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Sökning: WFRF:(Chalkiadaki Christina)

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1.
  • Green, Alanna C., et al. (författare)
  • Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells
  • 2023
  • Ingår i: Nature Metabolism. - : Springer Nature. - 2522-5812. ; 5:4, s. 642-659
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase–cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a ‘folate trap’. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.
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2.
  • Okamoto, Kenta, et al. (författare)
  • Structure and its transformation of elliptical nege- like virus Tanay virus
  • 2023
  • Ingår i: Journal of General Virology. - : Microbiology Society. - 0022-1317 .- 1465-2099. ; 104:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Negeviruses that infect insects are recently identified virus species that are phylogenetically related to several plant viruses. They exhibit a unique virion structure, an elliptical core with a short projection. Negeviruses encode two structural proteins, a glycoprotein that forms a short projection, and an envelope protein that forms an elliptical core. The glycoprotein has been reported only in the negeviruses' genes, and not in phylogenetically related plant viruses' genes. In this report, we first describe the three- dimensional electron cryo- microscopy (cryo- EM) structure of Tanay virus (TANAV), one of the nege- like viruses. TANAV particle demonstrates a periodical envelope structure consisting of three layers surrounding the centred viral RNA. The elliptical core dynamically changes its shape under acidic and even low detergent conditions to form bullet- like or tubular shapes. The further cryo- EM studies on these transformed TANAV particles reveal their overall structural rearrangement. These findings suggest putative geometries of TANAV and its transformation in the life cycle, and the potential importance of the short projection for enabling cell entry to the insect hosts.
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