Leucine
Branched-chain essential amino acid and the best-characterised nutrient input to mTORC1. Free leucine binds Sestrin2, releasing the GATOR2 brake; a competing model has leucyl-tRNA synthetase as the sensor instead.
The amino acid the cell watches most closely. An essential amino acid and the best-understood dietary trigger for mTORC1. Free leucine binds to the sensor Sestrin2, releasing its brake on GATOR2; a rival idea says the real sensor is actually an enzyme called leucyl-tRNA synthetase (LARS) instead.
Binds Sestrin2 with ~20 µM Kd – within the range over which intracellular leucine actually fluctuates, which is the main argument that Sestrin2 is a physiological sensor rather than a binder.
TL;DR. Leucine appears in 13 curated studies in Oliver's mTOR Atlas: 3 in animal models; 10 at the molecular level (cells, biochemistry, structure). No study in people is recorded for it in the Atlas yet. It has 2 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| Leucine activates LARS (leucyl-tRNA synthetase) mechanism: binding · this link in full · on the map table | One competing idea: the enzyme that loads leucine onto its transport molecule for protein-building doubles as the leucine sensor. Holds under: Proposed before the Sestrin2 model and never cleanly reconciled with it. not tested in people · disputed: at least one study points the other way | M | HAN2012 |
| Leucine inhibits Sestrin2 mechanism: binding · this link in full · on the map table | Leucine sticks to a pocket inside Sestrin2 and makes it let go of the next protein in line – that's how the cell notices leucine is around. Holds under: Affinity was measured in vitro; whether the same 20 uM setpoint holds in tissues with different leucine transport is untested. VAL2025 (2025 cryo-EM) shows the leucine-induced shape change in Sestrin2 that releases GATOR2, again in purified protein and cultured cells. SHIM2026 is a 2026 rat study (dexamethasone-induced muscle atrophy, not an ageing model) with human myotubes; it tests a leucine-mimetic prodrug and supports Sestrin2-dependent mTORC1 activation, not the 20 uM leucine setpoint. plausible in people, not shown directly · settled in the literature | A | WOL2015, SAX2015, SHIM2026, VAL2025 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| A | Animal model | 3 |
| M | Molecular — cells, biochemistry, structure | 10 |
No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.
Studies
| Year | Evidence | Study |
|---|---|---|
| 2026 | A | D-Amino Acid Prodrug DLMEH Activates mTORC1 via Sestrin2 to Restore Muscle Protein Synthesis in Sarcopenia. SHIM2026 DLMEH, a D-leucine ester prodrug, binds Sestrin2 with leucine-like potency (Kd 28.3 uM, equivalent to L-leucine) and activates mTORC1 in a Sestrin2-dependent way. It restored protein synthesis in human myotubes and preserved muscle mass, grip strength and endurance in a rat dexamethasone-induced atrophy model (not an ageing sarcopenia model). |
| 2013 | A | Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation SIN2013 Antigen-receptor-driven System-L (SLC7A5) amino-acid transport controls mTORC1 and T-cell differentiation. |
| 2006 | A | Hypothalamic mTOR signaling regulates food intake COT2006 In rats, hypothalamic mTOR signalling (phosphorylated S6K1 and S6) changed with energy status in specific hypothalamic regions and was found in NPY and POMC neurons of the arcuate nucleus. Injecting leucine into the brain ventricles raised hypothalamic mTOR signalling and lowered food intake and body weight. Leptin also raised hypothalamic mTOR activity, and blocking mTOR with rapamycin in the brain blunted leptin's effect on reducing food intake. The authors proposed that hypothalamic mTOR acts as a fuel sensor linked to how much an animal eats. Boundary: rats, direct brain (intracerebroventricular) dosing, short-term food intake; drawn from the abstract only, so doses and effect sizes are not given here. |
| 2026 | M | An SLC7A5-dependent nutrient-sensing circuit overcomes cisplatin tolerance via mTOR-autophagy signaling. RAO2026 A genome-wide CRISPR screen found that mTOR inhibition promotes cisplatin tolerance by activating cytoprotective autophagy — the opposite of the canonical view. SLC7A5 integrates this mTOR-autophagy axis, and leucine supplementation resensitises SLC7A5-expressing tumour cells to cisplatin. |
| 2017 | M | mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient WYA2017 SLC38A9 effluxes essential amino acids (e.g. leucine) from lysosomes to activate mTORC1. |
| 2016 | M | Dynamics of mTORC1 activation in response to amino acids MAN2016 Live imaging shows mTORC1 moves to lysosomes within 2 minutes of amino acid addition and peaks by 5 minutes, in step with leucine arriving in lysosomes; phosphorylation of classic mTORC1 targets lags behind, suggesting mTORC1 passes briefly through the lysosome before acting on substrates elsewhere. |
| 2016 | M | A systems study reveals concurrent activation of AMPK and mTOR by amino acids DAL2016 Adding amino acids back to starved cells switched on AMPK, PI3K and mTORC2 acutely and independently of mTORC1, at the same time as mTOR. AMPK activation ran through CaMKK-beta and, under amino acid sufficiency, AMPK kept autophagy going via ULK1. So the textbook picture of AMPK and mTORC1 as simple opposites does not hold in the first minutes after feeding - which matters for how the AMPK-ULK1 feedback arm behaves over time. |
| 2015 | M | Sestrin2 is a leucine sensor for the mTORC1 pathway WOL2015 Sestrin2 is a direct leucine sensor whose leucine binding releases GATOR2 to activate mTORC1. |
| 2015 | M | Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway SAX2015 Solves the crystal structure of Sestrin2 bound to leucine, revealing the molecular pocket that lets it act as mTORC1's dedicated leucine sensor. |
| 2015 | M | Metabolism. Differential regulation of mTORC1 by leucine and glutamine JEW2015 Glutamine activates mTORC1 via a Rag-independent, Arf1-dependent route distinct from leucine. |
| 2015 | M | Dynamic Visualization of mTORC1 Activity in Living Cells ZHO2015 TORCAR, described by its authors as the first genetically encoded FRET reporter of mTORC1 activity, lets mTORC1 be watched in living cells as it changes. It showed mTORC1 activity not only at the lysosome but also in the cytosol, nucleus and at the plasma membrane; growth factor spread activity widely, while a leucine surrogate kept it at the lysosome and nucleus. A growth-factor-induced calcium transient contributed to mTORC1 activity. The earliest live reader of mTORC1 held in the atlas. |
| 2012 | M | Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway HAN2012 Leucyl-tRNA synthetase acts as an intracellular leucine sensor activating mTORC1 via the Rag pathway. |
| 2012 | M | Leucyl-tRNA synthetase controls TORC1 via the EGO complex BON2012 In budding yeast, the leucyl-tRNA synthetase Cdc60 bound the Rag GTPase Gtr1, part of the EGO complex that activates TORC1, and this binding depended on leucine. The authors reported that the interaction was both necessary and sufficient to pass the leucine signal on to TORC1. When Cdc60 was busy editing wrongly charged tRNA(Leu), the interaction with Gtr1 was lost. The model is that TORC1 reads how well tRNA(Leu) is being charged as a stand-in for how much leucine the cell has. Together with Han et al. 2012 in human cells, it was one of the early papers to propose a tRNA synthetase as a leucine sensor upstream of the Rags. Boundary: Yeast only. The mammalian leucine sensor most widely accepted today is Sestrin2, and this yeast mechanism has not been reconciled with it. Drafted from the abstract only. |
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