Research paperSubstrate cycling between 5-amino-4-imidazolecarboxamide riboside and its monophosphate in isolated rat hepatocytes☆
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AICAR induces Nrf2 activation by an AMPK-independent mechanism in hepatocarcinoma cells
2014, Biochemical PharmacologyCitation Excerpt :Indeed, AMPK is activated by conditions that increase intracellular AMP such as hypoglycemia, hypoxia and exercise, as well as certain cytokines and drugs, such as metformin and 5-aminoimidazole-4-carboxamide riboside (AICA riboside or AICAR) [21]. AICAR is a cell-permeable nucleoside which could be metabolically converted to AICA ribotide (or ZMP), the antepenultimate metabolic intermediate of the de novo purine synthesis pathway [22]. The liver kinase B1 (LKB1) and Ca2+/calmodulin-dependent protein kinase kinase-β (CaMKKβ) are upstream kinases that activate AMPK by phosphorylating Thr172 in the activation loop of the catalytic α-subunits [23,24].
Phenotypes and circadian rhythm in utilization of formate in purine nucleotide biosynthesis de novo in adult humans
2011, Life SciencesCitation Excerpt :The above evidence indicates that PNB in mammalian liver stops at AICAR or at an earlier step. Since substrate cycling of AICAR to AICA-riboside (which crosses cell membranes) occurs in isolated rat hepatocytes (Vincent et al., 1996), and AICA, an AICAR metabolite, is normally found in human urine (McGreer et al., 1961), PNB in human liver probably stops at AICAR; therefore, its riboside is in circulation. AICAR to IMP metabolism should occur in rat liver since the specific activity of AICAR transformylase is greater than that of GAR transformylase (Deacon et al., 1985).
Methotrexate and erythro-9-(2-hydroxynon-3-yl) adenine therapy for rat adjuvant arthritis and the effect of methotrexate on in vivo purine metabolism
2007, European Journal of Pharmaceutical Sciences<sup>13</sup>C enrichment of carbons 2 and 8 of purine by folate-dependent reactions after [<sup>13</sup>C]formate and [2-<sup>13</sup>C]glycine dosing in adult humans
2007, Metabolism: Clinical and ExperimentalCitation Excerpt :Our finding differs from the previously reported C2/C8 ratio of about 1.0 in animals [6-8]. We postulate that the liver stops purine biosynthesis de novo at AICAR because isolated mammalian hepatocytes do not metabolize AICAR to inosine monophosphate (IMP) or to any other purines [24-28]. This is consistent with the low capacity of the mammalian hepatocytes or liver slices to synthesize purines in vitro from radioactive formate or serine [29-31].
AMP-activated protein kinase and the regulation of autophagic proteolysis
2006, Journal of Biological ChemistryCitation Excerpt :The ability of compound C, in contrast to amino acids, to inhibit AICAR-induced AMPK phosphorylation in hepatocytes on its own (Fig. 4), even though the accumulation of ZMP in both cases decreased similarly (Table 1) may be ascribed to small differences in intra/extracellular distribution of ZMP. Although most of the ZMP produced from AICAR is recovered inside the hepatocytes (50), it is possible that in the presence of amino acids, when cell volume increases (8), some of the ZMP leaks to the extracellular fluid so that the total amount of ZMP in the cell suspension overestimates the actual concentration of ZMP inside the cells. In summary, the data presented in this study confirm that the AMPK activator AICAR inhibits autophagy but do not support the conclusion that AMPK is responsible for this effect (11).
AICAR suppresses IL-2 expression through inhibition of GSK-3 phosphorylation and NF-AT activation in Jurkat T cells
2005, Biochemical and Biophysical Research Communications
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We thank T. Timmerman for expert technical assistance. This work was supported by an endowment from Gensia Inc., San Diego, CA, USA, by grant 3.4557.93 of the Belgian Fund for Medical Scientific Research, and by the Belgian Federal Service for Scientific, Technical and Cultural Affairs. G.V.D.B. is Research Director of the Belgian National Fund for Scientific Research.