Guanine is an inhibitor of c-jun terminal kinases
Abstract The toxicity of purine bases adenine and guanine is mostly recognized when associated with inborn errors of purine metabolism such as Lesch-Nyhan syndrome, and metabolic diseases with a lifestyle component including gout. In these pathologies, the peripheral toxicity of purine bases is attr...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-08-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-025-11617-3 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849343226243186688 |
|---|---|
| author | Jessica Treeby Sherihan El-Sayed Samuel Morgan Sophie Maddock George Taylor Stacey Warwood Julian Selley David Knight Benjamin Saer Richard A. Bryce Jean-Michel Fustin |
| author_facet | Jessica Treeby Sherihan El-Sayed Samuel Morgan Sophie Maddock George Taylor Stacey Warwood Julian Selley David Knight Benjamin Saer Richard A. Bryce Jean-Michel Fustin |
| author_sort | Jessica Treeby |
| collection | DOAJ |
| description | Abstract The toxicity of purine bases adenine and guanine is mostly recognized when associated with inborn errors of purine metabolism such as Lesch-Nyhan syndrome, and metabolic diseases with a lifestyle component including gout. In these pathologies, the peripheral toxicity of purine bases is attributed to the accumulation of their catabolite uric acid in the kidneys, causing nephrolithiasis or crystalluria, and the joints, causing gout. However, inborn errors of purine metabolism also present neurological and neurobehavioral abnormalities including motor disabilities, seizures, hypotonia and dystonia, and self-injurious behaviour. The mechanisms underlying these pathologies is less well-understood but does not seem to be caused by uric acid. In a different context, adenine and guanine have been shown to be cytotoxic and antiproliferative, highlighting their potential use in cancer chemotherapies, but the underlying mechanisms have not been identified. In our previous investigations, we have shown that adenine, a molecule classified as acutely toxic, is an inhibitor of 1-carbon metabolism and biological methylations. Using the same experimental paradigm based on real-time luminometry with mouse embryonic fibroblasts to probe in real-time the potential biological activity of small molecules, complemented with metabolite quantifications, in silico docking predictions, kinase assays and phosphoproteomics, we now reveal that guanine and to a lesser extent adenine are direct inhibitors of c-Jun N-terminal kinases, which may contribute to their toxicity and to the symptoms of Lesch-Nyhan syndrome. |
| format | Article |
| id | doaj-art-854a398cbc884e0c8e0ace606aae097a |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-854a398cbc884e0c8e0ace606aae097a2025-08-20T03:43:02ZengNature PortfolioScientific Reports2045-23222025-08-0115111510.1038/s41598-025-11617-3Guanine is an inhibitor of c-jun terminal kinasesJessica Treeby0Sherihan El-Sayed1Samuel Morgan2Sophie Maddock3George Taylor4Stacey Warwood5Julian Selley6David Knight7Benjamin Saer8Richard A. Bryce9Jean-Michel Fustin10Faculty of Biology, Medicine and Health, Centre for Biological Timing, The University of ManchesterDivision of Pharmacy and Optometry, School of Health Sciences, Manchester Academic Health Sciences Centre, University of ManchesterFaculty of Biology, Medicine and Health, Centre for Biological Timing, The University of ManchesterFaculty of Biology, Medicine and Health, Centre for Biological Timing, The University of ManchesterFBMH Platform Sciences, The University of Manchester, Enabling Technologies & Infrastructure, BioMSFBMH Platform Sciences, The University of Manchester, Enabling Technologies & Infrastructure, BioMSFBMH Platform Sciences, The University of Manchester, Enabling Technologies & Infrastructure, BioMSFBMH Platform Sciences, The University of Manchester, Enabling Technologies & Infrastructure, BioMSFaculty of Biology, Medicine and Health, Centre for Biological Timing, The University of ManchesterDivision of Pharmacy and Optometry, School of Health Sciences, Manchester Academic Health Sciences Centre, University of ManchesterFaculty of Biology, Medicine and Health, Centre for Biological Timing, The University of ManchesterAbstract The toxicity of purine bases adenine and guanine is mostly recognized when associated with inborn errors of purine metabolism such as Lesch-Nyhan syndrome, and metabolic diseases with a lifestyle component including gout. In these pathologies, the peripheral toxicity of purine bases is attributed to the accumulation of their catabolite uric acid in the kidneys, causing nephrolithiasis or crystalluria, and the joints, causing gout. However, inborn errors of purine metabolism also present neurological and neurobehavioral abnormalities including motor disabilities, seizures, hypotonia and dystonia, and self-injurious behaviour. The mechanisms underlying these pathologies is less well-understood but does not seem to be caused by uric acid. In a different context, adenine and guanine have been shown to be cytotoxic and antiproliferative, highlighting their potential use in cancer chemotherapies, but the underlying mechanisms have not been identified. In our previous investigations, we have shown that adenine, a molecule classified as acutely toxic, is an inhibitor of 1-carbon metabolism and biological methylations. Using the same experimental paradigm based on real-time luminometry with mouse embryonic fibroblasts to probe in real-time the potential biological activity of small molecules, complemented with metabolite quantifications, in silico docking predictions, kinase assays and phosphoproteomics, we now reveal that guanine and to a lesser extent adenine are direct inhibitors of c-Jun N-terminal kinases, which may contribute to their toxicity and to the symptoms of Lesch-Nyhan syndrome.https://doi.org/10.1038/s41598-025-11617-3GuaninePurineJNKMAPKLesch-NyhanMetabolism |
| spellingShingle | Jessica Treeby Sherihan El-Sayed Samuel Morgan Sophie Maddock George Taylor Stacey Warwood Julian Selley David Knight Benjamin Saer Richard A. Bryce Jean-Michel Fustin Guanine is an inhibitor of c-jun terminal kinases Scientific Reports Guanine Purine JNK MAPK Lesch-Nyhan Metabolism |
| title | Guanine is an inhibitor of c-jun terminal kinases |
| title_full | Guanine is an inhibitor of c-jun terminal kinases |
| title_fullStr | Guanine is an inhibitor of c-jun terminal kinases |
| title_full_unstemmed | Guanine is an inhibitor of c-jun terminal kinases |
| title_short | Guanine is an inhibitor of c-jun terminal kinases |
| title_sort | guanine is an inhibitor of c jun terminal kinases |
| topic | Guanine Purine JNK MAPK Lesch-Nyhan Metabolism |
| url | https://doi.org/10.1038/s41598-025-11617-3 |
| work_keys_str_mv | AT jessicatreeby guanineisaninhibitorofcjunterminalkinases AT sherihanelsayed guanineisaninhibitorofcjunterminalkinases AT samuelmorgan guanineisaninhibitorofcjunterminalkinases AT sophiemaddock guanineisaninhibitorofcjunterminalkinases AT georgetaylor guanineisaninhibitorofcjunterminalkinases AT staceywarwood guanineisaninhibitorofcjunterminalkinases AT julianselley guanineisaninhibitorofcjunterminalkinases AT davidknight guanineisaninhibitorofcjunterminalkinases AT benjaminsaer guanineisaninhibitorofcjunterminalkinases AT richardabryce guanineisaninhibitorofcjunterminalkinases AT jeanmichelfustin guanineisaninhibitorofcjunterminalkinases |