Thymidine kinase 2, mitochondrial (TK2) (TK2)

Thymidine kinase 2 (TK2) is a nuclear-encoded mitochondrial enzyme that plays a critical role in the mitochondrial pyrimidine salvage pathway by phosphorylating the deoxynucleosides thymidine and deoxycytidine into their respective monophosphates (UniProt P27707). This process is the rate-limiting step for providing the deoxyribonucleoside triphosphates (dNTPs) necessary for mitochondrial DNA (mtDNA) synthesis and maintenance, particularly in post-mitotic tissues like muscle and brain where de novo nucleotide synthesis is minimal (PubMed: 29906304). Mutations in the TK2 gene result in TK2 deficiency, a form of mitochondrial DNA depletion syndrome (MTDPS2) characterized by severe, progressive myopathy and depletion of mtDNA in affected tissues (NIH GARD). Therapeutic intervention for this condition involves substrate enhancement therapy, where high doses of thymidine and deoxycytidine are administered to bypass the enzymatic defect and restore mitochondrial dNTP pools (PubMed: 31439440). This approach, exemplified by the investigational drug MT1621, has shown significant clinical benefit in improving motor function and survival in patients with TK2 deficiency (ClinicalTrials.gov NCT03639701).

Other names

TK2Mitochondrial thymidine kinaseMTTKDeoxycytidine kinase (mitochondrial activity)

Substrate enhancement therapy to restore mitochondrial dNTP pools for DNA synthesis