Bacterial versus human thymidylate synthase: Kinetics and functionality
نویسندگان
چکیده
منابع مشابه
Concerted versus Stepwise Mechanism in Thymidylate Synthase
Thymidylate synthase (TSase) catalyzes the intracellular de novo formation of thymidylate (a DNA building block) in most living organisms, making it a common target for chemotherapeutic and antibiotic drugs. Two mechanisms have been proposed for the rate-limiting hydride transfer step in TSase catalysis: a stepwise mechanism in which the hydride transfer precedes the cleavage of the covalent bo...
متن کاملStructure-based design of inhibitors specific for bacterial thymidylate synthase.
Thymidylate synthase is an attractive target for antiproliferative drug design because of its key role in the synthesis of DNA. As such, the enzyme has been widely targeted for anticancer applications. In principle, TS should also be a good target for drugs used to fight infectious disease. In practice, TS is highly conserved across species, and it has proven to be difficult to develop inhibito...
متن کاملHydride transfer versus hydrogen radical transfer in thymidylate synthase.
The nature of a H-transfer in the thymidylate synthase catalyzed reaction was investigated by comparison of the wild-type enzyme with the W80M mutant. The nature of the H-transfer was not affected, as indicated by intrinsic isotope effects and their temperature dependence. These findings support a single-step hydride transfer instead of a two-step radical transfer.
متن کاملThymidylate synthase and drug resistance.
Thymidylate synthase is an important target for both fluorinated pyrimidines and for new folate analogues. Resistance to 5-fluorouracil (5FU) can be related to insufficient inhibition of thymidylate synthase. The 5FU-nucleotide FdUMP induces inhibition of thymidylate synthase which is enhanced and retained for longer in the presence of increased folate pools, for which leucovorin is a precursor...
متن کاملThymidylate Synthase Inhibitors
Folate analogues that inhibit thymidylate synthase (TS) selectively were developed based on TS and folate molecular structures and properties. The structure-activity relationship, preclinical and clinical development, and issues of potential importance in the future success of these TS inhibitors are reviewed herein. Properties of these new compounds depend mainly on the use of the reduced fola...
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ژورنال
عنوان ژورنال: PLOS ONE
سال: 2018
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0196506