Mechanistic target of rapamycin complex 1

evidence_access

Primary abstract

experimental_model

Cellular kinase and autophagy assays; mouse Ulk1 numbering.

limitations

Specific signaling mechanism, not a whole-body autophagic-flux measurement.

nutrient_topic

Fasting physiological-state collection; human protocols, cellular deprivation and refeeding are distinguished. · Fasting / abstention from energy intake

plain_language

Nutrient sufficiency can restrain this initiation route.

primary_references

AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21258367/ · DOI 10.1038/ncb2152

Fasting: fuel switching, nutrient sensing, ketone signaling, nutrient dependencies and refeeding (2026-09-18) · lines 304–310

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Cellular kinase and autophagy assays; mouse Ulk1 numbering. · source_derived_draft · unverified_draft

## fast-mtor-ulk Nutrient sufficiency can restrain this initiation route. High mTOR activity phosphorylated Ulk1 Ser757 and disrupted its interaction with AMPK. Model: Cellular kinase and autophagy assays; mouse Ulk1 numbering. Limitations: Specific signaling mechanism, not a whole-body autophagic-flux measurement. Evidence access: Primary abstract AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21258367/ · DOI 10.1038/ncb2152

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

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experimental_model

Transporter or kinase loss, T-cell homeostasis and infection experiments

exposure

Slc6a8 or Ckb deletion

limitations

The study distinguishes TCR–mTORC1 signaling from whole-cell adenylate energy charge; it does not demonstrate clinical immune benefits of supplements.

nutrient_topic

Creatine research collection; topical membership is not evidence of a direct dietary effect. · Creatine

organism

Mice

plain_language

The pathway also affected the signal telling T cells to expand.

primary_references

[creatine-p35235777] Creatine transport and creatine kinase activity is required for CD8+ T cell immunity. (2022). https://pubmed.ncbi.nlm.nih.gov/35235777/ DOI: 10.1016/j.celrep.2022.110446

tissue_or_cell_type

Naive and activated CD8 T cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Creatine: synthesis, transport, phosphocreatine energetics and nutrient interactions (2026-09-17) · lines 620–631

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transporter or kinase loss, T-cell homeostasis and infection experiments · source_derived_draft · unverified_draft

### creatine-tcell-mtor-loss Ckb or Slc6a8 loss weakened TCR-mediated mTORC1 activation required for CD8 T-cell expansion. Condition category: machinery_impairment nutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The pathway also affected the signal telling T cells to expand. organism: Mice tissue_or_cell_type: Naive and activated CD8 T cells experimental_model: Transporter or kinase loss, T-cell homeostasis and infection experiments limitations: The study distinguishes TCR–mTORC1 signaling from whole-cell adenylate energy charge; it does not demonstrate clinical immune benefits of supplements. exposure: Slc6a8 or Ckb deletion evidence_span: {"source_cache": "artifacts/creatine-research/35235777.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a81515a03473f41d52c2e13de56ac9b13ea5cd813e288d166159d517f9855958", "start_char": 0, "end_char": 1025, "text_sha256": "a81515a03473f41d52c2e13de56ac9b13ea5cd813e288d166159d517f9855958"} [creatine-p35235777] Creatine transport and creatine kinase activity is required for CD8+ T cell immunity. (2022). https://pubmed.ncbi.nlm.nih.gov/35235777/ DOI: 10.1016/j.celrep.2022.110446

evidence_access

Primary abstract

experimental_model

Cultured human cells.

limitations

Does not establish direct binding of spermidine to mTORC1 or a universal rapamycin-like effect.

nutrient_topic

Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine

plain_language

A nutrient-sensing signal changed alongside recycling.

primary_references

Spermidine induces autophagy by inhibiting the acetyltransferase EP300. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25526088/ · DOI 10.1038/cdd.2014.215

Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 166–172

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cultured human cells. · source_derived_draft · unverified_draft

## spermidine-mtorc1 A nutrient-sensing signal changed alongside recycling. Spermidine-associated autophagy induction coincided with inhibition of mTORC1 signaling in the human-cell study. Model: Cultured human cells. Limitations: Does not establish direct binding of spermidine to mTORC1 or a universal rapamycin-like effect. Evidence access: Primary abstract Spermidine induces autophagy by inhibiting the acetyltransferase EP300. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25526088/ · DOI 10.1038/cdd.2014.215

evidence_access

Primary abstract

experimental_model

Primary abstract-level biochemical/cellular pathway report.

limitations

Complete construct, dose and cell-specific mapping remains a follow-up; this route is distinct from ordinary dietary histidine intake.

nutrient_topic

L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine

plain_language

The adaptor connects this branch to nutrient-sensitive signaling and insulin response.

primary_references

Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30401435/ · DOI 10.1016/j.cell.2018.09.055

L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 314–320

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary abstract-level biochemical/cellular pathway report. · source_derived_draft · unverified_draft

## histidine-imp-p62-mtor The adaptor connects this branch to nutrient-sensitive signaling and insulin response. The study connected p62 phosphorylation to mTORC1 activation and impaired signaling at insulin receptor substrate. Model: Primary abstract-level biochemical/cellular pathway report. Limitations: Complete construct, dose and cell-specific mapping remains a follow-up; this route is distinct from ordinary dietary histidine intake. Evidence access: Primary abstract Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30401435/ · DOI 10.1016/j.cell.2018.09.055

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Human NSCLC cell cultures including H1299, H460, and A549

limitations

Abrupt medium depletion; no direct lysine-binding sensor established; no supplementation benefit inferred for healthy humans.

organism

Homo sapiens

plain_language

These cultured cancer cells needed available lysine for full nutrient-and-growth-factor signaling.

primary_references

[jang2020] Lysine is required for growth factor-induced mTORC1 activation (2020). https://pubmed.ncbi.nlm.nih.gov/33008594/ DOI: 10.1016/j.bbrc.2020.09.100

tissue_or_cell_type

Cultured lung cancer cells

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 819–827

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human NSCLC cell cultures including H1299, H460, and A549 · source_derived_draft · unverified_draft

### lysine-deprivation-mtorc1 Lysine withdrawal suppressed mTORC1 activity in NSCLC cell lines, and lysine restoration reversed the suppression; GCN2 and AMPK contributed to this response. Plain language: These cultured cancer cells needed available lysine for full nutrient-and-growth-factor signaling. Condition category: nutrient_deficiency organism: Homo sapiens tissue_or_cell_type: Cultured lung cancer cells experimental_model: Human NSCLC cell cultures including H1299, H460, and A549 limitations: Abrupt medium depletion; no direct lysine-binding sensor established; no supplementation benefit inferred for healthy humans. [jang2020] Lysine is required for growth factor-induced mTORC1 activation (2020). https://pubmed.ncbi.nlm.nih.gov/33008594/ DOI: 10.1016/j.bbrc.2020.09.100

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mammalian-cell signaling experiments and biochemical CASTOR1 binding.

limitations

Experimental starvation response; no universal dietary cutoff.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Low arginine is sensed through specific machinery.

primary_references

The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26972053/ · DOI 10.1016/j.cell.2016.02.035

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 190–196

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mammalian-cell signaling experiments and biochemical CASTOR1 binding. · source_derived_draft · unverified_draft

## arg-castor-starvation Low arginine is sensed through specific machinery. CASTOR1 was required for arginine deprivation to inhibit mTORC1. Model: Mammalian-cell signaling experiments and biochemical CASTOR1 binding. Limitations: Experimental starvation response; no universal dietary cutoff. Evidence access: Primary abstract The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26972053/ · DOI 10.1016/j.cell.2016.02.035

evidence_access

Primary abstract

experimental_model

Mouse C2C12 myotubes; pathway inhibitor experiments.

limitations

Inhibitor evidence does not establish direct binding of isoleucine to PI3K or identify the upstream sensor.

nutrient_topic

L-Isoleucine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Isoleucine

plain_language

This effect was not simply the familiar mTOR protein-growth pathway.

primary_references

Isoleucine, a potent plasma glucose-lowering amino acid, stimulates glucose uptake in C2C12 myotubes. · 2003 · https://pubmed.ncbi.nlm.nih.gov/14651987/ · DOI 10.1016/j.bbrc.2003.11.039

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 354–360

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse C2C12 myotubes; pathway inhibitor experiments. · source_derived_draft · unverified_draft

## isoleucine-myotube-pi3k This effect was not simply the familiar mTOR protein-growth pathway. Pharmacological experiments implicated PI3K, while mTOR inhibition did not account for the isoleucine glucose-uptake response. Model: Mouse C2C12 myotubes; pathway inhibitor experiments. Limitations: Inhibitor evidence does not establish direct binding of isoleucine to PI3K or identify the upstream sensor. Evidence access: Primary abstract Isoleucine, a potent plasma glucose-lowering amino acid, stimulates glucose uptake in C2C12 myotubes. · 2003 · https://pubmed.ncbi.nlm.nih.gov/14651987/ · DOI 10.1016/j.bbrc.2003.11.039

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse liver-specific Tsc1 knockout and littermate dietary experiments.

limitations

Does not exclude mTOR roles in other organs or settings.

nutrient_topic

L-Isoleucine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Isoleucine

plain_language

Suppressing liver mTORC1 was not necessary for these outcomes.

primary_references

The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33887198/ · DOI 10.1016/j.cmet.2021.03.025

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 394–400

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse liver-specific Tsc1 knockout and littermate dietary experiments. · source_derived_draft · unverified_draft

## isoleucine-restriction-mtor-boundary Suppressing liver mTORC1 was not necessary for these outcomes. Low isoleucine improved glucose tolerance and body composition despite liver-specific Tsc1 deletion and constitutive hepatic mTORC1 activity. Model: Mouse liver-specific Tsc1 knockout and littermate dietary experiments. Limitations: Does not exclude mTOR roles in other organs or settings. Evidence access: Primary full text The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33887198/ · DOI 10.1016/j.cmet.2021.03.025

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human doxycycline-regulated MAT2A cells; starvation and repletion.

limitations

Cellular SAM addition is not evidence for equivalent oral delivery.

nutrient_topic

L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine

plain_language

The amino acid must be converted before this sensor route works.

primary_references

SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29123071/ · DOI 10.1126/science.aao3265

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 252–258

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human doxycycline-regulated MAT2A cells; starvation and repletion. · source_derived_draft · unverified_draft

## methionine-mat2a-sensor-coupling The amino acid must be converted before this sensor route works. Acute MAT2A depletion reduced mTORC1 responsiveness to methionine while largely preserving responsiveness to supplied SAM. Model: Human doxycycline-regulated MAT2A cells; starvation and repletion. Limitations: Cellular SAM addition is not evidence for equivalent oral delivery. Evidence access: Primary full text SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29123071/ · DOI 10.1126/science.aao3265

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human HEK293T starvation/repletion experiments.

limitations

Specific acute culture context; mTORC1 integrates other nutrients and signals too.

nutrient_topic

L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine

plain_language

A shortage signal can pause growth signaling.

primary_references

SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29123071/ · DOI 10.1126/science.aao3265

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 236–242

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human HEK293T starvation/repletion experiments. · source_derived_draft · unverified_draft

## methionine-samtor-shortage A shortage signal can pause growth signaling. Two-hour methionine starvation lowered cellular SAM, promoted SAMTOR-GATOR1 association and inhibited mTORC1 signaling. Model: Human HEK293T starvation/repletion experiments. Limitations: Specific acute culture context; mTORC1 integrates other nutrients and signals too. Evidence access: Primary full text SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29123071/ · DOI 10.1126/science.aao3265

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human HEK293T knockout and re-expression experiments.

limitations

Loss of one sensor does not make methionine dispensable for proteins or methylation.

nutrient_topic

L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine

plain_language

Different amino acids enter the growth-control network through different sensors.

primary_references

SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29123071/ · DOI 10.1126/science.aao3265

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 244–250

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human HEK293T knockout and re-expression experiments. · source_derived_draft · unverified_draft

## methionine-samtor-specificity Different amino acids enter the growth-control network through different sensors. SAMTOR loss made mTORC1 resistant to methionine starvation while leaving leucine- and arginine-starvation sensitivity intact. Model: Human HEK293T knockout and re-expression experiments. Limitations: Loss of one sensor does not make methionine dispensable for proteins or methylation. Evidence access: Primary full text SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29123071/ · DOI 10.1126/science.aao3265

experimental_model

High-K mouse/human T-cell cultures; PP2A perturbations.

limitations

PP2A dependence does not demonstrate direct K binding; no diet manipulation.

nutrient_topic

Potassium research collection; topical membership is not evidence of a direct dietary effect. · Potassium

organism

Mouse and human

plain_language

Local potassium accumulation dampened T-cell activation signals.

primary_references

[eil-2016-tcells] Ionic immune suppression within the tumour microenvironment limits T cell effector function (2016). https://pmc.ncbi.nlm.nih.gov/articles/PMC5204372/ DOI: 10.1038/nature19364

tissue_or_cell_type

T cells

Potassium: cross-nutrient mechanisms and deficiency (2026-09-17) · lines 902–911

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · High-K mouse/human T-cell cultures; PP2A perturbations. · source_derived_draft · unverified_draft

### k-tcell-pp2a-suppression Elevated intracellular K suppressed TCR-driven AKT-mTOR signaling through a PP2A-dependent process. Condition category: normal nutrient_topic: Potassium research collection; topical membership is not evidence of a direct dietary effect. plain_language: Local potassium accumulation dampened T-cell activation signals. organism: Mouse and human tissue_or_cell_type: T cells experimental_model: High-K mouse/human T-cell cultures; PP2A perturbations. limitations: PP2A dependence does not demonstrate direct K binding; no diet manipulation. [eil-2016-tcells] Ionic immune suppression within the tumour microenvironment limits T cell effector function (2016). https://pmc.ncbi.nlm.nih.gov/articles/PMC5204372/ DOI: 10.1038/nature19364

evidence_access

Primary full text

experimental_model

Human-cell signaling, kinase assays and inhibitor/knockdown experiments.

limitations

Does not eliminate mTOR signaling from all imidazole-propionate effects; model and time point matter.

nutrient_topic

L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Histidine

plain_language

Two routes from the same metabolite have different timing and intermediates.

primary_references

Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012

L-Histidine: supply, catabolism, histamine, receptors and cross-nutrient mechanisms (2026-09-19) · lines 338–344

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human-cell signaling, kinase assays and inhibitor/knockdown experiments. · source_derived_draft · unverified_draft

## histidine-imp-mtor-boundary Two routes from the same metabolite have different timing and intermediates. The study distinguished p38-gamma-dependent basal Akt activation from mTORC1-dependent IRS loss; direct mTORC2 activation was not detected in the tested kinase assay. Model: Human-cell signaling, kinase assays and inhibitor/knockdown experiments. Limitations: Does not eliminate mTOR signaling from all imidazole-propionate effects; model and time point matter. Evidence access: Primary full text Microbial Imidazole Propionate Affects Responses to Metformin through p38γ-Dependent Inhibitory AMPK Phosphorylation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32783890/ · DOI 10.1016/j.cmet.2020.07.012

evidence_access

Primary abstract

experimental_model

Cellular interaction and mTORC1 signaling experiments.

limitations

GTP-bound RagC here belongs to the inactive Rag configuration; GTP status has different implications for RagA and RagC.

nutrient_topic

L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine

plain_language

A threonine-processing protein also links nutrient availability to a growth-control switch.

primary_references

Mitochondrial Threonyl-tRNA Synthetase TARS2 Is Required for Threonine-Sensitive mTORC1 Activation. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33340489/ · DOI 10.1016/j.molcel.2020.11.036

L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 98–104

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cellular interaction and mTORC1 signaling experiments. · source_derived_draft · unverified_draft

## l-threonine-tars2-rag A threonine-processing protein also links nutrient availability to a growth-control switch. TARS2 interacted with inactive Rag complexes, especially GTP-bound RagC, and promoted RagA GTP loading. Model: Cellular interaction and mTORC1 signaling experiments. Limitations: GTP-bound RagC here belongs to the inactive Rag configuration; GTP status has different implications for RagA and RagC. Evidence access: Primary abstract Mitochondrial Threonyl-tRNA Synthetase TARS2 Is Required for Threonine-Sensitive mTORC1 Activation. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33340489/ · DOI 10.1016/j.molcel.2020.11.036

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

TARS2 loss and threonine repletion in cultured cells.

limitations

This is a signaling endpoint, not a clinical threonine-repletion trial.

nutrient_topic

L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine

plain_language

Restoring the nutrient did not restore the signal when its machinery was missing.

primary_references

Mitochondrial Threonyl-tRNA Synthetase TARS2 Is Required for Threonine-Sensitive mTORC1 Activation. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33340489/ · DOI 10.1016/j.molcel.2020.11.036

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 106–112

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · TARS2 loss and threonine repletion in cultured cells. · source_derived_draft · unverified_draft

## l-threonine-tars2-repletion-failure Restoring the nutrient did not restore the signal when its machinery was missing. Cells lacking TARS2 failed to restore mTORC1 activation in response to threonine repletion; cytosolic TARS was not required for this signaling effect. Model: TARS2 loss and threonine repletion in cultured cells. Limitations: This is a signaling endpoint, not a clinical threonine-repletion trial. Evidence access: Primary abstract Mitochondrial Threonyl-tRNA Synthetase TARS2 Is Required for Threonine-Sensitive mTORC1 Activation. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33340489/ · DOI 10.1016/j.molcel.2020.11.036

evidence_access

Primary abstract

experimental_model

Cultured nutrient-stressed cells.

limitations

Cell survival and autophagy readouts must be distinguished.

nutrient_topic

Fasting physiological-state collection; human protocols, cellular deprivation and refeeding are distinguished. · Fasting / abstention from energy intake

plain_language

The same sensor can support recovery during persistent stress.

primary_references

Unexpected roles for AMPK in the suppression of autophagy and the reactivation of MTORC1 signaling during prolonged amino acid deprivation. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38744665/ · DOI 10.1080/15548627.2024.2355074

Fasting: fuel switching, nutrient sensing, ketone signaling, nutrient dependencies and refeeding (2026-09-18) · lines 320–326

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Cultured nutrient-stressed cells. · source_derived_draft · unverified_draft

## fast-ampk-reactivation The same sensor can support recovery during persistent stress. AMPK loss impaired mTORC1 reactivation during prolonged amino-acid deprivation and increased apoptosis. Model: Cultured nutrient-stressed cells. Limitations: Cell survival and autophagy readouts must be distinguished. Evidence access: Primary abstract Unexpected roles for AMPK in the suppression of autophagy and the reactivation of MTORC1 signaling during prolonged amino acid deprivation. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38744665/ · DOI 10.1080/15548627.2024.2355074

evidence_access

Primary full text

experimental_model

Human HEK293E CAD expression, phosphosite mutation and kinase assays; complementary mouse cell tracing.

limitations

This is a signaling dependency, not evidence that a specific nutrient supplement necessarily increases CAD activity.

nutrient_topic

L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate

plain_language

Growth signals can accelerate use of aspartate for nucleotide production.

primary_references

Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23429703/ · DOI 10.1126/science.1228792

L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19) · lines 154–160

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human HEK293E CAD expression, phosphosite mutation and kinase assays; complementary mouse cell tracing. · source_derived_draft · unverified_draft

## l-aspartate-cad-s6k1 Growth signals can accelerate use of aspartate for nucleotide production. S6K1 directly phosphorylated CAD at Ser1859, connecting mTORC1 signaling to increased de novo pyrimidine synthesis. Model: Human HEK293E CAD expression, phosphosite mutation and kinase assays; complementary mouse cell tracing. Limitations: This is a signaling dependency, not evidence that a specific nutrient supplement necessarily increases CAD activity. Evidence access: Primary full text Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23429703/ · DOI 10.1126/science.1228792

evidence_access

Primary abstract

experimental_model

Mammalian-cell signaling experiments and biochemical CASTOR1 binding.

limitations

Do not equate pathway activation with guaranteed muscle growth.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Binding releases a brake on nutrient signaling.

primary_references

The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26972053/ · DOI 10.1016/j.cell.2016.02.035

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 182–188

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Mammalian-cell signaling experiments and biochemical CASTOR1 binding. · source_derived_draft · unverified_draft

## arg-castor-release Binding releases a brake on nutrient signaling. Arginine binding disrupted the CASTOR1–GATOR2 complex; arginine-binding capacity was needed for pathway activation. Model: Mammalian-cell signaling experiments and biochemical CASTOR1 binding. Limitations: Do not equate pathway activation with guaranteed muscle growth. Evidence access: Primary abstract The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26972053/ · DOI 10.1016/j.cell.2016.02.035

evidence_access

Primary abstract

experimental_model

1.8-angstrom structure of arginine-bound CASTOR1 and functional analysis.

limitations

Structural homology to bacterial lysine sensors is not proof that lysine substitutes for arginine.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

The structure explains how binding can change signaling.

primary_references

Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27487210/ · DOI 10.1038/nature19079

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 198–204

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · 1.8-angstrom structure of arginine-bound CASTOR1 and functional analysis. · source_derived_draft · unverified_draft

## arg-castor-structure The structure explains how binding can change signaling. Arginine binds between two ACT domains, controlling the neighboring GATOR2-binding site. Model: 1.8-angstrom structure of arginine-bound CASTOR1 and functional analysis. Limitations: Structural homology to bacterial lysine sensors is not proof that lysine substitutes for arginine. Evidence access: Primary abstract Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27487210/ · DOI 10.1038/nature19079

evidence_access

Primary abstract

experimental_model

Cellular proteolysis and mTORC1 experiments.

limitations

Not evidence that a high blood arginine level guarantees lysosomal amino-acid release.

nutrient_topic

L-Arginine collection; tissue, species, dose and formulation distinctions retained. · L-Arginine

plain_language

Stored or ingested protein must be released from the lysosome before its amino acids can signal.

primary_references

mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29053970/ · DOI 10.1016/j.cell.2017.09.046

L-Arginine: transport, metabolic branches, nutrient interactions, availability and discovery questions (2026-09-18) · lines 214–220

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Cellular proteolysis and mTORC1 experiments. · source_derived_draft · unverified_draft

## arg-lysosome-growth Stored or ingested protein must be released from the lysosome before its amino acids can signal. Leucine generated by lysosomal proteolysis required SLC38A9 for export and subsequent mTORC1 activation. Model: Cellular proteolysis and mTORC1 experiments. Limitations: Not evidence that a high blood arginine level guarantees lysosomal amino-acid release. Evidence access: Primary abstract mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient. · 2017 · https://pubmed.ncbi.nlm.nih.gov/29053970/ · DOI 10.1016/j.cell.2017.09.046