Graphical Abstract Highlights d AICAR transformylase is targeted in cells with an ATIC homodimerization inhibitor d The resulting increase in endogenous ZMP is sufficient to activate AMPK d Downstream AMPK signaling is also activated, significantly altering cell metabolism d A mouse model of metabolic syndrome is used to show therapeutic viability Correspondence a.tavassoli@soton.ac.uk In Brief Asby et al. report a new approach to AMPK activation. Using an inhibitor of AICAR transformylase

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... imerization, the ninth step of de novo purine biosynthesis is blocked, causing a rise in endogenous ZMP, which activates AMPK and its downstream effectors. SUMMARY 5-Aminoimidazole-4-carboxamide ribonucleotide (known as ZMP) is a metabolite produced in de novo purine biosynthesis and histidine biosynthesis, but only utilized in the cell by a homodimeric bifunctional enzyme (called ATIC) that catalyzes the last two steps of de novo purine biosynthesis. ZMP is known to act as an allosteric activator of the cellular energy sensor adenosine monophosphate-activated protein kinase (AMPK), when exogenously administered as the corresponding cell-permeable ribonucleoside. Here, we demonstrate that endogenous ZMP, produced by the aforementioned metabolic pathways, is also capable of activating AMPK. Using an inhibitor of ATIC homodimerization to block the ninth step of de novo purine biosynthesis, we demonstrate that the subsequent increase in endogenous ZMP activates AMPK and its downstream signaling pathways. We go on to illustrate the viability of using this approach to AMPK activation as a therapeutic strategy with an in vivo mouse model for metabolic disorders.