title: AMPK Activation via Modulation of De Novo Purine Biosynthesis with an Inhibitor of ATIC Homodimerization.
abstract: 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.
authors.affiliation: Chemistry, University of Southampton, Southampton SO17 1BJ, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Asby
authors.affiliation: Chemistry, University of Southampton, Southampton SO17 1BJ, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cuda
authors.affiliation: Chemistry, University of Southampton, Southampton SO17 1BJ, UK.
authors.forename: Maxime
authors.initials: M
authors.lastname: Beyaert
authors.affiliation: Human Development and Health, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK; The Institute for Life Sciences, University of Southampton, Southampton, UK.
authors.forename: Franchesca D
authors.initials: FD
authors.lastname: Houghton
authors.affiliation: Human Development and Health, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK; The Institute for Life Sciences, University of Southampton, Southampton, UK.
authors.forename: Felino R
authors.initials: FR
authors.lastname: Cagampang
authors.affiliation: Chemistry, University of Southampton, Southampton SO17 1BJ, UK; The Institute for Life Sciences, University of Southampton, Southampton, UK. Electronic address: a.tavassoli@soton.ac.uk.
authors.forename: Ali
authors.initials: A
authors.lastname: Tavassoli
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D004789:Enzyme Activation; D045325:HCT116 Cells; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009709:Nucleotide Deaminases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D011687:Purines / Q000096:biosynthesis*; D012265:Ribonucleotides / Q000494:pharmacology*
chemical_list: D009097:Multienzyme Complexes; D011687:Purines; D012265:Ribonucleotides; C113120:inosine monophosphate synthase; D000620:Aminoimidazole Carboxamide; D019877:Hydroxymethyl and Formyl Transferases; D055372:AMP-Activated Protein Kinases; D009709:Nucleotide Deaminases; C031143:AICA ribonucleotide