerc, I., Salt, I.P., Doiron, B., Hardie, D.G., Kahn, A., Rutter, G.A. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  11. 5,10-Methylenetetrahydro-5-deazafolic acid and analogues: synthesis and biological activities. Gangjee, A., Patel, J., Kisliuk, R.L., Gaumont, Y. J. Med. Chem. (1992) [Pubmed]
  12. Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Kukidome, D., Nishikawa, T., Sonoda, K., Imoto, K., Fujisawa, K., Yano, M., Motoshima, H., Taguchi, T., Matsumura, T., Araki, E. Diabetes (2006) [Pubmed]
  13. The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid beta-oxidation. Buzzai, M., Bauer, D.E., Jones, R.G., Deberardinis, R.J., Hatzivassiliou, G., Elstrom, R.L., Thompson, C.B. Oncogene (2005) [Pubmed]
  14. Purine biosynthesis in Escherichia coli K12: structure and DNA sequence studies of the purHD locus. Flannigan, K.A., Hennigan, S.H., Vogelbacker, H.H., Gots, J.S., Smith, J.M. Mol. Microbiol. (1990) [Pubmed]
  15. Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine. Brusq, J.M., Ancellin, N., Grondin, P., Guillard, R., Martin, S., Saintillan, Y., Issandou, M. J. Lipid Res. (2006) [Pubmed]
  16. Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Dervieux, T., Furst, D., Lein, D.O., Capps, R., Smith, K., Walsh, M., Kremer, J. Arthritis Rheum. (2004) [Pubmed]
  17. ALK-ATIC fusion in urinary bladder inflammatory myofibroblastic tumor. Debiec-Rychter, M., Marynen, P., Hagemeijer, A., Pauwels, P. Genes Chromosomes Cancer (2003) [Pubmed]
  18. Crystal structures of human bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase in complex with potent sulfonyl-containing antifolates. Cheong, C.G., Wolan, D.W., Greasley, S.E., Horton, P.A., Beardsley, G.P., Wilson, I.A. J. Biol. Chem. (2004) [Pubmed]
  19. ATIC-ALK: A novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent cryptic chromosomal inversion, inv(2)(p23q35). Colleoni, G.W., Bridge, J.A., Garicochea, B., Liu, J., Filippa, D.A., Ladanyi, M. Am. J. Pathol. (2000) [Pubmed]
  20. Prolonged AMPK Activation Increases the Expression of Fatty Acid Transporters in Cardiac Myocytes and Perfused Hearts. Chabowski, A., Momken, I., Coort, S.L., Calles-Escandon, J., Tandon, N.N., Glatz, J.F., Luiken, J.J., Bonen, A. Mol. Cell. Biochem. (2006) [Pubmed]
  21. 5-amino-imidazole carboxamide riboside increases glucose transport and cell-surface GLUT4 content in skeletal muscle from subjects with type 2 diabetes. Koistinen, H.A., Galuska, D., Chibalin, A.V., Yang, J., Zierath, J.R., Holman, G.D., Wallberg-Henriksson, H. Diabetes (2003) [Pubmed]
  22. 5'-AMP-activated protein kinase phosphorylates IRS-1 on Ser-789 in mouse C2C12 myotubes in response to 5-aminoimidazole-4-carboxamide riboside. Jakobsen, S.N., Hardie, D.G., Morrice, N., Tornqvist, H.E. J. Biol. Chem. (2001) [Pubmed]
  23. 5-aminoimidazole-4-carboxamide ribonucleoside: a novel immunomodulator with therapeutic efficacy in experimental autoimmune encephalomyelitis. Nath, N., Giri, S., Prasad, R., Salem, M.L., Singh, A.K., Singh, I. J. Immunol. (2005) [Pubmed]
  24. Inhibition of Gluconeogenesis through Transcriptional Activation of EGR1 and DUSP4 by AMP-activated Kinase. Berasi, S.P., Huard, C., Li, D., Shih, H.H., Sun, Y., Zhong, W., Paulsen, J.E., Brown, E.L., Gimeno, R.E., Martinez, R.V. J. Biol. Chem. (2006) [Pubmed]
  25. A new variant anaplastic lymphoma kinase (ALK)-fusion protein (ATIC-ALK) in a case of ALK-positive anaplastic large cell lymphoma. Trinei, M., Lanfrancone, L., Campo, E., Pulford, K., Mason, D.Y., Pelicci, P.G., Falini, B. Cancer Res. (2000) [Pubmed]
  26. The kinetic mechanism of the human bifunctional enzyme ATIC (5-amino-4-imidazolecarboxamide ribonucleotide transformylase/inosine 5'-monophosphate cyclohydrolase). A surprising lack of substrate channeling. Bulock, K.G., Beardsley, G.P., Anderson, K.S. J. Biol. Chem. (2002) [Pubmed]
  27. The human purH gene product, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase. Cloning, sequencing, expression, purification, kinetic analysis, and domain mapping. Rayl, E.A., Moroson, B.A., Beardsley, G.P. J. Biol. Chem. (1996) [Pubmed]
  28. Structural insights into the human and avian IMP cyclohydrolase mechanism via crystal structures with the bound XMP inhibitor. Wolan, D.W., Cheong, C.G., Greasley, S.E., Wilson, I.A. Biochemistry (2004) [Pubmed]
  29. Small-molecule targeting of heat shock protein 90 chaperone function: rational identification of a new anticancer lead. Meli, M., Pennati, M., Curto, M., Daidone, M.G., Plescia, J., Toba, S., Altieri, D.C., Zaffaroni, N., Colombo, G. J. Med. Chem. (2006) [Pubmed]
  30. Regulation of muscle GLUT-4 transcription by AMP-activated protein kinase. Zheng, D., MacLean, P.S., Pohnert, S.C., Knight, J.B., Olson, A.L., Winder, W.W., Dohm, G.L. J. Appl. Physiol. (2001) [Pubmed]
  31. Residual adenylosuccinase activities in fibroblasts of adenylosuccinase-deficient children: parallel deficiency with adenylosuccinate and succinyl-AICAR in profoundly retarded patients and non-parallel deficiency in a mildly retarded girl. Van den Bergh, F., Vincent, M.F., Jaeken, J., Van den Berghe, G. J. Inherit. Metab. Dis. (1993) [Pubmed]
  32. Physiological modulation of CFTR activity by AMP-activated protein kinase in polarized T84 cells. Hallows, K.R., Kobinger, G.P., Wilson, J.M., Witters, L.A., Foskett, J.K. Am. J. Physiol., Cell Physiol. (2003) [Pubmed]
  33. AICAR stimulates adiponectin and inhibits cytokines in adipose tissue. Lihn, A.S., Jessen, N., Pedersen, S.B., Lund, S., Richelsen, B. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  34. AICAR suppresses IL-2 expression through inhibition of GSK-3 phosphorylation and NF-AT activation in Jurkat T cells. Jhun, B.S., Oh, Y.T., Lee, J.Y., Kong, Y., Yoon, K.S., Kim, S.S., Baik, H.H., Ha, J., Kang, I. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  35. Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hattori, Y., Suzuki, K., Hattori, S., Kasai, K. Hypertension (2006) [Pubmed]
  36. The NPM-ALK and the ATIC-ALK fusion genes can be detected in non-neoplastic cells. Maes, B., Vanhentenrijk, V., Wlodarska, I., Cools, J., Peeters, B., Marynen, P., de Wolf-Peeters, C. Am. J. Pathol. (2001) [Pubmed]
  37. ABCB1 C3435T polymorphism influences methotrexate sensitivity in rheumatoid arthritis patients. Takatori, R., Takahashi, K.A., Tokunaga, D., Hojo, T., Fujioka, M., Asano, T., Hirata, T., Kawahito, Y., Satomi, Y., Nishino, H., Tanaka, T., Hirota, Y., Kubo, T. Clin. Exp. Rheumatol. (2006) [Pubmed]
  38. Biochemical and biological studies on 2-desamino-2-methylaminopterin, an antifolate the polyglutamates of which are more potent than the monoglutamate against three key enzymes of folate metabolism. Rosowsky, A., Galivan, J., Beardsley, G.P., Bader, H., O'Connor, B.M., Russello, O., Moroson, B.A., DeYarman, M.T., Kerwar, S.S., Freisheim, J.H. Cancer Res. (1992) [Pubmed]
  39. Human 5-aminoimidazole-4-carboxamide ribonucleotide transformylase/inosine 5'-monophosphate cyclohydrolase. A bifunctional protein requiring dimerization for transformylase activity but not for cyclohydrolase activity. Vergis, J.M., Bulock, K.G., Fleming, K.G., Beardsley, G.P. J. Biol. Chem. (2001) [Pubmed]
WikiGenes - Universities