Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor
What this study shows
Malonyl-CoA, an intermediate of fatty-acid biosynthesis, binds the mTOR catalytic pocket directly and acts as a conserved ATP-competitive inhibitor of mTORC1; when fatty acid synthase is downregulated, rising malonyl-CoA feeds back to dampen mTORC1 activity, linking lipogenic capacity to overall biosynthetic output.
Abstract
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Cell growth is regulated by the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which functions both as a nutrient sensor and a master controller of virtually all biosynthetic pathways. This ensures that cells are metabolically active only when conditions are optimal for growth. Notably, although mTORC1 is known to regulate fatty acid biosynthesis, how and whether the cellular lipid biosynthetic capacity signals back to fine-tune mTORC1 activity remains poorly understood.
Read the full abstract on PubMed →At a glance
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| Evidence type | M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Yeast and mammalian cells) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is. |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Yeast and mammalian cells |
| Journal | Nature Cell Biology |
| Year | 2023 |
| Peer reviewed | Yes |
| Record last updated | 2026-10-01 |
| Source | DOI 10.1038/s41556-023-01198-6 · PMID 37563253 |
Where this study fits
How this study connects to the pathway map, open questions, people and other studies in the Atlas.
People in the Atlas
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Cell biologist at the University of Fribourg who studies TORC1 signalling in yeast and mammals, and first author of the discovery that malonyl-CoA is a natural mTORC1 inhibitor
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Showed as a postdoc in Aurelio Teleman's lab that starvation and other stresses pull TSC2 to the lysosome to switch mTORC1 off. His group, at the Max Planck Institute for Biology of Ageing in Cologne from 2017 and at ERIBA in Groningen since 2025, studies how cells sense nutrients and stress through mTORC1 and how this changes with age
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Cell biologist who studied how lipid metabolism and the lysosome feed into mTORC1, first at the University of Liège and then at the Max Planck Institute for Biology of Ageing in Cologne
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Co-author on two Demetriades-lab mTORC1 papers from Cologne: the spatial split of mTORC1 signalling by amino acid source and malonyl-CoA as a direct mTORC1 inhibitor.
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Cell biologist who studied how mTORC1 senses nutrients in Aurelio Teleman's group at the German Cancer Research Center, including the finding that glutamine is sensed through the kinase GCN2, and who now works at the Institute of Neuropathology in Aachen
More: 9 other authors
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First author of the 'Rag dimer code' study showing that the four Rag GTPase paralogues are not interchangeable: RagC/D sets substrate choice and RagA/B sets the response to amino acid withdrawal.
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First author of the study showing that lysosomal and cytoplasmic pools of mTORC1 respond to different amino acid sources and phosphorylate different substrates.
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Uses fruit-fly genetics and human cells to study how growth signalling through TOR controls cell and body size. His lab showed that starvation and other stresses move TSC2 to the lysosome to switch mTORC1 off
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Yeast geneticist whose lab found the EGO/Rag GTPase complex that activates TORC1 and showed that the SEACIT complex (Iml1–Npr2–Npr3) switches TORC1 off by acting as a GAP for the Rag GTPase Gtr1.
No profile yet: Alba J, Kipschull S, Romero-Pozuelo J, Lamprakis A, Vanni S
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Topics
Extracted findings
These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.
| Intervention | FASN downregulation/inhibition; malonyl-CoA |
| Target | mTOR catalytic pocket (mTORC1) |
| Model | Yeast and mammalian cells |
| Effect | Malonyl-CoA binds the mTOR ATP-binding pocket as a competitive inhibitor, so reduced fatty-acid synthesis capacity dampens mTORC1 activity. |
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