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- Green, Alanna C., et al.
(författare)
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Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells
- 2023
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Ingår i: Nature Metabolism. - : Springer Nature. - 2522-5812. ; 5:4, s. 642-659
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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. |
- Long, Maeve, et al.
(författare)
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DGAT1 activity synchronises with mitophagy to protect cells from metabolic rewiring by iron depletion
- 2022
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Ingår i: EMBO Journal. - : John Wiley & Sons. - 0261-4189 .- 1460-2075. ; 41
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Tidskriftsartikel (refereegranskat)abstract
- Mitophagy removes defective mitochondria via lysosomal elimination. Increased mitophagy coincides with metabolic reprogramming, yet it remains unknown whether mitophagy is a cause or consequence of such state changes. The signalling pathways that integrate with mitophagy to sustain cell and tissue integrity also remain poorly defined. We performed temporal metabolomics on mammalian cells treated with deferiprone, a therapeutic iron chelator that stimulates PINK1/PARKIN-independent mitophagy. Iron depletion profoundly rewired the metabolome, hallmarked by remodelling of lipid metabolism within minutes of treatment. DGAT1-dependent lipid droplet biosynthesis occurred several hours before mitochondrial clearance, with lipid droplets bordering mitochondria upon iron chelation. We demonstrate that DGAT1 inhibition restricts mitophagy in vitro, with impaired lysosomal homeostasis and cell viability. Importantly, genetic depletion of DGAT1 in vivo significantly impaired neuronal mitophagy and locomotor function in Drosophila. Our data define iron depletion as a potent signal that rapidly reshapes metabolism and establishes an unexpected synergy between lipid homeostasis and mitophagy that safeguards cell and tissue integrity.
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| 3. |
- Luttens, Andreas, et al.
(författare)
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Virtual Fragment Screening for DNA Repair Inhibitors in Vast Chemical Space
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Fragment-based screening can catalyze drug discovery by identifying novel scaffolds, but this approach is limited by the small chemical libraries studied by biophysical experiments and the challenging hit optimization step. In efforts to identify DNA repair inhibitors, we explored the use of structure-based virtual screening to access ultralarge fragment libraries that cover four orders of magnitude larger fractions of chemical space than traditional techniques. A set of 14 million fragments were docked to 8-oxoguanine DNA glycosylase (OGG1), a challenging drug target involved in cancer and inflammation. Of the 29 top-ranked fragments that were experimentally evaluated, four compounds were shown to bind to OGG1 and X-ray crystallography confirmed the predicted binding modes. Docking of readily synthesizable elaborations guided fragment optimization, leading to the discovery of submicromolar OGG1 inhibitors with anti-inflammatory and anti-cancer effects in cell models. Our results demonstrate that fragment-based virtual screening enables efficient exploration of vast chemical libraries.
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