# Guanine is an inhibitor of c-jun terminal kinases

## TL;DR

Guanine and adenine inhibit c-Jun N-terminal kinases, which may explain their toxicity and role in Lesch-Nyhan syndrome.

## Contribution

Guanine and adenine are identified as direct inhibitors of c-Jun N-terminal kinases.

## Key findings

- Guanine inhibits c-Jun N-terminal kinases, contributing to its toxicity.
- Adenine also inhibits these kinases but to a lesser extent.
- This inhibition may explain neurological symptoms in Lesch-Nyhan syndrome.

## 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.

The online version contains supplementary material available at 10.1038/s41598-025-11617-3.