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Molecular Mechanism of Thymidylate Synthase Inhibition by N4-Hydroxy-dCMP in View of Spectrophotometric and Crystallographic Studies

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dc.abstract.enNovel evidence is presented allowing further clarification of the mechanism of the slow-binding thymidylate synthase (TS) inhibition by N-4-hydroxy-dCMP (N-4-OH-dCMP). Spectrophotometric monitoring documented time- and temperature-, and N-4-OH-dCMP-dependent TS-catalyzed dihydrofolate production, accompanying the mouse enzyme incubation with N-4-OH-dCMP and N-5,N-10-methylenetetrahydrofolate, known to inactivate the enzyme by the covalent binding of the inhibitor, suggesting the demonstrated reaction to be uncoupled from the pyrimidine C(5) methylation. The latter was in accord with the hypothesis based on the previously presented structure of mouse TS (cf. PDB ID: 4EZ8), and with conclusions based on the present structure of the parasitic nematode Trichinella spiralis, both co-crystallized with N-4-OH-dCMP and N-5,N-10-methylenetetrahdrofolate. The crystal structure of the mouse TS-N-4-OH-dCMP complex soaked with N-5,N-10-methylenetetrahydrofolate revealed the reaction to run via a unique imidazolidine ring opening, leaving the one-carbon group bound to the N(10) atom, thus too distant from the pyrimidine C(5) atom to enable the electrophilic attack and methylene group transfer.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorMaj, Piotr
dc.contributor.authorJARMUŁA, ADAM
dc.contributor.authorWilk, Piotr
dc.contributor.authorProkopowicz, Małgorzata
dc.contributor.authorRypniewski, Wojciech
dc.contributor.authorZIELIŃSKI, ZBIGNIEW
dc.contributor.authorDowierciał, Anna
dc.contributor.authorRODE, WOJCIECH
dc.contributor.authorBzowska, Maria
dc.date.accessioned2024-01-25T12:53:24Z
dc.date.available2024-01-25T12:53:24Z
dc.date.issued2021
dc.description.accesstimeBEFORE_PUBLICATION
dc.description.financePublikacja bezkosztowa
dc.description.number9
dc.description.versionFINAL_PUBLISHED
dc.description.volume22
dc.identifier.doi10.3390/IJMS22094758
dc.identifier.issn1422-0067
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/112868
dc.identifier.weblinkhttps://www.mdpi.com/1422-0067/22/9/4758/pdf
dc.languageeng
dc.pbn.affiliationphysical sciences
dc.relation.ispartofInternational Journal of Molecular Sciences
dc.relation.pages4758
dc.rightsCC-BY-ND
dc.sciencecloudnosend
dc.subject.enthymidylate synthase
dc.subject.endihydrofolate production
dc.subject.enN-4-hydroxy-dCMP binding
dc.subject.enimidazolidine ring opening
dc.titleMolecular Mechanism of Thymidylate Synthase Inhibition by N4-Hydroxy-dCMP in View of Spectrophotometric and Crystallographic Studies
dc.typeJournalArticle
dspace.entity.typePublication