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AMPK activation via modulation of de novo purine biosynthesis with an inhibitor of ATIC homodimerization

AMPK activation via modulation of de novo purine biosynthesis with an inhibitor of ATIC homodimerization
AMPK activation via modulation of de novo purine biosynthesis with an inhibitor of ATIC homodimerization
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
1074-5521
838-848
Asby, Daniel J.
cf0462d7-e923-45eb-b4ce-7c1673f544d5
Cuda, Francesco
8c738a55-70a8-4063-b063-bf83cdf0f270
Beyaert, Maxime
6137b0ba-26f9-4fef-8d96-0127fee95c83
Houghton, Franchesca D.
53946041-127e-45a8-9edb-bf4b3c23005f
Cagampang, Felino R.
7cf57d52-4a65-4554-8306-ed65226bc50e
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2
Asby, Daniel J.
cf0462d7-e923-45eb-b4ce-7c1673f544d5
Cuda, Francesco
8c738a55-70a8-4063-b063-bf83cdf0f270
Beyaert, Maxime
6137b0ba-26f9-4fef-8d96-0127fee95c83
Houghton, Franchesca D.
53946041-127e-45a8-9edb-bf4b3c23005f
Cagampang, Felino R.
7cf57d52-4a65-4554-8306-ed65226bc50e
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2

Asby, Daniel J., Cuda, Francesco, Beyaert, Maxime, Houghton, Franchesca D., Cagampang, Felino R. and Tavassoli, Ali (2015) AMPK activation via modulation of de novo purine biosynthesis with an inhibitor of ATIC homodimerization. Chemistry & Biology, 22 (7), 838-848. (doi:10.1016/j.chembiol.2015.06.008). (PMID:26144885)

Record type: Article

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

Other
1-s2.0-S1074552115002343-main.pdf__tid=e85194f8-3b61-11e5-a708-00000aacb35f&acdnat=1438772920_e3d07b76ff997b5f5a0ee653dfe5f706 - Version of Record
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More information

Accepted/In Press date: 30 June 2015
e-pub ahead of print date: 2 July 2015
Published date: 23 July 2015
Organisations: Chemistry, Human Development & Health

Identifiers

Local EPrints ID: 378813
URI: https://eprints.soton.ac.uk/id/eprint/378813
ISSN: 1074-5521
PURE UUID: 64714adb-60d4-42d1-9a93-0135dacc33f3
ORCID for Felino R. Cagampang: ORCID iD orcid.org/0000-0003-4404-9853
ORCID for Ali Tavassoli: ORCID iD orcid.org/0000-0002-7420-5063

Catalogue record

Date deposited: 16 Jul 2015 10:51
Last modified: 31 Jul 2019 00:44

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