TYMP, encoding thymidine phosphorylase (TP), is a cytosolic metabolic enzyme. It is involved in nucleotide metabolism and its function is crucial for maintaining a balanced mitochondrial nucleotide pool, which is essential for mitochondrial DNA maintenance [2,4]. Mutations in TYMP are associated with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), highlighting its importance in mitochondrial-related biological processes [2,5].

In terms of disease associations, Mendelian randomization analysis has suggested that in plasma, per standard deviation increase in TYMP has a protective effect on multiple sclerosis, with an odds ratio of 0.59 (95% CI, 0.48-0.71), indicating its potential as a drug target for this autoimmune disease [1]. Additionally, TYMP deficiency in patients with MNGIE leads to not only mitochondrial dysfunction but also more widespread metabolic disturbance, including specific alterations in nucleosides, bile acids, and steroid metabolites, as well as disrupted cholesterol and fatty acid metabolism [2]. In clear cell renal cell carcinoma (ccRCC), TYMP is upregulated, and high expression is associated with poor prognosis. Knockdown of TYMP can suppress cell aggressiveness and cause cell death, and it is linked to immune cell invasion, fatty acid metabolism, and the P53 signaling pathway [3].

In conclusion, TYMP plays a vital role in nucleotide and mitochondrial-related metabolism. Its implications in multiple sclerosis, MNGIE, and ccRCC, as revealed through various studies, highlight its significance in understanding disease mechanisms. Functional studies, potentially including gene knockout or conditional knockout models in the future, could further elucidate its role in these and other disease conditions, providing new insights for disease treatment and prevention.

References:

1. Lin, Jianfeng, Zhou, Jiawei, Xu, Yan. . Potential drug targets for multiple sclerosis identified through Mendelian randomization analysis. In Brain : a journal of neurology, 146, 3364-3372. doi:10.1093/brain/awad070. https://pubmed.ncbi.nlm.nih.gov/36864689/

2. Du, Jixiang, Zhang, Chao, Liu, Fuchen, Zhao, Yuying, Yan, Chuanzhu. 2023. Distinctive metabolic remodeling in TYMP deficiency beyond mitochondrial dysfunction. In Journal of molecular medicine (Berlin, Germany), 101, 1237-1253. doi:10.1007/s00109-023-02358-9. https://pubmed.ncbi.nlm.nih.gov/37603049/

3. Chen, Shao-An, Zhang, Jun-Peng, Wang, Ning, Chen, Ji. . Identifying TYMP as an Immune Prognostic Marker in Clear Cell Renal Cell Carcinoma. In Technology in cancer research & treatment, 22, 15330338231194555. doi:10.1177/15330338231194555. https://pubmed.ncbi.nlm.nih.gov/38043946/

4. El-Hattab, Ayman W, Craigen, William J, Scaglia, Fernando. 2017. Mitochondrial DNA maintenance defects. In Biochimica et biophysica acta. Molecular basis of disease, 1863, 1539-1555. doi:10.1016/j.bbadis.2017.02.017. https://pubmed.ncbi.nlm.nih.gov/28215579/

5. Mojtabavi, Helia, Fatehi, Farzad, Shahkarami, Sepideh, Rezaei, Nima, Nafissi, Shahriar. 2021. Novel Mutations of the TYMP Gene in Mitochondrial Neurogastrointestinal Encephalomyopathy: Case Series and Literature Review. In Journal of molecular neuroscience : MN, 71, 2526-2533. doi:10.1007/s12031-021-01822-w. https://pubmed.ncbi.nlm.nih.gov/33825174/