Purpose: In non–small cell lung cancer, higher thymidylate synthase (TS) levels have Auth Univ Recei Gran dated (M. P The c of pa in ac Note zazio Requ Depa Luigi 39-01

The 26 S proteasomal complex, which is responsible for the bulk of protein degradation within the cell, recognizes its target substrates via covalently linked polyubiquitin moieties. However, a small but growing number of proteasomal substrates are degraded without a requirement for ubiquitinylation. One such substrate is the pyrimidine biosynthetic enzyme thymidylate synthase (EC 2.1.1.45), wh...

The combination of 5-fluorouracil (5-FU) and leucovorin has been the unofficial "standard" therapy for patients with colorectal cancer for over a decade. Recently, however, a number of new agents targeted against the enzyme thymidylate synthase have been synthesized and are in various stages of development. The currently available thymidylate synthase inhibitors are discussed. Enormous efforts ...

FdUMP[10], a 10mer of 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP), the thymidylate synthase inhibitory metabolite of 5-fluorouracil (FU), is most closely correlated with the DNA topoisomerase I (Top1) inhibitor camptothecin in the National Cancer Institute COMPARE analysis, but not with FU. FdUMP[10] exhibits more potent antiproliferative activity than FdUMP or 5-fluoro-2'-deoxyuridine (F...

Differential Thymidylate Synthase Expression in Different Variants of Large-Cell Carcinoma of the Lung. Valentina Monica, Giorgio V. Scagliotti, Paolo Ceppi, Luisella Righi, Alberto Cambieri, Marco Lo Iacono, Silvia Saviozzi, Marco Volante, Silvia Novello, and Mauro Papotti .............................................................................................................................

Combining drugs represent an approach to efficiently prevent and overcome drug resistance reduce toxicity; yet it is a highly challenging task, particularly if combinations of inhibitors the same enzyme target are considered. To show that crystallographic inhibition kinetic information can provide indicators cancer cell growth by two anti-human thymidylate synthase (hTS) drugs, we obtained X-ra...

Independently isolated thymidine-dependent strains were shown to be defective in thymidylate synthetase and mutated at separable but closely linked sites.

Thymidylate is a critical DNA nucleotide that has to be synthesized in cells de novo by all organisms. Flavin-dependent thymidylate synthase (FDTS) catalyzes the final step in this de novo production of thymidylate in many human pathogens, but it is absent from humans. The FDTS reaction proceeds via a chemical route that is different from its human enzyme analogue, making FDTS a potential antim...

Thymidylate synthetase from Escherichia coli has been shown to catalyze an exchange between water and the hydrogen on carbon atom 5 of deoxyuridylate at a rate which is approximately 5 to 10% of the rate of the over-all reaction. The exchange reaction exhibited an absolute requirement only for tetrahydrofolate. In the absence of formaldehyde or of Mg++, the exchange activity was reduced to abou...