L-Leucine

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/biotin-research/21918059.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5cf1d7e25ae7bdfeb2ac3225cee8e4e660723d5197fc057f63327b3ad9eb3aaf", "start_char": 0, "end_char": 1723, "text_sha256": "5cf1d7e25ae7bdfeb2ac3225cee8e4e660723d5197fc057f63327b3ad9eb3aaf"}

experimental_model

Leucine challenge during biotin depletion in two cohorts of 5 and 7 healthy adults

exposure

28-day egg-white depletion; weekly oral leucine challenge

limitations

The challenge was sensitive but not diagnostically superior to 24-hour urine measurements; no validated universal threshold follows.

nutrient_topic

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

organism

Homo sapiens

plain_language

Extra leucine made the impaired pathway easier to observe.

primary_references

[b7-p21918059] Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans. (2011). https://pubmed.ncbi.nlm.nih.gov/21918059/ DOI: 10.3945/jn.111.146126

tissue_or_cell_type

Urine

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Biotin: carboxylases, recycling, deficiency and nutrient interactions (2026-09-17) · lines 910–921

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Leucine challenge during biotin depletion in two cohorts of 5 and 7 healthy adults · source_derived_draft · unverified_draft

### b7-leucine-challenge-3hia Challenge-induced urinary 3-HIA rose more than twofold by day 14 in both biotin-depleted cohorts. Condition category: nutrient_deficiency nutrient_topic: Biotin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Extra leucine made the impaired pathway easier to observe. organism: Homo sapiens tissue_or_cell_type: Urine experimental_model: Leucine challenge during biotin depletion in two cohorts of 5 and 7 healthy adults limitations: The challenge was sensitive but not diagnostically superior to 24-hour urine measurements; no validated universal threshold follows. exposure: 28-day egg-white depletion; weekly oral leucine challenge evidence_span: {"source_cache": "artifacts/biotin-research/21918059.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5cf1d7e25ae7bdfeb2ac3225cee8e4e660723d5197fc057f63327b3ad9eb3aaf", "start_char": 0, "end_char": 1723, "text_sha256": "5cf1d7e25ae7bdfeb2ac3225cee8e4e660723d5197fc057f63327b3ad9eb3aaf"} [b7-p21918059] Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans. (2011). https://pubmed.ncbi.nlm.nih.gov/21918059/ DOI: 10.3945/jn.111.146126

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/biotin-research/21918059.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5cf1d7e25ae7bdfeb2ac3225cee8e4e660723d5197fc057f63327b3ad9eb3aaf", "start_char": 0, "end_char": 1723, "text_sha256": "5cf1d7e25ae7bdfeb2ac3225cee8e4e660723d5197fc057f63327b3ad9eb3aaf"}

experimental_model

Leucine challenge during biotin depletion in two cohorts of 5 and 7 healthy adults

exposure

28-day egg-white depletion; weekly oral leucine challenge

limitations

The challenge was sensitive but not diagnostically superior to 24-hour urine measurements; no validated universal threshold follows.

nutrient_topic

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

organism

Homo sapiens

plain_language

The carnitine-linked side product also increased as biotin became limited.

primary_references

[b7-p21918059] Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans. (2011). https://pubmed.ncbi.nlm.nih.gov/21918059/ DOI: 10.3945/jn.111.146126

tissue_or_cell_type

Urine

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Biotin: carboxylases, recycling, deficiency and nutrient interactions (2026-09-17) · lines 923–934

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Leucine challenge during biotin depletion in two cohorts of 5 and 7 healthy adults · source_derived_draft · unverified_draft

### b7-leucine-challenge-c5oh Challenge-induced urinary 3-hydroxyisovalerylcarnitine rose more than twofold by day 14 in both biotin-depleted cohorts. Condition category: nutrient_deficiency nutrient_topic: Biotin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The carnitine-linked side product also increased as biotin became limited. organism: Homo sapiens tissue_or_cell_type: Urine experimental_model: Leucine challenge during biotin depletion in two cohorts of 5 and 7 healthy adults limitations: The challenge was sensitive but not diagnostically superior to 24-hour urine measurements; no validated universal threshold follows. exposure: 28-day egg-white depletion; weekly oral leucine challenge evidence_span: {"source_cache": "artifacts/biotin-research/21918059.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5cf1d7e25ae7bdfeb2ac3225cee8e4e660723d5197fc057f63327b3ad9eb3aaf", "start_char": 0, "end_char": 1723, "text_sha256": "5cf1d7e25ae7bdfeb2ac3225cee8e4e660723d5197fc057f63327b3ad9eb3aaf"} [b7-p21918059] Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans. (2011). https://pubmed.ncbi.nlm.nih.gov/21918059/ DOI: 10.3945/jn.111.146126

evidence_access

Primary abstract

experimental_model

Mouse islet and dispersed-cell experiments; paracrine blockers and metabolic inhibitors.

limitations

Cyanide is broad; the experiment does not identify one unique mitochondrial enzyme as the leucine target.

nutrient_topic

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

plain_language

Part of the suppression arose inside the glucagon-producing cell.

primary_references

Leucine Suppresses α-Cell cAMP and Glucagon Secretion via a Combination of Cell-Intrinsic and Islet Paracrine Signaling. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38870025/ · DOI 10.2337/db23-1013

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 352–358

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse islet and dispersed-cell experiments; paracrine blockers and metabolic inhibitors. · source_derived_draft · unverified_draft

## alanine-leucine-alpha-camp Part of the suppression arose inside the glucagon-producing cell. Leucine reduced mouse alpha-cell cAMP even when beta/delta-cell paracrine signaling was limited; cyanide blocked the inhibitory response, supporting mitochondrial-metabolism dependence. Model: Mouse islet and dispersed-cell experiments; paracrine blockers and metabolic inhibitors. Limitations: Cyanide is broad; the experiment does not identify one unique mitochondrial enzyme as the leucine target. Evidence access: Primary abstract Leucine Suppresses α-Cell cAMP and Glucagon Secretion via a Combination of Cell-Intrinsic and Islet Paracrine Signaling. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38870025/ · DOI 10.2337/db23-1013

evidence_access

Primary abstract

experimental_model

Human and mouse islet perifusion; low-glucose amino-acid challenges.

limitations

Mixed-species functional observation, not a human supplementation trial; nutrient concentrations and glucose state determine interpretation.

nutrient_topic

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

plain_language

One amino acid can reduce the hormone response to another.

primary_references

Leucine Suppresses α-Cell cAMP and Glucagon Secretion via a Combination of Cell-Intrinsic and Islet Paracrine Signaling. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38870025/ · DOI 10.2337/db23-1013

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 344–350

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human and mouse islet perifusion; low-glucose amino-acid challenges. · source_derived_draft · unverified_draft

## alanine-leucine-glucagon One amino acid can reduce the hormone response to another. Leucine suppressed alanine- and arginine-stimulated glucagon secretion in isolated human and mouse islets under the tested low-glucose conditions. Model: Human and mouse islet perifusion; low-glucose amino-acid challenges. Limitations: Mixed-species functional observation, not a human supplementation trial; nutrient concentrations and glucose state determine interpretation. Evidence access: Primary abstract Leucine Suppresses α-Cell cAMP and Glucagon Secretion via a Combination of Cell-Intrinsic and Islet Paracrine Signaling. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38870025/ · DOI 10.2337/db23-1013

evidence_access

Primary abstract

experimental_model

Overnight-fasted rats receiving defined meals with different amino-acid mixtures.

limitations

Not a validated universal human threshold or proof that protein-rich meals worsen mood.

nutrient_topic

Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan

plain_language

A higher blood level need not mean more tryptophan reaches the brain.

primary_references

Acute reduction of brain serotonin and 5-HIAA following food consumption: correlation with the ratio of serum tryptophan to the sum of competing amino acids. · 1975 · https://pubmed.ncbi.nlm.nih.gov/1080186/ · DOI 10.1007/BF01256759

Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 58–64

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Overnight-fasted rats receiving defined meals with different amino-acid mixtures. · source_derived_draft · unverified_draft

## tryptophan-brain-competition A higher blood level need not mean more tryptophan reaches the brain. In rat meal experiments, brain tryptophan and 5-hydroxyindoles tracked the serum tryptophan-to-competing-neutral-amino-acid ratio better than serum tryptophan alone. Model: Overnight-fasted rats receiving defined meals with different amino-acid mixtures. Limitations: Not a validated universal human threshold or proof that protein-rich meals worsen mood. Evidence access: Primary abstract Acute reduction of brain serotonin and 5-HIAA following food consumption: correlation with the ratio of serum tryptophan to the sum of competing amino acids. · 1975 · https://pubmed.ncbi.nlm.nih.gov/1080186/ · DOI 10.1007/BF01256759

evidence_span

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experimental_model

Cell uptake and stable human-transporter expression

exposure

Radiolabeled theanine with leucine/BCH competition and sodium replacement

limitations

Human transporter identity confirmed in the public primary PDF methods. Engineered cells do not prove which transporter dominates human blood-brain-barrier flux or a clinical meal interaction.

nutrient_topic

L-Theanine research collection; topical membership is not evidence of a direct dietary effect. · L-Theanine

organism

Mammalian cell lines; human LAT1 and LAT2 expressed in mouse S2 cells

plain_language

Another dietary amino acid can compete at the transport step.

primary_references

[theanine-p23221699] The involvement of L-type amino acid transporters in theanine transport. (2012). https://pubmed.ncbi.nlm.nih.gov/23221699/ DOI: 10.1271/bbb.120519

tissue_or_cell_type

System L amino acid transport

L-Theanine: metabolism, neural signaling, nutrient connections and human outcomes (2026-09-17) · lines 198–209

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell uptake and stable human-transporter expression · source_derived_draft · unverified_draft

### theanine-leucine-competition Leucine inhibited theanine uptake in the tested mammalian cell systems. Condition category: normal nutrient_topic: L-Theanine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Another dietary amino acid can compete at the transport step. organism: Mammalian cell lines; human LAT1 and LAT2 expressed in mouse S2 cells tissue_or_cell_type: System L amino acid transport experimental_model: Cell uptake and stable human-transporter expression limitations: Human transporter identity confirmed in the public primary PDF methods. Engineered cells do not prove which transporter dominates human blood-brain-barrier flux or a clinical meal interaction. exposure: Radiolabeled theanine with leucine/BCH competition and sodium replacement evidence_span: {"source_cache": "artifacts/theanine-research/23221699.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "0f79abd668759eccd12f86ec895af75dadf94f6412c29d51a2b6cfde712f9372", "start_char": 0, "end_char": 1143, "text_sha256": "0f79abd668759eccd12f86ec895af75dadf94f6412c29d51a2b6cfde712f9372"} [theanine-p23221699] The involvement of L-type amino acid transporters in theanine transport. (2012). https://pubmed.ncbi.nlm.nih.gov/23221699/ DOI: 10.1271/bbb.120519

cross_nutrient

Niacin (vitamin B3) (repleted_nutrient); L-Tryptophan (measured_precursor); Oxidized nicotinamide adenine dinucleotide phosphate (co_measured_pool)

evidence_span

{"source_cache": "artifacts/niacin-clinical-sources/fu1989.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "ca6d94c101aca84f1e41f35898434f44770ca563c5bff986fe52e33f797b0fbc", "start_char": 0, "end_char": 1340, "text_sha256": "ca6d94c101aca84f1e41f35898434f44770ca563c5bff986fe52e33f797b0fbc"}

experimental_model

Controlled metabolic-unit feeding; seven men, 80 days

exposure

6.1 or 10.1 niacin equivalents/day, followed by adequate/high intakes; repletion with or without 7.8 g/day leucine

limitations

Small controlled male metabolic-unit study. Erythrocytes are not every tissue; historical adequate intake is not a current recommendation. Jacob and Fu reports may describe related participants and are not counted as independent trials.

nutrient_topic

Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

organism

Homo sapiens

plain_language

Extra leucine did not block niacin recovery under this tested diet.

primary_references

[nia-clin-fu1989] Biochemical markers for assessment of niacin status in young men: levels of erythrocyte niacin coenzymes and plasma tryptophan. (1989). https://pubmed.ncbi.nlm.nih.gov/2621487/ DOI: 10.1093/jn/119.12.1949

tissue_or_cell_type

Erythrocytes and plasma

Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1135–1147

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Controlled metabolic-unit feeding; seven men, 80 days · source_derived_draft · unverified_draft

### nia-clin-leucine-repletion Adding 7.8 g/day leucine during repletion did not change end-period erythrocyte NAD or NADP or plasma tryptophan in this study. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Extra leucine did not block niacin recovery under this tested diet. organism: Homo sapiens tissue_or_cell_type: Erythrocytes and plasma experimental_model: Controlled metabolic-unit feeding; seven men, 80 days limitations: Small controlled male metabolic-unit study. Erythrocytes are not every tissue; historical adequate intake is not a current recommendation. Jacob and Fu reports may describe related participants and are not counted as independent trials. exposure: 6.1 or 10.1 niacin equivalents/day, followed by adequate/high intakes; repletion with or without 7.8 g/day leucine cross_nutrient: Niacin (vitamin B3) (repleted_nutrient); L-Tryptophan (measured_precursor); Oxidized nicotinamide adenine dinucleotide phosphate (co_measured_pool) evidence_span: {"source_cache": "artifacts/niacin-clinical-sources/fu1989.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "ca6d94c101aca84f1e41f35898434f44770ca563c5bff986fe52e33f797b0fbc", "start_char": 0, "end_char": 1340, "text_sha256": "ca6d94c101aca84f1e41f35898434f44770ca563c5bff986fe52e33f797b0fbc"} [nia-clin-fu1989] Biochemical markers for assessment of niacin status in young men: levels of erythrocyte niacin coenzymes and plasma tryptophan. (1989). https://pubmed.ncbi.nlm.nih.gov/2621487/ DOI: 10.1093/jn/119.12.1949

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human patient series with enzyme allostery and dietary-response observations.

limitations

Observational genotype/phenotype evidence, not a controlled general-population dietary trial.

nutrient_topic

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

plain_language

Another amino acid regulates how glutamate is processed, but the response varies by enzyme defect.

primary_references

Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11518822/ · DOI 10.1203/00006450-200109000-00010

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Glutamate / L-glutamic acid: carbon and nitrogen allocation, signaling and cross-nutrient mechanisms (2026-09-19) · lines 186–192

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human patient series with enzyme allostery and dietary-response observations. · source_derived_draft · unverified_draft

## glutamate-gdh-leucine-context Another amino acid regulates how glutamate is processed, but the response varies by enzyme defect. Leucine activation of lymphoblast GDH varied among twelve patients with hyperinsulinism/hyperammonemia; reduced leucine sensitivity tracked failure of leucine restriction to improve glucose in four patients. Model: Human patient series with enzyme allostery and dietary-response observations. Limitations: Observational genotype/phenotype evidence, not a controlled general-population dietary trial. Evidence access: Primary abstract Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11518822/ · DOI 10.1203/00006450-200109000-00010

cross_nutrient

Essential amino-acid nitrogen transfer; net direction depends on substrate/product conditions.

experimental_model

Recombinant human BCAT1 and BCAT2; pre-steady-state kinetics and structures

limitations

Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

B6-dependent transamination starts leucine processing and transfers nitrogen to glutamate.

primary_references

[b6-bcat1-2005] Structural determinants for branched-chain aminotransferase isozyme-specific inhibition by the anticonvulsant drug gabapentin (2005). https://pubmed.ncbi.nlm.nih.gov/16141215/ DOI: 10.1074/jbc.M506486200

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 717–727

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human BCAT1 and BCAT2; pre-steady-state kinetics and structures · source_derived_draft · unverified_draft

### b6-met-bcat1-leucine Human BCAT1 transfers the leucine amino group to 2-oxoglutarate, producing alpha-ketoisocaproate and glutamate. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: B6-dependent transamination starts leucine processing and transfers nitrogen to glutamate. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human BCAT1 and BCAT2; pre-steady-state kinetics and structures limitations: Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds. cross_nutrient: Essential amino-acid nitrogen transfer; net direction depends on substrate/product conditions. [b6-bcat1-2005] Structural determinants for branched-chain aminotransferase isozyme-specific inhibition by the anticonvulsant drug gabapentin (2005). https://pubmed.ncbi.nlm.nih.gov/16141215/ DOI: 10.1074/jbc.M506486200

cross_nutrient

Essential amino-acid nitrogen transfer; net direction depends on substrate/product conditions.

experimental_model

Recombinant human BCAT1 and BCAT2; pre-steady-state kinetics and structures

limitations

Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds.

nutrient_topic

Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6

organism

Homo sapiens

plain_language

B6-dependent transamination starts leucine processing and transfers nitrogen to glutamate.

primary_references

[b6-bcat1-2005] Structural determinants for branched-chain aminotransferase isozyme-specific inhibition by the anticonvulsant drug gabapentin (2005). https://pubmed.ncbi.nlm.nih.gov/16141215/ DOI: 10.1074/jbc.M506486200

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 729–739

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human BCAT1 and BCAT2; pre-steady-state kinetics and structures · source_derived_draft · unverified_draft

### b6-met-bcat2-leucine Human BCAT2 transfers the leucine amino group to 2-oxoglutarate, producing alpha-ketoisocaproate and glutamate. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: B6-dependent transamination starts leucine processing and transfers nitrogen to glutamate. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Recombinant human BCAT1 and BCAT2; pre-steady-state kinetics and structures limitations: Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds. cross_nutrient: Essential amino-acid nitrogen transfer; net direction depends on substrate/product conditions. [b6-bcat1-2005] Structural determinants for branched-chain aminotransferase isozyme-specific inhibition by the anticonvulsant drug gabapentin (2005). https://pubmed.ncbi.nlm.nih.gov/16141215/ DOI: 10.1074/jbc.M506486200

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/biotin-research/12399279.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "38158dd10cfc6528b65a3304fac58a5b5d8ec82e20673534b5bf6e9e79f14b09", "start_char": 0, "end_char": 1718, "text_sha256": "38158dd10cfc6528b65a3304fac58a5b5d8ec82e20673534b5bf6e9e79f14b09"}

experimental_model

Experimental depletion/repletion in 11 healthy adults; leucine challenge in 5

exposure

28 days of egg-white diet followed by general diet with or without 80 micrograms supplemental biotin

limitations

An intentional undenatured egg-white diet is not ordinary cooked-egg intake. Small experimental cohorts do not establish a population-wide threshold.

nutrient_topic

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

organism

Homo sapiens

plain_language

A bottleneck in leucine breakdown became measurable before a universal clinical syndrome was required.

primary_references

[b7-p12399279] Indicators of marginal biotin deficiency and repletion in humans: validation of 3-hydroxyisovaleric acid excretion and a leucine challenge. (2002). https://pubmed.ncbi.nlm.nih.gov/12399279/ DOI: 10.1093/ajcn/76.5.1061

tissue_or_cell_type

Dietary exposure and urinary metabolites

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Biotin: carboxylases, recycling, deficiency and nutrient interactions (2026-09-17) · lines 897–908

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Experimental depletion/repletion in 11 healthy adults; leucine challenge in 5 · source_derived_draft · unverified_draft

### b7-depletion-3hia Urinary 3-HIA increased during 28-day biotin depletion in 11 adults; biotin-status indicators normalized in most after one week on a general diet. Condition category: nutrient_deficiency nutrient_topic: Biotin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A bottleneck in leucine breakdown became measurable before a universal clinical syndrome was required. organism: Homo sapiens tissue_or_cell_type: Dietary exposure and urinary metabolites experimental_model: Experimental depletion/repletion in 11 healthy adults; leucine challenge in 5 limitations: An intentional undenatured egg-white diet is not ordinary cooked-egg intake. Small experimental cohorts do not establish a population-wide threshold. exposure: 28 days of egg-white diet followed by general diet with or without 80 micrograms supplemental biotin evidence_span: {"source_cache": "artifacts/biotin-research/12399279.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "38158dd10cfc6528b65a3304fac58a5b5d8ec82e20673534b5bf6e9e79f14b09", "start_char": 0, "end_char": 1718, "text_sha256": "38158dd10cfc6528b65a3304fac58a5b5d8ec82e20673534b5bf6e9e79f14b09"} [b7-p12399279] Indicators of marginal biotin deficiency and repletion in humans: validation of 3-hydroxyisovaleric acid excretion and a leucine challenge. (2002). https://pubmed.ncbi.nlm.nih.gov/12399279/ DOI: 10.1093/ajcn/76.5.1061

availability_state

biomarker_context Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/biotin-research/25122647.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6066b007a013c3c0c69336e7aba0e51baa39e3a24b6eb918cb4778e792376a9b", "start_char": 0, "end_char": 2354, "text_sha256": "6066b007a013c3c0c69336e7aba0e51baa39e3a24b6eb918cb4778e792376a9b"}

experimental_model

Controlled feeding: 26 pregnant, 28 lactating and 21 control women

exposure

57 micrograms dietary biotin per day for 10–12 weeks

limitations

Groups differed in reproductive state. Marker changes do not establish fetal outcomes, universal deficiency or a treatment dose.

nutrient_topic

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

organism

Homo sapiens

plain_language

Biotin breakdown and leucine-derived markers can diverge during lactation.

primary_references

[b7-p25122647] Pregnancy and lactation alter biomarkers of biotin metabolism in women consuming a controlled diet. (2014). https://pubmed.ncbi.nlm.nih.gov/25122647/ DOI: 10.3945/jn.114.194472

tissue_or_cell_type

Urine and plasma

trigger_kind

biomarker_context Imported condition classification; unverified.

Biotin: carboxylases, recycling, deficiency and nutrient interactions (2026-09-17) · lines 1001–1012

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Controlled feeding: 26 pregnant, 28 lactating and 21 control women · source_derived_draft · unverified_draft

### b7-lactation-bisnor Lactating women excreted 76% more bisnorbiotin than controls, while 3-HIA and 3-HIA-carnitine excretion were lower. Condition category: biomarker_context nutrient_topic: Biotin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Biotin breakdown and leucine-derived markers can diverge during lactation. organism: Homo sapiens tissue_or_cell_type: Urine and plasma experimental_model: Controlled feeding: 26 pregnant, 28 lactating and 21 control women limitations: Groups differed in reproductive state. Marker changes do not establish fetal outcomes, universal deficiency or a treatment dose. exposure: 57 micrograms dietary biotin per day for 10–12 weeks evidence_span: {"source_cache": "artifacts/biotin-research/25122647.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6066b007a013c3c0c69336e7aba0e51baa39e3a24b6eb918cb4778e792376a9b", "start_char": 0, "end_char": 2354, "text_sha256": "6066b007a013c3c0c69336e7aba0e51baa39e3a24b6eb918cb4778e792376a9b"} [b7-p25122647] Pregnancy and lactation alter biomarkers of biotin metabolism in women consuming a controlled diet. (2014). https://pubmed.ncbi.nlm.nih.gov/25122647/ DOI: 10.3945/jn.114.194472

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/biotin-research/22642865.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f0c40118afe81e9b597d2d2cbe6a785c2b96a4dbd7f4dcb634230070c61865ee", "start_char": 0, "end_char": 1384, "text_sha256": "f0c40118afe81e9b597d2d2cbe6a785c2b96a4dbd7f4dcb634230070c61865ee"}

experimental_model

Retrospective clinical, biochemical and molecular study of 88 MCC-deficient individuals

exposure

MCCC1/MCCC2 defects; mixed newborn screening and clinical ascertainment

limitations

Ascertainment bias and incomplete penetrance limit predictions. This is an isolated inherited enzyme defect, not biotin intake deficiency.

nutrient_topic

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

organism

Homo sapiens

plain_language

A striking biochemical marker does not determine how ill a person will be.

primary_references

[b7-p22642865] 3-methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical, enzymatic and molecular studies in 88 individuals. (2012). https://pubmed.ncbi.nlm.nih.gov/22642865/ DOI: 10.1186/1750-1172-7-31

tissue_or_cell_type

Clinical and biochemical phenotype

trigger_kind

machinery_impairment Imported condition classification; unverified.

Biotin: carboxylases, recycling, deficiency and nutrient interactions (2026-09-17) · lines 1027–1038

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Retrospective clinical, biochemical and molecular study of 88 MCC-deficient individuals · source_derived_draft · unverified_draft

### b7-mcc-genetic-variability In the 88-person MCC-deficiency series, 57% were asymptomatic; 12 had acute metabolic decompensations, and genotype or biochemical phenotype did not reliably predict the course. Condition category: machinery_impairment nutrient_topic: Biotin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A striking biochemical marker does not determine how ill a person will be. organism: Homo sapiens tissue_or_cell_type: Clinical and biochemical phenotype experimental_model: Retrospective clinical, biochemical and molecular study of 88 MCC-deficient individuals limitations: Ascertainment bias and incomplete penetrance limit predictions. This is an isolated inherited enzyme defect, not biotin intake deficiency. exposure: MCCC1/MCCC2 defects; mixed newborn screening and clinical ascertainment evidence_span: {"source_cache": "artifacts/biotin-research/22642865.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f0c40118afe81e9b597d2d2cbe6a785c2b96a4dbd7f4dcb634230070c61865ee", "start_char": 0, "end_char": 1384, "text_sha256": "f0c40118afe81e9b597d2d2cbe6a785c2b96a4dbd7f4dcb634230070c61865ee"} [b7-p22642865] 3-methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical, enzymatic and molecular studies in 88 individuals. (2012). https://pubmed.ncbi.nlm.nih.gov/22642865/ DOI: 10.1186/1750-1172-7-31

evidence_span

{"source_cache": "artifacts/biotin-research/21918059.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5cf1d7e25ae7bdfeb2ac3225cee8e4e660723d5197fc057f63327b3ad9eb3aaf", "start_char": 0, "end_char": 1723, "text_sha256": "5cf1d7e25ae7bdfeb2ac3225cee8e4e660723d5197fc057f63327b3ad9eb3aaf"}

experimental_model

Two human egg-white biotin-depletion cohorts with leucine challenges

exposure

28-day depletion in cohorts of 5 and 7 adults

limitations

Biomarker challenge study; the core MCC reaction is pathway background, not a new structural discovery.

nutrient_topic

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

organism

Homo sapiens

plain_language

Biotin helps process a carbon intermediate produced while breaking down leucine.

primary_references

[b7-p21918059] Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans. (2011). https://pubmed.ncbi.nlm.nih.gov/21918059/ DOI: 10.3945/jn.111.146126

tissue_or_cell_type

Leucine metabolism and urine

Biotin: carboxylases, recycling, deficiency and nutrient interactions (2026-09-17) · lines 793–804

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two human egg-white biotin-depletion cohorts with leucine challenges · source_derived_draft · unverified_draft

### b7-mcc-reaction MCC converts 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA in the leucine breakdown pathway using biotin. Condition category: normal nutrient_topic: Biotin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Biotin helps process a carbon intermediate produced while breaking down leucine. organism: Homo sapiens tissue_or_cell_type: Leucine metabolism and urine experimental_model: Two human egg-white biotin-depletion cohorts with leucine challenges limitations: Biomarker challenge study; the core MCC reaction is pathway background, not a new structural discovery. exposure: 28-day depletion in cohorts of 5 and 7 adults evidence_span: {"source_cache": "artifacts/biotin-research/21918059.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5cf1d7e25ae7bdfeb2ac3225cee8e4e660723d5197fc057f63327b3ad9eb3aaf", "start_char": 0, "end_char": 1723, "text_sha256": "5cf1d7e25ae7bdfeb2ac3225cee8e4e660723d5197fc057f63327b3ad9eb3aaf"} [b7-p21918059] Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans. (2011). https://pubmed.ncbi.nlm.nih.gov/21918059/ DOI: 10.3945/jn.111.146126

evidence_access

Primary abstract

experimental_model

Normal rats; BCAAs compared at matched doses.

limitations

Not a human diabetes intervention or equivalent to prolonged high-isoleucine feeding.

nutrient_topic

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

plain_language

An acute dose changed the handling of a glucose challenge.

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 338–344

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Normal rats; BCAAs compared at matched doses. · source_derived_draft · unverified_draft

## isoleucine-acute-rat-glucose An acute dose changed the handling of a glucose challenge. A single 0.3 g/kg oral isoleucine dose reduced glucose at 30 and 60 minutes after a 2 g/kg glucose bolus in rats. Model: Normal rats; BCAAs compared at matched doses. Limitations: Not a human diabetes intervention or equivalent to prolonged high-isoleucine feeding. 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

Conditional mouse knockout under defined temperature and diet conditions.

limitations

Different perturbations and conditions from prior Bckdha-loss thermogenesis work; no universal requirement for a weight change.

nutrient_topic

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

plain_language

The metabolic effect was separable from measured heat production and weight.

primary_references

BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38653240/ · DOI 10.1016/j.cell.2024.03.030

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism 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 · Conditional mouse knockout under defined temperature and diet conditions. · source_derived_draft · unverified_draft

## isoleucine-bat-insulin-beyond-heat The metabolic effect was separable from measured heat production and weight. BAT-specific Slc25a44 knockout impaired BCAA clearance and insulin tolerance without a significant difference in energy expenditure or body weight in this study. Model: Conditional mouse knockout under defined temperature and diet conditions. Limitations: Different perturbations and conditions from prior Bckdha-loss thermogenesis work; no universal requirement for a weight change. Evidence access: Primary full text BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38653240/ · DOI 10.1016/j.cell.2024.03.030

evidence_access

Primary abstract

experimental_model

Isolated human lymphocyte concentration-response assays.

limitations

Does not quantify whole-body competition after a meal or prove a nutritional deficiency.

nutrient_topic

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

plain_language

Shared breakdown machinery can create substrate interactions.

primary_references

Assessment of effects of amino acids and branched chain keto acids on leucine oxidation in human lymphocytes. · 1988 · https://pubmed.ncbi.nlm.nih.gov/2905828/ · DOI 10.3109/00365518809085769

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 290–296

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Isolated human lymphocyte concentration-response assays. · source_derived_draft · unverified_draft

## isoleucine-bcaa-competition Shared breakdown machinery can create substrate interactions. Isoleucine at 80-200 micromolar and valine at 250-500 micromolar reduced leucine transamination/oxidation by up to 25% in human peripheral lymphocytes. Model: Isolated human lymphocyte concentration-response assays. Limitations: Does not quantify whole-body competition after a meal or prove a nutritional deficiency. Evidence access: Primary abstract Assessment of effects of amino acids and branched chain keto acids on leucine oxidation in human lymphocytes. · 1988 · https://pubmed.ncbi.nlm.nih.gov/2905828/ · DOI 10.3109/00365518809085769

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse BAT carrier-loss and isotope/metabolite experiments.

limitations

Does not establish isoleucine supplementation as a glutathione intervention; the traced amino acids and cell context remain explicit.

nutrient_topic

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

plain_language

Transport and nitrogen handling can affect antioxidant production.

primary_references

BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38653240/ · DOI 10.1016/j.cell.2024.03.030

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 90–96

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse BAT carrier-loss and isotope/metabolite experiments. · source_derived_draft · unverified_draft

## isoleucine-bcaa-glutathione Transport and nitrogen handling can affect antioxidant production. Impaired mitochondrial BCAA nitrogen flux reduced synthesis of downstream metabolites including glutathione and increased oxidative stress in the tested BAT system. Model: Mouse BAT carrier-loss and isotope/metabolite experiments. Limitations: Does not establish isoleucine supplementation as a glutathione intervention; the traced amino acids and cell context remain explicit. Evidence access: Primary full text BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38653240/ · DOI 10.1016/j.cell.2024.03.030

evidence_access

Primary full text

experimental_model

Mouse brown adipocytes with 15N-valine/leucine; cellular tracing.

limitations

Isoleucine is a connected BCAA substrate, but was not the tracer in these experiments.

nutrient_topic

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

plain_language

Shared BCAA chemistry carries nitrogen as well as carbon.

primary_references

BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38653240/ · DOI 10.1016/j.cell.2024.03.030

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 82–88

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse brown adipocytes with 15N-valine/leucine; cellular tracing. · source_derived_draft · unverified_draft

## isoleucine-bcaa-nitrogen Shared BCAA chemistry carries nitrogen as well as carbon. Nitrogen-labeled valine and leucine supplied glutamate and alanine rapidly in brown-adipocyte tracing experiments. Model: Mouse brown adipocytes with 15N-valine/leucine; cellular tracing. Limitations: Isoleucine is a connected BCAA substrate, but was not the tracer in these experiments. Evidence access: Primary full text BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38653240/ · DOI 10.1016/j.cell.2024.03.030

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human families with biallelic BCKDK variants and supporting mouse experiments.

limitations

This is a rare genetic syndrome, not a general explanation for autism.

nutrient_topic

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

plain_language

A kinase normally slows amino-acid breakdown.

primary_references

Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22956686/ · DOI 10.1126/science.1224631

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 258–264

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human families with biallelic BCKDK variants and supporting mouse experiments. · source_derived_draft · unverified_draft

## isoleucine-bckdk-brake A kinase normally slows amino-acid breakdown. BCKDK phosphorylates BCKDH E1-alpha; inactivating human BCKDK variants reduced E1-alpha phosphorylation and circulating BCAAs. Model: Human families with biallelic BCKDK variants and supporting mouse experiments. Limitations: This is a rare genetic syndrome, not a general explanation for autism. Evidence access: Primary abstract Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22956686/ · DOI 10.1126/science.1224631

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Bckdk-knockout mouse dietary rescue.

limitations

Mixture intervention; cannot assign rescue uniquely to isoleucine or infer benefit in unrelated disorders.

nutrient_topic

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

plain_language

Replacing the shared substrates helped in the excessive-breakdown model.

primary_references

Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22956686/ · DOI 10.1126/science.1224631

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 266–272

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Bckdk-knockout mouse dietary rescue. · source_derived_draft · unverified_draft

## isoleucine-bckdk-mouse-rescue Replacing the shared substrates helped in the excessive-breakdown model. Dietary BCAA supplementation improved neurobehavioral abnormalities in Bckdk-knockout mice. Model: Bckdk-knockout mouse dietary rescue. Limitations: Mixture intervention; cannot assign rescue uniquely to isoleucine or infer benefit in unrelated disorders. Evidence access: Primary abstract Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22956686/ · DOI 10.1126/science.1224631

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse BAT-targeted Bckdha manipulation and metabolic assays.

limitations

Mixed BCAA pathway; not a claim that isolated isoleucine intake causes obesity.

nutrient_topic

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

plain_language

Loss of a tissue processing route changed whole-body amino-acid handling.

primary_references

BCAA catabolism in brown fat controls energy homeostasis through SLC25A44. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31435015/ · DOI 10.1038/s41586-019-1503-x

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 66–72

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse BAT-targeted Bckdha manipulation and metabolic assays. · source_derived_draft · unverified_draft

## isoleucine-brown-fat-catabolic-loss Loss of a tissue processing route changed whole-body amino-acid handling. BAT-specific BCAA catabolic impairment reduced BCAA clearance and thermogenic fuel oxidation and promoted glucose intolerance in the tested mice. Model: Mouse BAT-targeted Bckdha manipulation and metabolic assays. Limitations: Mixed BCAA pathway; not a claim that isolated isoleucine intake causes obesity. Evidence access: Primary full text BCAA catabolism in brown fat controls energy homeostasis through SLC25A44. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31435015/ · DOI 10.1038/s41586-019-1503-x

evidence_access

Primary abstract

experimental_model

Human proteins expressed in Xenopus oocytes; large-neutral-amino-acid panel.

limitations

Accessed abstract does not resolve a separate isoleucine kinetic value. Shared transport is not proof that an ordinary mixed meal causes deficiency.

nutrient_topic

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

plain_language

Shared transport depends on amino acids on both sides of the membrane.

primary_references

Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11557028/ · DOI 10.1016/s0005-2736(01)00384-4

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 42–48

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human proteins expressed in Xenopus oocytes; large-neutral-amino-acid panel. · source_derived_draft · unverified_draft

## isoleucine-lat1-exchange Shared transport depends on amino acids on both sides of the membrane. Human LAT1 with SLC3A2 transported large neutral amino acids and exchanged intracellular leucine or glutamine with extracellular substrates. Model: Human proteins expressed in Xenopus oocytes; large-neutral-amino-acid panel. Limitations: Accessed abstract does not resolve a separate isoleucine kinetic value. Shared transport is not proof that an ordinary mixed meal causes deficiency. Evidence access: Primary abstract Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11557028/ · DOI 10.1016/s0005-2736(01)00384-4

evidence_access

Primary full text

experimental_model

Mouse brown adipocytes/Neuro2a and membrane/proteoliposome assays.

limitations

Direct transport tracers highlighted here were valine and leucine; do not relabel them as an isolated isoleucine transport assay.

nutrient_topic

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

plain_language

Access to mitochondria is a separate gate from entry into the cell.

primary_references

BCAA catabolism in brown fat controls energy homeostasis through SLC25A44. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31435015/ · DOI 10.1038/s41586-019-1503-x

transport_effect

raises The object already names mitochondrial BCAA uptake.

transport_pool

the mitochondrial matrix The object already names mitochondrial BCAA uptake.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 50–56

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse brown adipocytes/Neuro2a and membrane/proteoliposome assays. · source_derived_draft · unverified_draft

## isoleucine-mitochondrial-carrier Access to mitochondria is a separate gate from entry into the cell. Slc25a44 loss reduced mitochondrial valine and leucine uptake; ectopic expression and reconstituted liposomes supported transporter function. Model: Mouse brown adipocytes/Neuro2a and membrane/proteoliposome assays. Limitations: Direct transport tracers highlighted here were valine and leucine; do not relabel them as an isolated isoleucine transport assay. Evidence access: Primary full text BCAA catabolism in brown fat controls energy homeostasis through SLC25A44. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31435015/ · DOI 10.1038/s41586-019-1503-x

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Small human treatment study plus patient-cell assays.

limitations

Not universal MSUD efficacy or long-term outcome evidence.

nutrient_topic

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

plain_language

The same drug interaction can help or deplete depending on the disease and remaining enzyme function.

primary_references

Phenylbutyrate therapy for maple syrup urine disease. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21098507/ · DOI 10.1093/hmg/ddq507

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism 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 · Small human treatment study plus patient-cell assays. · source_derived_draft · unverified_draft

## isoleucine-msud-drug-response The same drug interaction can help or deplete depending on the disease and remaining enzyme function. Phenylbutyrate reduced BCAA/BCKA pools in controls and some late-onset/intermediate MSUD patients; cultured-cell responses did not simply predict the clinical biochemical response. Model: Small human treatment study plus patient-cell assays. Limitations: Not universal MSUD efficacy or long-term outcome evidence. Evidence access: Primary abstract Phenylbutyrate therapy for maple syrup urine disease. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21098507/ · DOI 10.1093/hmg/ddq507

evidence_access

Primary abstract

experimental_model

Recombinant enzyme assays with supporting cellular/in-vivo experiments.

limitations

Protein species is not inferred from the patient part of the paper; activity responses varied among disease samples.

nutrient_topic

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

plain_language

A medicine can remove the brake on BCAA breakdown.

primary_references

Phenylbutyrate therapy for maple syrup urine disease. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21098507/ · DOI 10.1093/hmg/ddq507

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 298–304

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant enzyme assays with supporting cellular/in-vivo experiments. · source_derived_draft · unverified_draft

## isoleucine-phenylbutyrate-kinase A medicine can remove the brake on BCAA breakdown. Phenylbutyrate inhibited recombinant BCKDH kinase, reduced E1-alpha phosphorylation and increased overall BCKDH activity in the reported assays. Model: Recombinant enzyme assays with supporting cellular/in-vivo experiments. Limitations: Protein species is not inferred from the patient part of the paper; activity responses varied among disease samples. Evidence access: Primary abstract Phenylbutyrate therapy for maple syrup urine disease. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21098507/ · DOI 10.1093/hmg/ddq507

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human stable-isotope-study sampling and treated control comparisons.

limitations

Mixed BCAA effect; dietary decisions in urea-cycle disorders require the full clinical context.

nutrient_topic

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

plain_language

A low amino-acid pool can reflect drug-related handling, not just low intake.

primary_references

New insights in nutritional management and amino acid supplementation in urea cycle disorders. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20299258/ · DOI 10.1016/j.ymgme.2010.02.019

trigger_kind

biomarker_context Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 306–312

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human stable-isotope-study sampling and treated control comparisons. · source_derived_draft · unverified_draft

## isoleucine-phenylbutyrate-plasma A low amino-acid pool can reflect drug-related handling, not just low intake. Sodium phenylbutyrate-treated urea-cycle-disorder patients had lower circulating BCAAs despite adequate protein intake; low steady-state BCAAs were also observed in treated controls. Model: Human stable-isotope-study sampling and treated control comparisons. Limitations: Mixed BCAA effect; dietary decisions in urea-cycle disorders require the full clinical context. Evidence access: Primary abstract New insights in nutritional management and amino acid supplementation in urea cycle disorders. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20299258/ · DOI 10.1016/j.ymgme.2010.02.019

evidence_access

Primary abstract

experimental_model

Mouse and cultured-cell protein interaction/phosphorylation experiments.

limitations

Rate depends on substrate and regulatory state; this is a shared BCAA step.

nutrient_topic

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

plain_language

A phosphatase removes the inhibitory mark and permits more breakdown.

primary_references

Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19411760/ · DOI 10.1172/JCI38151

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 274–280

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse and cultured-cell protein interaction/phosphorylation experiments. · source_derived_draft · unverified_draft

## isoleucine-ppm1k-activation A phosphatase removes the inhibitory mark and permits more breakdown. PP2Cm bound the BCKDH complex and promoted substrate-dependent dephosphorylation of E1-alpha Ser293. Model: Mouse and cultured-cell protein interaction/phosphorylation experiments. Limitations: Rate depends on substrate and regulatory state; this is a shared BCAA step. Evidence access: Primary abstract Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19411760/ · DOI 10.1172/JCI38151

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Ppm1k-deficient mice and cultured cells.

limitations

Mouse MSUD-like phenotype is not a diagnosis of dietary BCAA excess.

nutrient_topic

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

plain_language

Failure to release the brake can produce accumulation rather than shortage.

primary_references

Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19411760/ · DOI 10.1172/JCI38151

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 282–288

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Ppm1k-deficient mice and cultured cells. · source_derived_draft · unverified_draft

## isoleucine-ppm1k-loss Failure to release the brake can produce accumulation rather than shortage. Ppm1k loss abolished substrate-induced E1-alpha dephosphorylation and impaired BCAA catabolism in mice. Model: Ppm1k-deficient mice and cultured cells. Limitations: Mouse MSUD-like phenotype is not a diagnosis of dietary BCAA excess. Evidence access: Primary abstract Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19411760/ · DOI 10.1172/JCI38151

evidence_access

Primary abstract

experimental_model

Isolated normal adult rat islets.

limitations

This setting differs from clonal cells; model and substrate conditions are retained rather than treated as an unexplained contradiction.

nutrient_topic

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

plain_language

The accompanying nutrient changed whether alanine increased insulin.

primary_references

The stimulus-secretion coupling of amino acid-induced insulin release. Insulinotropic action of L-alanine. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12383948/ · DOI 10.1016/s0304-4165(02)00337-9

L-Alanine: carbon, nitrogen, protein synthesis and cross-nutrient mechanisms (2026-09-19) · lines 376–382

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Isolated normal adult rat islets. · source_derived_draft · unverified_draft

## alanine-islet-leucine-combination The accompanying nutrient changed whether alanine increased insulin. Alanine augmented insulin release evoked by leucine or 2-ketoisocaproate in normal adult rat islets, while not significantly changing glucose-induced secretion. Model: Isolated normal adult rat islets. Limitations: This setting differs from clonal cells; model and substrate conditions are retained rather than treated as an unexplained contradiction. Evidence access: Primary abstract The stimulus-secretion coupling of amino acid-induced insulin release. Insulinotropic action of L-alanine. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12383948/ · DOI 10.1016/s0304-4165(02)00337-9

evidence_access

Primary abstract

experimental_model

Human transporter in Xenopus oocytes; tracer influx and efflux.

limitations

Does not show that ordinary mixed meals deplete methionine.

nutrient_topic

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

plain_language

Transport depends on substrates on both sides of the membrane.

primary_references

Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12117417/ · DOI 10.1042/BJ20020841

L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 28–34

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human transporter in Xenopus oocytes; tracer influx and efflux. · source_derived_draft · unverified_draft

## methionine-lat2-exchange Transport depends on substrates on both sides of the membrane. Human LAT2/SLC3A2 transported methionine; leucine and phenylalanine stimulated methionine efflux even against an inward methionine gradient. Model: Human transporter in Xenopus oocytes; tracer influx and efflux. Limitations: Does not show that ordinary mixed meals deplete methionine. Evidence access: Primary abstract Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12117417/ · DOI 10.1042/BJ20020841

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

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Dietary B1 deprivation perturbed branched-chain amino-acid metabolism.

evidence

[{"paper_key": "shigematsu-1989-bcaa", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["abstract"], "locator": "Primary publication abstract", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}]

experimental_model

Four-week dietary depletion.

limitations

Severe animal depletion; not a plasma B1 diagnostic cutoff.

nutrient

Thiamine (vitamin B1) · Thiamine (vitamin B1)

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Rattus norvegicus

plain_language

Severe dietary B1 deprivation altered the circulating pool of leucine, isoleucine and valine in this rat experiment.

primary_references

[shigematsu-1989-bcaa] Branched-chain alpha-ketoacids and related acids in thiamin-deprived rats (1989). https://pubmed.ncbi.nlm.nih.gov/2760689/ DOI: 10.3177/jnsv.35.163

tissue_or_cell_type

Plasma; liver thiamine measured

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 814–826

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Four-week dietary depletion. · source_derived_draft · unverified_draft

### b1-deficiency-plasma-bcaa-rise Four-week thiamine-deprived rats had mean total plasma branched-chain amino acids 1.6 times control. Condition category: nutrient_deficiency nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: Severe dietary B1 deprivation altered the circulating pool of leucine, isoleucine and valine in this rat experiment. organism: Rattus norvegicus tissue_or_cell_type: Plasma; liver thiamine measured experimental_model: Four-week dietary depletion. limitations: Severe animal depletion; not a plasma B1 diagnostic cutoff. evidence: [{"paper_key": "shigematsu-1989-bcaa", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["abstract"], "locator": "Primary publication abstract", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}] cross_nutrient: Dietary B1 deprivation perturbed branched-chain amino-acid metabolism. nutrient: Thiamine (vitamin B1) [shigematsu-1989-bcaa] Branched-chain alpha-ketoacids and related acids in thiamin-deprived rats (1989). https://pubmed.ncbi.nlm.nih.gov/2760689/ DOI: 10.3177/jnsv.35.163

evidence_access

Primary full text

experimental_model

Recombinant enzyme validation alongside docking.

limitations

The causal evidence recorded here is the enzyme assay, not the docking prediction; whole-body contribution is unresolved.

nutrient_topic

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

plain_language

Glycine conjugation can intersect with leucine-breakdown metabolites.

primary_references

The glycine N-acyltransferases, GLYAT and GLYATL1, contribute to the detoxification of isovaleryl-CoA - an in-silico and in vitro validation. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36817957/ · DOI 10.1016/j.csbj.2023.01.041

Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 290–296

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant enzyme validation alongside docking. · source_derived_draft · unverified_draft

## glycine-glyat-isovaleryl Glycine conjugation can intersect with leucine-breakdown metabolites. Purified GLYAT formed N-isovalerylglycine from isovaleryl-CoA and glycine in vitro, with lower affinity than for its preferred substrate. Model: Recombinant enzyme validation alongside docking. Limitations: The causal evidence recorded here is the enzyme assay, not the docking prediction; whole-body contribution is unresolved. Evidence access: Primary full text The glycine N-acyltransferases, GLYAT and GLYATL1, contribute to the detoxification of isovaleryl-CoA - an in-silico and in vitro validation. · 2023 · https://pubmed.ncbi.nlm.nih.gov/36817957/ · DOI 10.1016/j.csbj.2023.01.041

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Gcn2-deficient mice crossed to TCR-transgenic backgrounds; defined amino-acid limitation.

limitations

Not identical to every IDO-dendritic-cell preparation; the authors explicitly challenge the earlier necessity model.

nutrient_topic

Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan

plain_language

Another study found the division block persisted without that sensor.

primary_references

Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27880901/ · DOI 10.1016/j.celrep.2016.10.079

trigger_kind

machinery_impairment Imported condition classification; unverified.

Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 378–384

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Gcn2-deficient mice crossed to TCR-transgenic backgrounds; defined amino-acid limitation. · source_derived_draft · unverified_draft

## tryptophan-gcn2-not-required Another study found the division block persisted without that sensor. GCN2-deficient mouse CD8 T cells still failed to proliferate under limiting tryptophan, arginine, leucine, lysine or asparagine in the 2016 study. Model: Gcn2-deficient mice crossed to TCR-transgenic backgrounds; defined amino-acid limitation. Limitations: Not identical to every IDO-dendritic-cell preparation; the authors explicitly challenge the earlier necessity model. Evidence access: Primary abstract Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27880901/ · DOI 10.1016/j.celrep.2016.10.079

evidence_access

Primary abstract

experimental_model

Human transporter proteins in frog oocytes; human T24-cell disulfide-linked complex also detected.

limitations

This is an exchange assay, not a direct human brain-uptake trial.

nutrient_topic

Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan

plain_language

Transport depends on a partner protein and amino acids on both sides of the membrane.

primary_references

Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11557028/ · DOI 10.1016/s0005-2736(01)00384-4

Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 42–48

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human transporter proteins in frog oocytes; human T24-cell disulfide-linked complex also detected. · source_derived_draft · unverified_draft

## tryptophan-lat1-partner Transport depends on a partner protein and amino acids on both sides of the membrane. Human LAT1 coexpressed with human SLC3A2/4F2hc in Xenopus oocytes transported large neutral amino acids; extracellular substrates exchanged intracellular leucine and glutamine. Model: Human transporter proteins in frog oocytes; human T24-cell disulfide-linked complex also detected. Limitations: This is an exchange assay, not a direct human brain-uptake trial. Evidence access: Primary abstract Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. · 2001 · https://pubmed.ncbi.nlm.nih.gov/11557028/ · DOI 10.1016/s0005-2736(01)00384-4

experimental_model

Human/mouse cloning, Xenopus transport and renal localization

limitations

Leucine is an example exchange substrate, not the obligatory unique counter-substrate.

organism

Human and mouse proteins; Xenopus expression system

plain_language

This transporter admits lysine at the gut or kidney lumen-facing surface.

primary_references

[pfeiffer1999b0] Luminal Heterodimeric Amino Acid Transporter Defective in Cystinuria (1999). https://pmc.ncbi.nlm.nih.gov/articles/PMC25748/ DOI: 10.1091/mbc.10.12.4135

tissue_or_cell_type

Renal proximal-tubule brush border; intestinal apical context

transport_effect

depends The record names sodium-independent lysine exchange and not which way lysine moves in it.

transport_pool

the enterocyte interior across the apical membrane The record names sodium-independent lysine exchange and not which way lysine moves in it.

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 24–32

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human/mouse cloning, Xenopus transport and renal localization · source_derived_draft · unverified_draft

### apical-lysine-exchange SLC7A9 associated with SLC3A1 mediates sodium-independent lysine exchange at the apical epithelial membrane. Plain language: This transporter admits lysine at the gut or kidney lumen-facing surface. Condition category: normal organism: Human and mouse proteins; Xenopus expression system tissue_or_cell_type: Renal proximal-tubule brush border; intestinal apical context experimental_model: Human/mouse cloning, Xenopus transport and renal localization limitations: Leucine is an example exchange substrate, not the obligatory unique counter-substrate. [pfeiffer1999b0] Luminal Heterodimeric Amino Acid Transporter Defective in Cystinuria (1999). https://pmc.ncbi.nlm.nih.gov/articles/PMC25748/ DOI: 10.1091/mbc.10.12.4135

experimental_model

Human/mouse heterodimer expression and exchange assays

limitations

Neutral-substrate transport is sodium-dependent; lysine binding itself should not be mislabeled a sodium cotransport step.

organism

Homo sapiens

plain_language

This route helps lysine leave epithelial cells toward blood.

primary_references

[pfeiffer1999yl] Amino acid transport of y+L-type by heterodimers of 4F2hc/CD98 and members of the glycoprotein-associated amino acid transporter family. (1999). https://pubmed.ncbi.nlm.nih.gov/9878049/ DOI: 10.1093/emboj/18.1.49

tissue_or_cell_type

Basolateral intestinal and renal epithelial membranes

transport_effect

lowers Exchanges intracellular cationic amino acids including lysine for extracellular neutral amino acids, so lysine leaves the cell.

transport_pool

the enterocyte interior Exchanges intracellular cationic amino acids including lysine for extracellular neutral amino acids, so lysine leaves the cell.

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 34–42

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human/mouse heterodimer expression and exchange assays · source_derived_draft · unverified_draft

### basolateral-lysine-exchange SLC7A7-SLC3A2 exchanges intracellular cationic amino acids including lysine for extracellular neutral amino acids with sodium. Plain language: This route helps lysine leave epithelial cells toward blood. Condition category: normal organism: Homo sapiens tissue_or_cell_type: Basolateral intestinal and renal epithelial membranes experimental_model: Human/mouse heterodimer expression and exchange assays limitations: Neutral-substrate transport is sodium-dependent; lysine binding itself should not be mislabeled a sodium cotransport step. [pfeiffer1999yl] Amino acid transport of y+L-type by heterodimers of 4F2hc/CD98 and members of the glycoprotein-associated amino acid transporter family. (1999). https://pubmed.ncbi.nlm.nih.gov/9878049/ DOI: 10.1093/emboj/18.1.49

experimental_model

Randomized parallel trial in 45 healthy young men comparing 20 g high-glycation milk protein plus 2 g free leucine, 20 g low-glycation milk protein plus 2 g free leucine, and noncaloric placebo

limitations

Both protein arms included 2 g free leucine. Processing-related protein modification was manipulated; this was not a free-lysine supplementation or anti-glycation treatment trial.

organism

Homo sapiens

plain_language

Chemical modification of food protein changed how much lysine appeared in circulation.

primary_references

[vanlieshout2025] Milk Protein Glycation Compromises Postprandial Lysine Bioavailability but does not Modulate Postprandial Muscle Protein Synthesis Rates In Vivo in Males: A Double-blind, Randomized Parallel Trial (2025). https://pmc.ncbi.nlm.nih.gov/articles/PMC12308134/ DOI: 10.1016/j.tjnut.2025.05.032

tissue_or_cell_type

Blood after feeding

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 799–807

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized parallel trial in 45 healthy young men comparing 20 g high-glycation milk protein plus 2 g free leucine, 20 g low-glycation milk protein plus 2 g free leucine, and noncaloric placebo · source_derived_draft · unverified_draft

### milk-glycation-lysine-availability After resistance exercise, 20 g highly glycated milk protein yielded lower six-hour plasma lysine availability than less glycated protein in young men; both protein arms also received 2 g free leucine. Plain language: Chemical modification of food protein changed how much lysine appeared in circulation. Condition category: normal organism: Homo sapiens tissue_or_cell_type: Blood after feeding experimental_model: Randomized parallel trial in 45 healthy young men comparing 20 g high-glycation milk protein plus 2 g free leucine, 20 g low-glycation milk protein plus 2 g free leucine, and noncaloric placebo limitations: Both protein arms included 2 g free leucine. Processing-related protein modification was manipulated; this was not a free-lysine supplementation or anti-glycation treatment trial. [vanlieshout2025] Milk Protein Glycation Compromises Postprandial Lysine Bioavailability but does not Modulate Postprandial Muscle Protein Synthesis Rates In Vivo in Males: A Double-blind, Randomized Parallel Trial (2025). https://pmc.ncbi.nlm.nih.gov/articles/PMC12308134/ DOI: 10.1016/j.tjnut.2025.05.032

experimental_model

Randomized parallel trial in 45 healthy young men comparing 20 g high-glycation milk protein plus 2 g free leucine, 20 g low-glycation milk protein plus 2 g free leucine, and noncaloric placebo

limitations

Both protein arms included 2 g free leucine. Acute muscle synthesis rates were 0.059, 0.061, and 0.061 percent per hour for low-glycation, high-glycation, and placebo groups respectively; no significant treatment separation (P=0.939). This null is not proof of equivalence or long-term irrelevance.

organism

Homo sapiens

plain_language

A changed blood nutrient measurement did not translate into a detectable synthesis difference in this experiment.

primary_references

[vanlieshout2025] Milk Protein Glycation Compromises Postprandial Lysine Bioavailability but does not Modulate Postprandial Muscle Protein Synthesis Rates In Vivo in Males: A Double-blind, Randomized Parallel Trial (2025). https://pmc.ncbi.nlm.nih.gov/articles/PMC12308134/ DOI: 10.1016/j.tjnut.2025.05.032

tissue_or_cell_type

Skeletal muscle

L-Lysine: mechanism-first literature curation (2026-09-17) · lines 809–817

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized parallel trial in 45 healthy young men comparing 20 g high-glycation milk protein plus 2 g free leucine, 20 g low-glycation milk protein plus 2 g free leucine, and noncaloric placebo · source_derived_draft · unverified_draft

### milk-glycation-muscle-synthesis-null Six-hour postexercise muscle protein synthesis showed no significant difference among high-glycation milk protein plus 2 g free leucine, low-glycation milk protein plus 2 g free leucine, and noncaloric placebo groups (P=0.939). Plain language: A changed blood nutrient measurement did not translate into a detectable synthesis difference in this experiment. Condition category: normal organism: Homo sapiens tissue_or_cell_type: Skeletal muscle experimental_model: Randomized parallel trial in 45 healthy young men comparing 20 g high-glycation milk protein plus 2 g free leucine, 20 g low-glycation milk protein plus 2 g free leucine, and noncaloric placebo limitations: Both protein arms included 2 g free leucine. Acute muscle synthesis rates were 0.059, 0.061, and 0.061 percent per hour for low-glycation, high-glycation, and placebo groups respectively; no significant treatment separation (P=0.939). This null is not proof of equivalence or long-term irrelevance. [vanlieshout2025] Milk Protein Glycation Compromises Postprandial Lysine Bioavailability but does not Modulate Postprandial Muscle Protein Synthesis Rates In Vivo in Males: A Double-blind, Randomized Parallel Trial (2025). https://pmc.ncbi.nlm.nih.gov/articles/PMC12308134/ DOI: 10.1016/j.tjnut.2025.05.032

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

evidence_access

Primary abstract

experimental_model

Lysosomal transport and mammalian-cell experiments.

limitations

This is a compartment-specific mechanism, not a demonstrated arginine–leucine supplement synergy.

nutrient_topic

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

plain_language

Arginine sensing helps make another amino acid available to the cell.

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 206–212

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Lysosomal transport and mammalian-cell experiments. · source_derived_draft · unverified_draft

## arg-lysosome-leucine Arginine sensing helps make another amino acid available to the cell. SLC38A9 mediated arginine-regulated export of essential amino acids, including leucine, from lysosomes. Model: Lysosomal transport and mammalian-cell experiments. Limitations: This is a compartment-specific mechanism, not a demonstrated arginine–leucine supplement synergy. 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