ArticleOpen biology2012
Mechanistic and structural basis for inhibition of thymidylate synthase ThyX.
Article in Open biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 46 citations in OpenAlex.
- Natural Products with Potent Antimycobacterial Activity (2000-2024): A Review.Molecules (Basel, Switzerland) · 2025Review
- Selective Inhibitor Design against Thymidylate Synthase ofACS omega · 2025Article
- Niche-specific metabolic phenotypes can be used to identify antimicrobial targets in pathogens.PLoS biology · 2024Article
- Synthesis and Structure-Activity Relationship Studies of Pyrido [1,2-Molecules (Basel, Switzerland) · 2022Article
- Comparative genomics reveals electron transfer and syntrophic mechanisms differentiating methanotrophic and methanogenic archaea.PLoS biology · 2022Review
- Genome Study of a Novel Virulent Phage vB_SspS_KASIA and Mu-like Prophages ofInternational journal of molecular sciences · 2021Article
- Mechanism of Naphthoquinone Selectivity of Thymidylate Synthase ThyX.Biophysical journal · 2020Article
- Mycobacterium tuberculosis thymidylate synthase (ThyX) is a target for plumbagin, a natural product with antimycobacterial activity.PloS one · 2020Article
- Targeting Methyltransferases in Human Pathogenic Bacteria: Insights into Thymidylate Synthase (TS) and Flavin-Dependent TS (FDTS).Molecules (Basel, Switzerland) · 2019Review
- Unique Features and Anti-microbial Targeting of Folate- and Flavin-Dependent Methyltransferases Required for Accurate Maintenance of Genetic Information.Frontiers in microbiology · 2018Review
- Flavin-dependent thymidylate synthase: N5 of flavin as a Methylene carrier.Archives of biochemistry and biophysics · 2017Review
- DNA Replication in Mycobacterium tuberculosis.Microbiology spectrum · 2017Review
- Predictive modeling targets thymidylate synthase ThyX in Mycobacterium tuberculosis.Scientific reports · 2016Article
- Targeting of Helicobacter pylori thymidylate synthase ThyX by non-mitotoxic hydroxy-naphthoquinones.Open biology · 2015Article
- Article
- Selective peptide inhibitors of bifunctional thymidylate synthase-dihydrofolate reductase from Toxoplasma gondii provide insights into domain-domain communication and allosteric regulation.Protein science : a publication of the Protein Society · 2013Article
- Flavin-Dependent Thymidylate Synthase as a Drug Target for Deadly Microbes: Mutational Study and a Strategy for Inhibitor Design.Journal of bioterrorism & biodefense · 2013Article
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Nature has established two mechanistically and structurally unrelated families of thymidylate synthases that produce de novo thymidylate or dTMP, an essential DNA precursor. Representatives of the alternative flavin-dependent thymidylate synthase family, ThyX, are found in a large number of microbial genomes, but are absent in humans. We have exploited the nucleotide binding pocket of ThyX proteins to identify non-substrate-based tight-binding ThyX inhibitors that inhibited growth of genetically modified Escherichia coli cells dependent on thyX in a manner mimicking a genetic knockout of thymidylate synthase. We also solved the crystal structure of a viral ThyX bound to 2-hydroxy-3-(4-methoxybenzyl)-1,4-naphthoquinone at a resolution of 2.6 Å. This inhibitor was found to bind within the conserved active site of the tetrameric ThyX enzyme, at the interface of two monomers, partially overlapping with the dUMP binding pocket. Our studies provide new chemical tools for investigating the ThyX reaction mechanism and establish a novel mechanistic and structural basis for inhibition of thymidylate synthesis. As essential ThyX proteins are found e.g. in Mycobacterium tuberculosis and Helicobacter pylori, our studies have also potential to pave the way towards the development of new anti-microbial compounds.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.