AMPK Activation via Modulation of De Novo Purine Biosynthesis with an Inhibitor of ATIC Homodimerization
| Autor: | Franchesca D. Houghton, Felino R. Cagampang, Daniel J. Asby, Maxime Beyaert, Ali Tavassoli, F. Cuda |
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| Rok vydání: | 2015 |
| Předmět: |
Hydroxymethyl and Formyl Transferases
Male Ribonucleotide Allosteric regulation Clinical Biochemistry Biology AMP-Activated Protein Kinases Biochemistry Enzyme activator Mice Multienzyme Complexes Drug Discovery medicine Animals Humans Phosphofructokinase 2 Protein kinase A Molecular Biology Pharmacology AMPK General Medicine Ribonucleotides Aminoimidazole Carboxamide HCT116 Cells Adenosine Enzyme Activation Mice Inbred C57BL Metabolic pathway Nucleotide Deaminases Purines Models Animal MCF-7 Cells Molecular Medicine Protein Multimerization medicine.drug |
| Zdroj: | Chemistrybiology. 22(7) |
| ISSN: | 1879-1301 |
| Popis: | Summary5-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. |
| Databáze: | OpenAIRE |
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