A mathematical model of human thymidine kinase 2 activity

Abstract

The mitochondrial enzyme thymidine kinase 2 (TK2) phosphorylates deoxythymidine (dT) and deoxycytidine (dC) to form dTMP and dCMP, which in cells rapidly become the negative-feedback end-products dTTP and dCTP. TK2 kinetic activity exhibits Hill coefficients of ∼0.5 (apparent negative cooperativity) for dT and ∼1 for dC. We present a mathematical model of TK2 activity that is applicable if TK2 exists as two monomer forms in equilibrium.

Figure 1

TK2 bisubstrate inhibition by dNTP (dCTP or dTTP) binding to the dN pocket.

Figure 2

Fit of model in Eq. (1) to data of Wang et al 2003 (9). See Methods regarding deleted outliers X and Table 1 for parameter estimates. Concentrations in the legends are in μM.

Figure 3

Graph of model represented by Eqs. (1). A and B represent two different TK2 monomer forms in equilibrium, C = dC, T = dT, t = dTTP and c = dCTP.

Figure 4

Predicted dT (left) and dC (right) TK2 kinase activities of the A (red) and B (blue) monomer forms versus [dT] × [dC] with no inhibition ([dCTP] = 0 and [dTTP] = 0). Units are log₁₀ μM, i.e. [dN] = 0.1 to 1000 μM. The sum of the two forms (gray) fits the data (9) (shown as points, these are the same points as in the upper panels of Fig. 2) well. To avoid log(0) = −∞ an offset of 10⁻¹ μM was added to data [dN] values, i.e. points at −1 are actually [dN] = 0 values.

Figure 5

Proportion activity due to A at data points in Fig. 2. Legend concentrations are in μM.