Format

Send to

Choose Destination
Chem Biol. 2015 Jul 23;22(7):838-48. doi: 10.1016/j.chembiol.2015.06.008. Epub 2015 Jul 2.

AMPK Activation via Modulation of De Novo Purine Biosynthesis with an Inhibitor of ATIC Homodimerization.

Author information

1
Chemistry, University of Southampton, Southampton SO17 1BJ, UK.
2
Human Development and Health, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK; The Institute for Life Sciences, University of Southampton, Southampton, UK.
3
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.

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.

PMID:
26144885
DOI:
10.1016/j.chembiol.2015.06.008
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center