ArticleMolecular microbiology2009
Methylene tetrahydrofolate dehydrogenase/cyclohydrolase and the synthesis of 10-CHO-THF are essential in Leishmania major.
Article in Molecular microbiology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 54 citations in OpenAlex.
- CYP5122A1 encodes an essential sterol C4-methyl oxidase in Leishmania donovani and determines the antileishmanial activity of antifungal azoles.Nature communications · 2024Article
- Molecular Characterization of Sterol C4-Methyl Oxidase inInternational journal of molecular sciences · 2024Article
- Ethanolaminephosphate cytidylyltransferase is essential for survival, lipid homeostasis and stress tolerance in Leishmania major.PLoS pathogens · 2023Article
- Ethanolaminephosphate cytidyltransferase is essential for survival, lipid homeostasis and stress tolerance inbioRxiv : the preprint server for biology · 2023Article
- The Golgi-localized sphingosine-1-phosphate phosphatase is indispensable for Leishmania major.Scientific reports · 2022Article
- Impact of Genetic Diversity and Genome Plasticity ofFrontiers in cellular and infection microbiology · 2022Review
- Article
- A broadly active fucosyltransferase LmjFUT1 whose mitochondrial localization and activity are essential in parasiticProceedings of the National Academy of Sciences of the United States of America · 2021Article
- Article
- Genetic validation of Leishmania genes essential for amastigote survival in vivo using N-myristoyltransferase as a model.Parasites & vectors · 2020Article
- Farnesyl pyrophosphate synthase is essential for the promastigote and amastigote stages in Leishmania major.Molecular and biochemical parasitology · 2019Article
- Leishmania phosphatase PP5 is a regulator of HSP83 phosphorylation and essential for parasite pathogenicity.Parasitology research · 2018Article
- Glucose Transporters and Virulence inmSphere · 2018Article
- Genetically Validated Drug Targets in Leishmania: Current Knowledge and Future Prospects.ACS infectious diseases · 2018Review
- Spontaneous excision and facilitated recovery as a control for phenotypes arising from RNA interference and other dominant transgenes.Molecular and biochemical parasitology · 2018Article
- Genetic metabolic complementation establishes a requirement for GDP-fucose inThe Journal of biological chemistry · 2017Article
- Functional compartmentalization of Rad9 and Hus1 reveals diverse assembly of the 9-1-1 complex components during the DNA damage response in Leishmania.Molecular microbiology · 2016Article
- Targeting Ergosterol biosynthesis in Leishmania donovani: essentiality of sterol 14 alpha-demethylase.PLoS neglected tropical diseases · 2015Article
- One-carbon metabolic pathway rewiring in Escherichia coli reveals an evolutionary advantage of 10-formyltetrahydrofolate synthetase (Fhs) in survival under hypoxia.Journal of bacteriology · 2015Article
- Kinases as druggable targets in trypanosomatid protozoan parasites.Chemical reviews · 2014Review
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
10-Formyl tetrahydrofolate (10-CHO-THF) is a key metabolite in C1 carbon metabolism, arising through the action of formate-tetrahydrofolate ligase (FTL) and/or 5,10-methenyltetrahydrofolate cyclohydrolase/5,10-methylene tetrahydrofolate dehydrogenase (DHCH). Leishmania major possesses single DHCH1 and FTL genes encoding exclusively cytosolic proteins, unlike other organisms where isoforms occur in the mitochondrion as well. Recombinant DHCH1 showed typical NADP(+)-dependent methylene tetrahydrofolate DH and 5,10-methenyltetrahydrofolate CH activities, and the DH activity was potently inhibited by a substrate analogue 5,10-CO-THF (K(i) 105 nM), as was Leishmania growth (EC(50) 1.1 microM). Previous studies showed null ftl(-) mutants were normal, raising the possibility that loss of the purine synthetic pathway had rendered 10-CHO-THF dispensable in evolution. We were unable to generate dhch1(-) null mutants by gene replacement, despite using a wide spectrum of nutritional supplements expected to bypass DHCH function. We applied an improved method for testing essential genes in Leishmania, based on segregational loss of episomal complementing genes rather than transfection; analysis of approximately 1400 events without successful loss of DHCH1 again established its requirement. Lastly, we employed 'genetic metabolite complementation' using ectopically expressed FTL as an alternative source of 10-CHO-THF; now dhch1(-) null parasites were readily obtained. These data establish a requirement for 10-CHO-THF metabolism in L. major, and provide genetic and pharmacological validation of DHCH as a target for chemotherapy, in this and potentially other protozoan parasites.
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