More About TMPK
Thymidylate kinase (aka TMPK; EC 2.7.4.9) is involved in the pathway dTTP biosynthesis, which is part of Pyrimidine metabolism. It phosphorylates thymidine 5′-monophosphate (dTMP) to thymidine 5′-diphosphate (dTDP), and finally by nucleoside-diphosphate kinase (NDK; EC 2.7.4.6) to thymidine triphosphate (dTTP), a building block of DNA. This pathway is unique in that all other dNDPs, including dUDP, are directly produced by ribonucleotide reductase (RNR; EC 1.17.4.1). TMPK has an important function in cell proliferation, and is well recognized as a potential drug target, with the most notable function being in the activation of anti-HIV nucleoside prodrugs. Recent studies have shown that TMPK is a validated target for antibiotic development against grampositive bacteria of M.tuberculosis and S.aureus as well[1], and a modulator that can increase the potential of anticancer agent doxorubicin toward colon cancer cells regardless of p53 status[2]. Mechanistic studies have demonstrated that the lack of TMPK functionality in cancer cells leads to dUTP misincorporation in DNA repair, resulting in cancer cell death[3].
[1] L Song et al. Elaboration of a proprietary thymidylate kinase inhibitor motif towards anti-tuberculosis agents. Bioorg Med Chem. 2016 Nov 1;24(21):5172-5182.
[2] Q Cui et al. Thymidylate kinase: an old topic brings new perspectives. Curr Med Chem. 2013;20(10):1286-305.
[3] CM Hu et al. Tumor cells require thymidylate kinase to prevent dUTP incorporation during DNA repair. Cancer Cell. 2012 Jul 10;22(1):36-50.