Thymidine kinase 1 regulatory fine‐tuning through tetramer formation

Thymidine kinase 1 ( TK 1) provides a crucial precursor, deoxythymidine monophosphate, for nucleic acid synthesis, and the activity of TK 1 increases by up to 200‐fold during the S‐phase of cell division in humans. An important part of the regulatory checkpoints is the ATP and enzyme concentration‐dependent transition of TK 1 from a dimer with low catalytic efficiency to a tetramer with high catalytic efficiency. This regulatory fine‐tuning serves as an additional control to provide a balanced pool of nucleic acid precursors in the cell. We subcloned and over‐expressed 10 different TK 1s, originating from widely different organisms, and characterized their kinetic and oligomerization properties. Whilst bacteria, plants and D ictyostelium only exhibited dimeric TK 1, we found that all animals had a tetrameric TK 1. However, a clear ATP ‐dependent switch between dimer and tetramer was found only in higher vertebrates and was especially pronounced in mammalian and bird TK 1s. We suggest that the dimer form is the original form and that the tetramer originated in the animal lineage after the split of D ictyostelium and the lineages leading to invertebrates and vertebrates. The efficient switching mechanism was probably first established in warm‐blooded animals when they separated from the rest of the vertebrates.