Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers DOI Creative Commons

Edouard Mullarky,

Natasha C. Lucki,

Reza Beheshti Zavareh

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2016, Volume and Issue: 113(7), P. 1778 - 1783

Published: Feb. 1, 2016

Cancer cells reprogram their metabolism to promote growth and proliferation. The genetic evidence pointing the importance of amino acid serine in tumorigenesis is striking. gene encoding enzyme 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes first committed step biosynthesis, overexpressed tumors cancer cell lines via focal amplification nuclear factor erythroid-2-related 2 (NRF2)-mediated up-regulation. PHGDH-overexpressing are exquisitely sensitive ablation pathway. Here, we report discovery a selective small molecule inhibitor PHGDH, CBR-5884, identified by screening library 800,000 drug-like compounds. CBR-5884 inhibited de novo synthesis was selectively toxic with high biosynthetic activity. Biochemical characterization revealed that it noncompetitive showed time-dependent onset inhibition disrupted oligomerization state PHGDH. identification PHGDH not only enables thorough preclinical evaluation as target cancers, but also provides tool study metabolism.

Language: Английский

Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease DOI Creative Commons
Daniel Erny, Nikolaos Dokalis,

Charlotte Mezö

et al.

Cell Metabolism, Journal Year: 2021, Volume and Issue: 33(11), P. 2260 - 2276.e7

Published: Nov. 1, 2021

Language: Английский

Citations

318
NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism DOI
Li Chen, Zhaoyue Zhang, Atsushi Hoshino

et al.

Nature Metabolism, Journal Year: 2019, Volume and Issue: 1(3), P. 404 - 415

Published: March 11, 2019

Language: Английский

Citations

308
Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation DOI Creative Commons
Daniel J. Puleston, Michael D. Buck, Ramon I. Klein Geltink

et al.

Cell Metabolism, Journal Year: 2019, Volume and Issue: 30(2), P. 352 - 363.e8

Published: May 23, 2019

How cells adapt metabolism to meet demands is an active area of interest across biology. Among a broad range functions, the polyamine spermidine needed hypusinate translation factor eukaryotic initiation 5A (eIF5A). We show here that hypusinated eIF5A (eIF5AH) promotes efficient expression subset mitochondrial proteins involved in TCA cycle and oxidative phosphorylation (OXPHOS). Several these have targeting sequences (MTSs) part confer increased dependency on eIF5AH. In macrophages, metabolic switching between OXPHOS glycolysis supports divergent functional fates stimulated by activation signals. cells, hypusination appears be dynamically regulated after activation. Using vivo vitro models, we acute inhibition this pathway blunts OXPHOS-dependent alternative activation, while leaving aerobic glycolysis-dependent classical intact. These results might implications for therapeutically controlling macrophage polyamine-eIF5A-hypusine axis.

Language: Английский

Citations

304
Lipid signalling enforces functional specialization of Treg cells in tumours DOI
Seon Ah Lim, Jun Wei,

Thanh-Long M. Nguyen

et al.

Nature, Journal Year: 2021, Volume and Issue: 591(7849), P. 306 - 311

Published: Feb. 24, 2021

Language: Английский

Citations

293
Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers DOI Creative Commons

Edouard Mullarky,

Natasha C. Lucki,

Reza Beheshti Zavareh

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2016, Volume and Issue: 113(7), P. 1778 - 1783

Published: Feb. 1, 2016

Cancer cells reprogram their metabolism to promote growth and proliferation. The genetic evidence pointing the importance of amino acid serine in tumorigenesis is striking. gene encoding enzyme 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes first committed step biosynthesis, overexpressed tumors cancer cell lines via focal amplification nuclear factor erythroid-2-related 2 (NRF2)-mediated up-regulation. PHGDH-overexpressing are exquisitely sensitive ablation pathway. Here, we report discovery a selective small molecule inhibitor PHGDH, CBR-5884, identified by screening library 800,000 drug-like compounds. CBR-5884 inhibited de novo synthesis was selectively toxic with high biosynthetic activity. Biochemical characterization revealed that it noncompetitive showed time-dependent onset inhibition disrupted oligomerization state PHGDH. identification PHGDH not only enables thorough preclinical evaluation as target cancers, but also provides tool study metabolism.

Language: Английский

Citations

286