Synthesis and Structure–Activity Relationship Studies of Benzo[<i>b</i>][1,4]oxazin‐3(4<i>H</i>)‐one Analogues as Inhibitors of Mycobacterial Thymidylate Synthase X

Modranka, Jakub; Li, Jiahong; Parchina, Anastasia; Vanmeert, Michiel; Dumbre, Shrinivas G.; Salman, Mayla; Myllykallio, Hannu; Becker, Hubert F.; Vanhoutte, Roeland; Margamuljana, Lia; Nguyen, Hoai Viet; El‐Asrar, Rania Abu; Rozenski, Jef; Herdewijn, Piet; Jonghe, Steven De; Lescrinier, Eveline

doi:10.1002/cmdc.201800739

Cited by 11 publications

(4 citation statements)

References 30 publications

(49 reference statements)

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“…Among these organisms, many pathogenic ones are found such as Mycobacterium tuberculosis , Helicobacter pylori or Clostridium difficile . For this reason new drugs are being synthesized since the past few years to target FDTS, taking advantage of the differential binding modes of the substrates when compared with normal TS enzyme [19,20,21].…”

Section: Mechanisms Of Action Of Antifolatesmentioning

confidence: 99%

Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications

Fernández‐Villa

Aguilar

Rojo

2019

IJMS

137

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Bacterial, protozoan and other microbial infections share an accelerated metabolic rate. In order to ensure a proper functioning of cell replication and proteins and nucleic acids synthesis processes, folate metabolism rate is also increased in these cases. For this reason, folic acid antagonists have been used since their discovery to treat different kinds of microbial infections, taking advantage of this metabolic difference when compared with human cells. However, resistances to these compounds have emerged since then and only combined therapies are currently used in clinic. In addition, some of these compounds have been found to have an immunomodulatory behavior that allows clinicians using them as anti-inflammatory or immunosuppressive drugs. Therefore, the aim of this review is to provide an updated state-of-the-art on the use of antifolates as antibacterial and immunomodulating agents in the clinical setting, as well as to present their action mechanisms and currently investigated biomedical applications.

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Section: Mechanisms Of Action Of Antifolatesmentioning

confidence: 99%

Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications

Fernández‐Villa

Aguilar

Rojo

2019

IJMS

137

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“…To provide additional experimental support for this notion, we further characterized Psyn ThyX enzymatic activity by performing kinetics measurements in the presence of molecules that bind to the folate binding pocket of bacterial ThyX proteins. These inhibitory studies of Psyn ThyX were performed using H 4 folate (reaction product), CH 2 H 4 folate (substrate), and the tight-binding Mycobacterium tuberculosis ThyX inhibitor 2716 34 , 35 , which all inhibit the NADPH oxidase activity of bacterial ThyX. This analysis revealed that the three bacterial folate analogs tested substantially inhibit Psyn ThyX activity compared to an assay without the addition of any molecule (Fig.…”

Section: Resultsmentioning

confidence: 98%

Bacterial origins of thymidylate metabolism in Asgard archaea and Eukarya

et al. 2023

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Asgard archaea include the closest known archaeal relatives of eukaryotes. Here, we investigate the evolution and function of Asgard thymidylate synthases and other folate-dependent enzymes required for the biosynthesis of DNA, RNA, amino acids and vitamins, as well as syntrophic amino acid utilization. Phylogenies of Asgard folate-dependent enzymes are consistent with their horizontal transmission from various bacterial groups. We experimentally validate the functionality of thymidylate synthase ThyX of the cultured ‘Candidatus Prometheoarchaeum syntrophicum’. The enzyme efficiently uses bacterial-like folates and is inhibited by mycobacterial ThyX inhibitors, even though the majority of experimentally tested archaea are known to use carbon carriers distinct from bacterial folates. Our phylogenetic analyses suggest that the eukaryotic thymidylate synthase, required for de novo DNA synthesis, is not closely related to archaeal enzymes and might have been transferred from bacteria to protoeukaryotes during eukaryogenesis. Altogether, our study suggests that the capacity of eukaryotic cells to duplicate their genetic material is a sum of archaeal (replisome) and bacterial (thymidylate synthase) characteristics. We also propose that recent prevalent lateral gene transfer from bacteria has markedly shaped the metabolism of Asgard archaea.

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“…To provide additional support for this notion, we further characterized the Psyn ThyX enzymatic activity by performing kinetics measurements in the presence of molecules that bind to the folate binding pocket of bacterial ThyX proteins. These inhibitory studies of Psyn ThyX were performed using H 4 folate (reaction product), CH 2 H 4 folate (substrate), and the tight-binding Mycobacterium tuberculosis ThyX inhibitor 2716 27, 28 , which all inhibit the NADPH oxidase activity of bacterial ThyX. This analysis revealed that the three bacterial folate analogs tested substantially inhibit Psyn ThyX activity compared to an assay without the addition of any molecule (Fig.…”

Section: Resultsmentioning

confidence: 98%

Bacterial origin of thymidylate and folate metabolism in Asgard Archaea

Filée

Becker

Mellottee

et al. 2021

Preprint

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Little is known about the evolution and biosynthetic function of DNA precursor and the folate metabolism in the Asgard group of archaea. As Asgard occupy a key position in the archaeal and eukaryotic phylogenetic trees, we have exploited very recently emerged genome and metagenome sequence information to investigate these central metabolic pathways. Our genome-wide analyses revealed that the recently cultured Asgard archaeon Candidatus Prometheoarchaeum syntrophicum strain MK-D1 (Psyn) contains a complete folate-dependent network for the biosynthesis of DNA/RNA precursors, amino acids and syntrophic amino acid utilization. Altogether our experimental and computational data suggest that phylogenetic incongruences of functional folate-dependent enzymes from Asgard archaea reflect their persistent horizontal transmission from various bacterial groups, which has rewired the key metabolic reactions in an important and recently identified archaeal phylogenetic group. We also experimentally validated the functionality of the lateral gene transfer of Psyn thymidylate synthase ThyX. This enzyme uses bacterial-like folates efficiently and is inhibited by mycobacterial ThyX inhibitors. Our data raise the possibility that the thymidylate metabolism, required for de novo DNA synthesis, originated in bacteria and has been independently transferred to archaea and eukaryotes. In conclusion, our study has revealed that recent prevalent lateral gene transfer has markedly shaped the evolution of Asgard archaea by allowing them to adapt to specific ecological niches.

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Synthesis and Structure–Activity Relationship Studies of Benzo[b][1,4]oxazin‐3(4H)‐one Analogues as Inhibitors of Mycobacterial Thymidylate Synthase X

Cited by 11 publications

References 30 publications

Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications

Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications

Bacterial origins of thymidylate metabolism in Asgard archaea and Eukarya

Bacterial origin of thymidylate and folate metabolism in Asgard Archaea

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