Thymidylate Synthetase

Friedkin, Morris

doi:10.1002/9780470122839.ch5

Cited by 15 publications

(5 citation statements)

References 142 publications

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“…15,16 Studies of the molecular mechanism of thymidylate formation identified the transient formation of a ternary complex consisting of the substrate dUMP, the folate cofactor 5,10-methylenetetrahydrofolate (MTHF), and thymidylate synthase. 17,18 The next key advance in the development of 5-FU-based chemotherapy was the finding that inhibition of thymidylate synthase by 5-FU could be potentiated by increased intracellular levels of reduced folates. 12,[19][20][21][22] At this juncture, it is interesting to note that the antitumor activity of folic acid analogues, including aminopterin and amethopterin (methotrexate), was first demonstrated in 1948 by Sidney Farber and Louis Diamond in children with leukemia.…”

Section: -Fluorouracil and Leucovorinmentioning

confidence: 99%

A Review of the Evolution of Systemic Chemotherapy in the Management of Colorectal Cancer

Gustavsson

Carlsson

Machover

et al. 2015

Clinical Colorectal Cancer

431

313

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Herein we present a historical review of the development of systemic chemotherapy for colorectal cancer (CRC) in the metastatic and adjuvant treatment settings. We describe the discovery of 5-fluorouracil (5-FU) by Heidelberger and colleagues in 1957, the potentiation of 5-FU cytotoxicity by the reduced folate leucovorin, and the advent of novel cytotoxic agents, including the topoisomerase I inhibitor irinotecan, the platinum-containing agent oxaliplatin, and the 5-FU prodrug capecitabine. The combination therapies, FOLFOX (5-FU/leucovorin and oxaliplatin) and FOLFIRI (5-FU/leucovorin and irinotecan), have become established as efficacious cytotoxic regimens for the treatment of metastatic CRC, resulting in overall survival times of approximately 2 years. When used as adjuvant therapy, FOLFOX also improves survival and is now the gold standard of care in this setting. Biological agents have been discovered that enhance the effect of cytotoxic therapy, including bevacizumab (a humanized monoclonal antibody that targets vascular endothelial growth factor, a central regulator of angiogenesis) and cetuximab/panitumumab (monoclonal antibodies directed against the epidermal growth factor receptor). Despite the ongoing development of novel antitumor agents and therapeutic principles as we enter the era of personalized cancer medicine, systemic chemotherapy involving infusional 5-FU/leucovorin continues to be the cornerstone of treatment for patients with CRC.

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Section: -Fluorouracil and Leucovorinmentioning

confidence: 99%

A Review of the Evolution of Systemic Chemotherapy in the Management of Colorectal Cancer

Gustavsson

Carlsson

Machover

et al. 2015

Clinical Colorectal Cancer

431

313

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“…Dihydrofolate species are generated from reduced folates as a byproduct of thymidylate synthase, which catalyzes the conversion of dUMP ( 19 ) and 5,10- methylene-H 4 PteGlu n to dTMP ( 20 ) and H 2 PteGlu n (refs. 14–18). …”

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confidence: 99%

A domino effect in antifolate drug action in Escherichia coli

et al. 2008

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Mass spectrometry technologies for measurement of cellular metabolism are opening new avenues to explore drug activity. Trimethoprim is an antibiotic that inhibits bacterial dihydrofolate reductase (DHFR). Kinetic flux profiling with 15 N-labeled ammonia in Escherichia coli reveals that trimethoprim leads to blockade not only of DHFR but also of another critical enzyme of folate metabolism: folylpoly-γ-glutamate synthetase (FP-γ-GS). Inhibition of FP-γ-GS is not directly due to trimethoprim. Instead, it arises from accumulation of DHFR's substrate dihydrofolate, which we show is a potent FP-γ-GS inhibitor. Thus, owing to the inherent connectivity of the metabolic network, falling DHFR activity leads to falling FP-γ-GS activity in a domino-like cascade. This cascade results in complex folate dynamics, and its incorporation in a computational model of folate metabolism recapitulates the dynamics observed experimentally. These results highlight the potential for quantitative analysis of cellular metabolism to reveal mechanisms of drug action.Enzyme inhibition is among the best established mechanisms of drug action 1 . Nevertheless, even for enzyme inhibitors, the mechanisms of action are often incompletely understood 2 . For example, drugs known to be inhibitors of one enzyme may further bind to unidentified enzymes or indirectly interact with other pathways. In part, this limited understanding is due to the scope and complexity of cellular chemical reactions as well as the associated difficulty of tracking many reactions at once. The recent development of technologies that can measure many cellular metabolites 3-5 and metabolic fluxes 6-8 in parallel may allow for more complete elucidation of actions of enzyme inhibitors. Here we apply LC-MS/MS to explore the effects of the DHFR inhibitor trimethoprim (1) in Escherichia coli by tracking both metabolite concentrations and fluxes throughout the folate pathway.Folates are cofactors that accept or donate one-carbon units for the biosynthesis of essential metabolites including purines, thymine (2), methionine (3) and glycine (4). Folate metabolism is the target of many therapeutics, including antibiotics (trimethoprim and sulfa drugs) 9-11 and anticancer agents (methotrexate, 5, and pemetrexed, 6) 12 . Folates are synthesized from GTP (7), p-aminobenzoic acid (pABA, 8) and glutamates (9) and can exist in three different oxidation/reduction states: PteGlu n (pteroylglutamate, or folate,

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“…1). The discovery of ternary complex formation including dUMP, 5,10-methylenetetrahydrofolate, and thymidylate synthase was critical to the mechanistic understanding of 5-FU action [34,35]. 5-FU is converted to 5fluorodeoxyuridine monophosphate (FdUMP), which can, in turn, replace dUMP in the covalent complex and achieve higher binding affinity and greater ternary complex stabilisation as a result of FdUMPmediated electrostatic interactions [36][37][38].…”

Section: -Fu Mechanism Of Action and The Role Of Leucovorinmentioning

confidence: 99%