EC Number   |
General Information |
Reference |
|---|
    2.1.1.45 | evolution |
dihydrofolate reductase (DHFR) and thymidylate synthase (TS) have undergone a fusion event generating a single polypeptide but conserving the two functions in trypanosomatids |
742057 |
| 2.1.1.45 | malfunction |
growth of single-knockout lines of dihydrofolate reductase-thymidylate synthase in vitro are identical to wild type cells, whereas double-knockout lines of dihydrofolate reductase-thymidylate synthase have an absolute requirement for thymidine |
689059 |
| 2.1.1.45 | metabolism |
ThyA is the sole catalyst for thymidylate biosynthesis in Corynebacterium glutamicum |
-, 718969 |
| 2.1.1.45 | more |
in vitro, one human thymidylate synthase dimer binds to up to six human dihydrofolate reductase monomers, protein-protein docking process, overview. Existence of bound-state conformations of the human DHFR and TS proteins where a continuous positive surface potential region, connecting the TS and DHFR active sites, is formed |
743758 |
| 2.1.1.45 | more |
TS domain structure analysis, overview. The TS domain of the enzyme forms the largest portion of the dimerization interface mainly through a five-stranded beta-sheet from each monomer. The catalytic cysteine 489 is responsible for catalysis, te active site is comprised of residues from both monomers. Several conserved arginines bind dUMP, i.e. R344, R510 as well as R469 and R470 from the adjacent monomer |
741889 |
| 2.1.1.45 | physiological function |
DHFR-TS is essential for cell survival of Trypanosoma brucei |
-, 743569 |
| 2.1.1.45 | physiological function |
DHFRTS is essential for parasite survival |
689059 |
| 2.1.1.45 | physiological function |
dihydrofolate reductase is an essential enzyme in the tetrahydrofolate pathway which catalyzes the NADPH-dependent reduction of 7,8-dihydrofolate (H2F) to the 5,6,7,8-tetrahydrofolate needed to maintain intracellular pools of tetrahydrofolate and its derivatives. These are essential cofactors in the biosynthesis of purines, pyrimidines and several amino acids |
742057 |
| 2.1.1.45 | physiological function |
human thymidylate synthase and dihydrofolate reductase form a strong complex in vitro and colocalize in human normal and colon cancer cell cytoplasm and nucleus. Treatment of cancer cells with methotrexate or 5-fluorouracil does not affect the distribution of either enzyme within the cells. 5-fluorouracil, but not methotrexate, lowers the presence of dihydrofolate reductase-thymidylate synthase complex in the nucleus by 2.5fold |
757252 |
| 2.1.1.45 | physiological function |
several parasitic protozoa, including Toxoplasma gondii, contain a unique bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) having the catalytic activities contained on a single polypeptide chain in contrast to the human enzyme. Three-dimensional structures of Toxoplasma gondii enzyme TS-DHFR and of a loop truncated TS-DHFR enzyme, removing several flexible surface loops in the DHFR domain, shows that the TS-DHFR homodimer includes a junctional region containing a linked crossover helix between the DHFR domains of the two adjacent monomers, a long linker connecting the TS and DHFR domains, and a DHFR domain that is positively charged. The crystal structure suggests that the positively charged DHFR domain governs this electrostatically mediated movement of dihydrofolate, preventing release from the enzyme. Importance of this region not only in DHFR catalysis but also in modulating the distal TS activity suggests a role for TS-DHFR interdomain interactions |
741889 |
