Development of a biomarker to monitor target engagement after treatment with dihydroorotate dehydrogenase inhibitors

Pontikos, Michael A.; Leija, Christopher; Zhao, Zhiyu; Wang, Xiaoyu; Kilgore, Jessica A.; Tornesi, Belén; Adenmatten, Nicole; Phillips, Margaret A.; Williams, Noelle S.

doi:10.1016/j.bcp.2022.115237

Cited by 2 publications

(2 citation statements)

References 44 publications

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“…Metabolites were analyzed by LC-MS/MS using an AB Sciex 6500+ QTRAP mass spectrometer coupled to a Shimadzu Nexera X2 LC. LC method details are as described in [69] Data is reported either as pmoles/10 6 cells (for glutamine only) or as percent labeled, calculated as the ratio of peak areas between the labeled compound and the sum of labeled with unlabeled compound as described without correction for natural isotope abundance [71].…”

Section: W I T H D R a W N S E E M A N U S C R I P T D O I F O R D E ...mentioning

confidence: 99%

WITHDRAWN: Knockout of HD domain 5’-nucleotidase inT. bruceitriggers cell death linked to DNA damage and downregulation of glutamine uptake

Deng

Pontikos

Baniasadi

et al. 2023

Preprint

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African trypanosomiasis is a fatal vector-borne disease caused by the protozoal parasite Trypanosoma brucei. This parasite encodes both de novo and salvage pathways for pyrimidine nucleotide biosynthesis, but in contrast to other eukaryotes, it lacks a dedicated enzyme to interconvert between cytidine (C) and uridine (U) nucleotide pools. Instead, we previously reported that nucleotide interconversion was mediated by thymidine kinase (TK) and an unknown 5’-nucleotidase enzyme. T. brucei encodes multiple potential 5’-nucelotidases, including one from the histidine-aspartate (HD) family (5’-HDNT) and two from the haloacid dehalogenase (HAD1 and HAD2) superfamily of metalloenzymes, but their relative roles and function in nucleotide metabolism remained unexplored. Herein we report that enzymes from both families catalyze dephosphorylation of pyrimidine monophosphate nucleotides, but only 5’-HDNT exhibited high activity on dCMP and was essential for T. brucei growth, while HAD1 and HAD2 were dispensable. Growth arrest upon loss of 5’-HDNT expression was rescued by ectopic expression of human dCMP deaminase (HsDCTD), which creates an alternate route for conversion between C and U pools. Knockout of 5’-HDNT led to depletion of pyrimidine pathway metabolites, altered ratios of pyrimidine to purine nucleotides, and DNA damage. Surprisingly, intracellular glutamine, the precursor of de novo pyrimidine biosynthesis, was also significantly reduced, and isotope tracing assays identified a deficiency in glutamine uptake, suggesting that the glutamine transporter was downregulated in response to loss of 5’-HDNT. This response would likely exacerbate perturbation of pyrimidine pathway homeostasis, suggesting we have uncovered a potential regulated cell death pathway in T. brucei.

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Section: W I T H D R a W N S E E M A N U S C R I P T D O I F O R D E ...mentioning

confidence: 99%

WITHDRAWN: Knockout of HD domain 5’-nucleotidase inT. bruceitriggers cell death linked to DNA damage and downregulation of glutamine uptake

Deng

Pontikos

Baniasadi

et al. 2023

Preprint

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“…In 2022, the group of Williams and Phillips proposed the use of dihydroorotate (DHO), an upstream metabolite of DHODH, as biomarker of DHODH inhibition. 42 It appeared that the treatment of mammalian cells with DSM265 89 led to increases in DHO where the extent of biomarker buildup correlated with both dose and inhibitor potency on DHODH. It was found that DSM265 89 selectively inhibits Plasmodium DHODH over the human enzyme.…”

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confidence: 99%

Recent Advances in the Chemistry and Application of SF5-Compounds

Bizet,

Abd El Sater,

Popek

et al. 2024

Synthesis

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This review article outlines the literature covering last three years on the recent developments of the SF5 chemistry. Recent synthesis methodologies of SF5-containing building blocks are reported. These methods include the synthesis of SF5Cl, its use in pentafluorosulfanylation reactions, and oxidative fluorination reactions. Moreover, the reactivity of SF5-alkynes as versatile platform to access new SF5-compounds is described. Finally, effect of SF5 moiety is highlighted according to its application in different fields such as biological/medicinal chemistry, catalysis and material sciences.

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Development of a biomarker to monitor target engagement after treatment with dihydroorotate dehydrogenase inhibitors

Cited by 2 publications

References 44 publications

WITHDRAWN: Knockout of HD domain 5’-nucleotidase inT. bruceitriggers cell death linked to DNA damage and downregulation of glutamine uptake

WITHDRAWN: Knockout of HD domain 5’-nucleotidase inT. bruceitriggers cell death linked to DNA damage and downregulation of glutamine uptake

Recent Advances in the Chemistry and Application of SF5-Compounds

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