Evidence from chemical degradation studies for a covalent bond from 5-fluoro-2‘-deoxyuridylate to N-5 of tetrahydrofolate in the ternary complex of thymidylate synthetase-5-fluoro-2‘-deoxyuridylate-5,10-methylenetetrahydrofolate.

Pellino, August M.; Danenberg, Peter V.

doi:10.1016/s0021-9258(17)39137-8

Cited by 9 publications

(6 citation statements)

References 21 publications

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“…In this model the pterin ring of the cofactor and the pyrimidine ring of dUMP are nearly superimposed on the positions of the quinazoline ring of CB3717 and the pyrimidine ring of dUMP in the crystal structure. The methyl group covalently bound to C-5 of dUMP is attached to N-5 of the cofactor, in agreement with chemical studies (Pogolotti et al, 1976;Pellino & Danenberg, 1985). N-10 in CB3717 is 4.75 Á from C-5 of dUMP and a methylene bridge could not joint these two atoms without large shifts in the ligand positions.…”

Section: Resultssupporting

confidence: 84%

“…The mechanism for the formal transfer of a hydride may occur in two steps: transfer of an electron followed by transfer of H* (Slieker & Benkovic, 1984), as suggested in Figures 2 and 4. Danenberg, 1985) suggest that the methyl group being transferred to dUMP remains attached to N-5 of the cofactor (rather than N-10) in the ternary complex. The methylene bridge and enzyme sulfhydryl are trans-equatorial after unfolding (James et al, 1976;Byrd et al, 1978) but are in a trans-diaxial conformation in the folded protein (Byrd et al, 1978).…”

mentioning

confidence: 98%

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Pairwise specificity and sequential binding in enzyme catalysis: thymidylate synthase

Finer-Moore¹,

Montfort²,

Stroud³

1990

Biochemistry

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The structures of thymidylate synthase (TS) from Escherichia coli, in ternary complexes with substrate and an analogue of the cofactor, are the basis of a stereochemical model for a key reaction intermediate in the catalyzed reaction. This model is used to compare the reaction chemistry and chirality of the transferred methyl group with structures of the components, to identify those residues that participate, and to propose a stereochemical mechanism for catalysis by TS. Effects of chemical modification of specific amino acid residues and site-directed mutations of residues are correlated with structure and effects on enzyme mechanism. The ordered binding sequence of substrate deoxyuridine monophosphate and methylenetetrahydrofolate can be understood from the structure, where each forms a large part of the binding site for the other. The catalytic site serves to orient the reactants, which are sequestered along with many water molecules within a cavernous active center. Conformational changes during the reaction could involve nearby residues in ways that are not obvious in this complex.

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Section: Resultssupporting

confidence: 84%

mentioning

confidence: 98%

Pairwise specificity and sequential binding in enzyme catalysis: thymidylate synthase

Finer-Moore¹,

Montfort²,

Stroud³

1990

Biochemistry

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“…17) The active metabolites of 5-FU inhibit DNA synthesis, cause DNA damage, disrupt RNA processing, and alter normal RNA function. [19][20][21][22][23][24][25] Taken together, these results suggest the possibility that 5-FU suppresses CYP protein expression by inhibiting its transcriptional regulation. Additionally, since R-WF has a longer half-life 6) and is also a non-competitive inhibitor of CYP2C9, 26) the clinical involvement of CYP3A4 may be more significant, wherein the effects of 5-FU co-administration become apparent after at least a few weeks.…”

Section: Introductionmentioning

confidence: 95%

Changes in Pharmacodynamic Parameters during Co-administration of 5-FU with Warfarin: A Retrospective Case Series

Tayag

Ishii

Kokuba

et al. 2022

Biological & Pharmaceutical Bulletin

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Drug-drug interactions (DDIs) between warfarin (WF) and fluoropyrimidines are well known. Coadministration of WF and 5-fluorouracil (5-FU) leads to elevations in prothrombin time international normalised ratio (PT-INR). The inhibition of drug metabolism through suppression of CYP activity is a possible cause of prolonged PT-INR elevations. 5-FU and its metabolites are suspected to inhibit CYPs, but the precise mechanisms of action remain unknown. This study aimed to investigate the possible DDI effects of the co-administration of 5-FU with WF using PT-INR and PT-INR/dose ratio as pharmacodynamic parameters. Retrospective case series data were collected from patients who received parenteral 5-FU chemotherapy from April 2009 to December 2019 at the University of the Ryukyus Hospital. Seven patients who received 5-FU in combination with WF were analysed. There was a significant increase in PT-INR and PT-INR/dose during the co-administration of WF and 5-FU ( p 0.0018 and p 0.0187, respectively; paired t-test). The findings demonstrated significant DDI between 5-FU and WF evident as elevated PT-INR and PT-INR/dose ratio.

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“…After being metabolized, 5-FU enters a complex anabolic process that causes cytotoxicity at the cellular level by interfering with normal DNA and RNA function (Rich et al 2004). Several mechanisms are responsible for this cytotoxic activity of 5-FU: 1) conversion of 5-FU to 5-fluoro-2-deoxyuridine monophosphate, an inhibitor of thymidylate synthase in a ternary com-plex with 5-methylenetetrahydrofolate, which inhibits DNA synthesis (Pellino et al 1985;Longley et al 2003), 2) 5-FU causes DNA damage, precisely double-strand (and single-strand) breaks, during S phase because of the misincorporation of 5-fluorodeoxyuridine triphosphate into DNA (Curtin et al 1991;Peters et al 2000); and 3) disruption of normal RNA processing and function because of the incorporation of the 5-FU metabolite, fluorouridine triphosphate (FUTP), into RNA (Longley et al 2003). Several proteins families including enzymes and transporters are related to pharmacokinetics in humans.…”

Section: Introductionmentioning

confidence: 99%

Effect of 5-fluorouracil on mRNA expression of drug metabolizing enzyme and transporter genes in human hepatoma cell lines

et al. 2021

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Fluoropyrimidines such as 5-fluorouracil (5-FU) are well known to have drug-drug interactions with anticoagulant medications such as warfarin. This study investigated the mRNA expression of pharmacokinetic (PK)-related genes in response to 5-FU using the hepatocarcinoma cell lines after examining relevant gene expression via RNA sequencing. We used HepaRG cells for 5-FU treatment analysis because these cells displayed PK-related gene expression. 5-FU exposure significantly reduced cytochrome P450 3A4 (CYP3A4) mRNA expression. Additionally, the mRNA expression of nuclear receptor subfamily 1 group I member 2 (also known as pregnane X receptor), a nuclear receptor transcription factor that promotes the expression of many CYP genes, was also decreased in HepaRG cells following 5-FU treatment. The mRNA expressions of the CYP2B6 and ATP-binding cassette transporter genes were decreased after 5-FU treatment. This study revealed that 5-FU treatment reduced PK-related gene expression in HepaRG cells. These findings should be useful for further drug-drug interaction research.

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Evidence from chemical degradation studies for a covalent bond from 5-fluoro-2‘-deoxyuridylate to N-5 of tetrahydrofolate in the ternary complex of thymidylate synthetase-5-fluoro-2‘-deoxyuridylate-5,10-methylenetetrahydrofolate.

Cited by 9 publications

References 21 publications

Pairwise specificity and sequential binding in enzyme catalysis: thymidylate synthase

Pairwise specificity and sequential binding in enzyme catalysis: thymidylate synthase

Changes in Pharmacodynamic Parameters during Co-administration of 5-FU with Warfarin: A Retrospective Case Series

Effect of 5-fluorouracil on mRNA expression of drug metabolizing enzyme and transporter genes in human hepatoma cell lines

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