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Methotrexate promotes AMPK activation by inhibiting 5\u2010aminoimidazole\u20104\u2010carboxamide ribonucleotide (ZMP) formyltransferase\/inosine monophosphate (IMP) cyclohydrolase (ATIC), which converts ZMP, an endogenous purine precursor and an active form of the pharmacological AMPK activator AICAR, to IMP during de novo purine synthesis. In addition to methotrexate, inhibition of purine synthesis underpins the therapeutic effects of a number of commonly used immunosuppressive, anticancer, and antimicrobial drugs, raising the question of whether activation of AMPK in skeletal muscle could be a recurrent feature of these drugs. Using L6 myotubes, we found that AICAR\u2010induced AMPK activation and glucose uptake were enhanced by inhibitors of the conversion of IMP to GMP (mycophenolate mofetil) or of IMP to AMP (alanosine) as well as by indirect inhibitors of human (trimetrexate) and bacterial ATIC (sulfamethoxazole). 6\u2010Mercaptopurine, which inhibits the conversion of IMP to GMP and AMP, activated AMPK, increased glucose uptake, and suppressed insulin signaling, but did not enhance the effect of AICAR. As determined by measuring oxygen consumption rate, none of these agents suppressed mitochondrial function. Overall, our results indicate that IMP metabolism is a gateway for the modulation of AMPK and its metabolic effects in skeletal muscle cells.<\/jats:p>","DOI":"10.1002\/biof.70037","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T12:45:27Z","timestamp":1755002727000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Diverse Inhibitors of De Novo Purine Synthesis Promote\n                    <scp>AICAR<\/scp>\n                    \u2010Induced\n                    <scp>AMPK<\/scp>\n                    Activation and Glucose Uptake in\n                    <scp>L6<\/scp>\n                    Myotubes"],"prefix":"10.1002","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3903-6321","authenticated-orcid":false,"given":"Klemen","family":"Dolinar","sequence":"first","affiliation":[{"name":"Institute of Pathophysiology, Faculty of Medicine University of Ljubljana  Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1726-2686","authenticated-orcid":false,"given":"Katarina","family":"Mi\u0161","sequence":"additional","affiliation":[{"name":"Institute of Pathophysiology, Faculty of Medicine University of Ljubljana  Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6074-7528","authenticated-orcid":false,"given":"Katja","family":"\u0160opar","sequence":"additional","affiliation":[{"name":"Institute of Pathophysiology, Faculty of Medicine University of Ljubljana  Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6544-7046","authenticated-orcid":false,"given":"Mateja","family":"\u0160utar","sequence":"additional","affiliation":[{"name":"Institute of Pathophysiology, Faculty of Medicine University of Ljubljana  Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5720-6643","authenticated-orcid":false,"given":"Meta","family":"Bo\u017ei\u010d","sequence":"additional","affiliation":[{"name":"Institute of Pathophysiology, Faculty of Medicine University of Ljubljana  Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0197-2744","authenticated-orcid":false,"given":"Matic","family":"Kolar","sequence":"additional","affiliation":[{"name":"Institute of Pathophysiology, Faculty of Medicine University of Ljubljana  Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4591-8160","authenticated-orcid":false,"given":"Tim","family":"Hropot","sequence":"additional","affiliation":[{"name":"Institute of Pathophysiology, Faculty of Medicine University of Ljubljana  Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8371-2067","authenticated-orcid":false,"given":"Pablo M.","family":"Garcia\u2010Roves","sequence":"additional","affiliation":[{"name":"Department of Physiological Sciences, Faculty of Medicine and Health Sciences University of Barcelona  Barcelona Spain"},{"name":"Nutrition, Metabolism and Gene Therapy Group, Diabetes and Metabolism Program Institut D'investigaci\u00f3 Biom\u00e9dica de Bellvitge (IDIBELL)  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6339-6271","authenticated-orcid":false,"given":"Alexander V.","family":"Chibalin","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Surgery, Integrative Physiology Karolinska Institutet  Stockholm Sweden"},{"name":"National Research Tomsk State University  Tomsk Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1459-6936","authenticated-orcid":false,"given":"Sergej","family":"Pirkmajer","sequence":"additional","affiliation":[{"name":"Institute of Pathophysiology, Faculty of Medicine University of Ljubljana  Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,12]]},"reference":[{"key":"e_1_2_9_2_1","first-page":"241","article-title":"AMPK Activation: A Therapeutic Target for Type 2 Diabetes?","volume":"7","author":"Coughlan K. 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