L-Isoleucine

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

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

evidence_access

Primary abstract

experimental_model

Epithelial expression study; precise species/construct not resolved in accessed abstract.

limitations

A pattern-recognition receptor was hypothesized, not identified; not clinical immunity enhancement.

nutrient_topic

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

plain_language

The free amino acid can act as a signal in an epithelial model.

primary_references

An essential amino acid induces epithelial beta -defensin expression. · 2000 · https://pubmed.ncbi.nlm.nih.gov/11058160/ · DOI 10.1073/pnas.220424597

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Epithelial expression study; precise species/construct not resolved in accessed abstract. · source_derived_draft · unverified_draft

## isoleucine-epithelial-defensin The free amino acid can act as a signal in an epithelial model. L-isoleucine and selected analogs induced epithelial beta-defensin transcription with NF-kappaB/Rel activation in the study assays. Model: Epithelial expression study; precise species/construct not resolved in accessed abstract. Limitations: A pattern-recognition receptor was hypothesized, not identified; not clinical immunity enhancement. Evidence access: Primary abstract An essential amino acid induces epithelial beta -defensin expression. · 2000 · https://pubmed.ncbi.nlm.nih.gov/11058160/ · DOI 10.1073/pnas.220424597

evidence_access

Primary full text

experimental_model

Human A549 cells; reported peak L-form response at 25 micrograms/mL for eighteen hours.

limitations

Cancer-derived cell line and defined exposure; not a demonstrated dietary effect in human airways.

nutrient_topic

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

plain_language

Chirality mattered in the airway-cell experiment.

primary_references

Induction of β-defensins by l-isoleucine as novel immunotherapy in experimental murine tuberculosis. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21235540/ · DOI 10.1111/j.1365-2249.2010.04313.x

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 442–448

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human A549 cells; reported peak L-form response at 25 micrograms/mL for eighteen hours. · source_derived_draft · unverified_draft

## isoleucine-human-airway-defensin Chirality mattered in the airway-cell experiment. L-isoleucine induced human beta-defensin-2 expression in A549 cells; the D-isoleucine comparison did not reproduce induction. Model: Human A549 cells; reported peak L-form response at 25 micrograms/mL for eighteen hours. Limitations: Cancer-derived cell line and defined exposure; not a demonstrated dietary effect in human airways. Evidence access: Primary full text Induction of β-defensins by l-isoleucine as novel immunotherapy in experimental murine tuberculosis. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21235540/ · DOI 10.1111/j.1365-2249.2010.04313.x

evidence_access

Primary full text

experimental_model

Human food-frequency/dietary observational analysis.

limitations

Diet reporting, other dietary components and reverse causation can affect the result.

nutrient_topic

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

plain_language

The human evidence here is an association, not a restriction trial.

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

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human food-frequency/dietary observational analysis. · source_derived_draft · unverified_draft

## isoleucine-human-diet-association The human evidence here is an association, not a restriction trial. Higher dietary isoleucine content was associated with higher BMI in the study human dietary analysis. Model: Human food-frequency/dietary observational analysis. Limitations: Diet reporting, other dietary components and reverse causation can affect the result. 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 abstract

experimental_model

Uncontrolled human case series with preclinical patient-cell testing; multiple different ARS disorders.

limitations

Do not attribute every pooled outcome to IARS or generalize to all IARS variants; not a randomized trial.

nutrient_topic

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

plain_language

Some residual-function disorders may respond to carefully selected substrate support.

primary_references

Treatment of ARS deficiencies with specific amino acids. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34194004/ · DOI 10.1038/s41436-021-01249-z

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 138–144

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Uncontrolled human case series with preclinical patient-cell testing; multiple different ARS disorders. · source_derived_draft · unverified_draft

## isoleucine-iars-clinical-supplement Some residual-function disorders may respond to carefully selected substrate support. The IARS patients within a small personalized ARS-treatment series received cognate amino-acid supplementation and showed reported clinical benefit during follow-up. Model: Uncontrolled human case series with preclinical patient-cell testing; multiple different ARS disorders. Limitations: Do not attribute every pooled outcome to IARS or generalize to all IARS variants; not a randomized trial. Evidence access: Primary abstract Treatment of ARS deficiencies with specific amino acids. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34194004/ · DOI 10.1038/s41436-021-01249-z

evidence_access

Primary full text

experimental_model

BALB/c mice treated after sixty days of H37Rv or MDR-isolate infection.

limitations

Route is intratracheal, not oral nutrition; does not establish a substitute for human antimicrobial treatment.

nutrient_topic

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

plain_language

Local airway delivery changed innate-defense expression in infected mice.

primary_references

Induction of β-defensins by l-isoleucine as novel immunotherapy in experimental murine tuberculosis. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21235540/ · DOI 10.1111/j.1365-2249.2010.04313.x

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 450–456

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · BALB/c mice treated after sixty days of H37Rv or MDR-isolate infection. · source_derived_draft · unverified_draft

## isoleucine-mouse-tb-defensin Local airway delivery changed innate-defense expression in infected mice. Intratracheal isoleucine at 250 micrograms every forty-eight hours increased beta-defensins 3/4 in mice with established pulmonary tuberculosis. Model: BALB/c mice treated after sixty days of H37Rv or MDR-isolate infection. Limitations: Route is intratracheal, not oral nutrition; does not establish a substitute for human antimicrobial treatment. Evidence access: Primary full text Induction of β-defensins by l-isoleucine as novel immunotherapy in experimental murine tuberculosis. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21235540/ · DOI 10.1111/j.1365-2249.2010.04313.x

evidence_access

Primary full text

experimental_model

Mouse progressive pulmonary tuberculosis; 250 micrograms intratracheally every forty-eight hours.

limitations

No defensin-specific genetic rescue demonstrated exclusive mediation; human efficacy not tested.

nutrient_topic

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

plain_language

The animal study measured infection outcomes as well as gene expression.

primary_references

Induction of β-defensins by l-isoleucine as novel immunotherapy in experimental murine tuberculosis. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21235540/ · DOI 10.1111/j.1365-2249.2010.04313.x

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 458–464

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse progressive pulmonary tuberculosis; 250 micrograms intratracheally every forty-eight hours. · source_derived_draft · unverified_draft

## isoleucine-mouse-tb-outcome The animal study measured infection outcomes as well as gene expression. The same local isoleucine regimen reduced lung bacillary load and tissue injury alongside defensin induction. Model: Mouse progressive pulmonary tuberculosis; 250 micrograms intratracheally every forty-eight hours. Limitations: No defensin-specific genetic rescue demonstrated exclusive mediation; human efficacy not tested. Evidence access: Primary full text Induction of β-defensins by l-isoleucine as novel immunotherapy in experimental murine tuberculosis. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21235540/ · DOI 10.1111/j.1365-2249.2010.04313.x

evidence_access

Primary abstract

experimental_model

Mouse C2C12 cells; millimolar amino-acid exposures.

limitations

Insulin-free culture is not proof of insulin independence in all intact organisms.

nutrient_topic

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

plain_language

Muscle cells responded without added insulin in this experiment.

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 346–352

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse C2C12 cells; millimolar amino-acid exposures. · source_derived_draft · unverified_draft

## isoleucine-myotube-glucose Muscle cells responded without added insulin in this experiment. Isoleucine at 1-10 mM increased 2-deoxyglucose uptake in insulin-free C2C12 myotube assays. Model: Mouse C2C12 cells; millimolar amino-acid exposures. Limitations: Insulin-free culture is not proof of insulin independence in all intact organisms. 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

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

evidence_access

Primary abstract

experimental_model

SILEC-SF fractionation/tracing; specific cell lines and exposure not resolved in accessed abstract.

limitations

Not a claim that all tissues use the same carbon source or that oral isoleucine controls human gene expression.

nutrient_topic

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

plain_language

An amino-acid carbon skeleton can reach a chromatin modification.

primary_references

Quantitative subcellular acyl-CoA analysis reveals distinct nuclear metabolism and isoleucine-dependent histone propionylation. · 2022 · https://pubmed.ncbi.nlm.nih.gov/34856123/ · DOI 10.1016/j.molcel.2021.11.006

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 466–472

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · SILEC-SF fractionation/tracing; specific cell lines and exposure not resolved in accessed abstract. · source_derived_draft · unverified_draft

## isoleucine-nuclear-propionyl An amino-acid carbon skeleton can reach a chromatin modification. Isotope tracing and controlled subcellular acyl-CoA measurement identified isoleucine as a major source of nuclear propionyl-CoA and histone propionyl groups in the tested cells. Model: SILEC-SF fractionation/tracing; specific cell lines and exposure not resolved in accessed abstract. Limitations: Not a claim that all tissues use the same carbon source or that oral isoleucine controls human gene expression. Evidence access: Primary abstract Quantitative subcellular acyl-CoA analysis reveals distinct nuclear metabolism and isoleucine-dependent histone propionylation. · 2022 · https://pubmed.ncbi.nlm.nih.gov/34856123/ · DOI 10.1016/j.molcel.2021.11.006

evidence_access

Primary preprint full text; not peer reviewed

experimental_model

Mouse KPC2838c3/KPC6419c5 and human MIA-PaCa-2, Panc-1, HPAC and patient-derived cells.

limitations

Primary preprint, not peer reviewed; fractional tracer contribution is not absolute pathway flux.

nutrient_topic

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

plain_language

Cancer-cell carbon allocation favored one branch of the pathway.

primary_references

A nuclear branched-chain amino acid catabolism pathway controls histone propionylation in pancreatic cancer. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40568091/ · DOI 10.1101/2025.04.23.650241

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 474–480

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse KPC2838c3/KPC6419c5 and human MIA-PaCa-2, Panc-1, HPAC and patient-derived cells. · source_derived_draft · unverified_draft

## isoleucine-pancreatic-preprint-flux Cancer-cell carbon allocation favored one branch of the pathway. A pancreatic-cancer preprint traced isoleucine carbon prominently into propionyl-CoA in mouse KPC and human PDA cell lines, with smaller contributions to acetyl-CoA/succinyl-CoA in those assays. Model: Mouse KPC2838c3/KPC6419c5 and human MIA-PaCa-2, Panc-1, HPAC and patient-derived cells. Limitations: Primary preprint, not peer reviewed; fractional tracer contribution is not absolute pathway flux. Evidence access: Primary preprint full text; not peer reviewed A nuclear branched-chain amino acid catabolism pathway controls histone propionylation in pancreatic cancer. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40568091/ · DOI 10.1101/2025.04.23.650241

evidence_access

Primary abstract

experimental_model

Prostate-cancer cell and tumor models; detailed species/exposure unresolved in accessed abstract.

limitations

Not proof that dietary intake causes prostate cancer or that restriction treats patients.

nutrient_topic

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

plain_language

Two amino-acid branches converged on the same signaling metabolite.

primary_references

Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol metabolism. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42625032/ · DOI 10.1038/s42255-026-01583-z

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 498–504

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Prostate-cancer cell and tumor models; detailed species/exposure unresolved in accessed abstract. · source_derived_draft · unverified_draft

## isoleucine-prostate-carbon Two amino-acid branches converged on the same signaling metabolite. A 2026 prostate-cancer study identified isoleucine and valine catabolism as major sources of intracellular propionyl-CoA in its experimental models. Model: Prostate-cancer cell and tumor models; detailed species/exposure unresolved in accessed abstract. Limitations: Not proof that dietary intake causes prostate cancer or that restriction treats patients. Evidence access: Primary abstract Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol metabolism. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42625032/ · DOI 10.1038/s42255-026-01583-z

evidence_access

Primary abstract

experimental_model

Rat oral exposure and tissue tracer/kinase assays; dose not resolved in accessed abstract.

limitations

Acute food-deprived rat context, not a human dose-response or long-term outcome.

nutrient_topic

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

plain_language

Glucose uptake increased without the often-assumed AMPK activation.

primary_references

Isoleucine, a blood glucose-lowering amino acid, increases glucose uptake in rat skeletal muscle in the absence of increases in AMP-activated protein kinase activity. · 2005 · https://pubmed.ncbi.nlm.nih.gov/16140883/ · DOI 10.1093/jn/135.9.2103

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat oral exposure and tissue tracer/kinase assays; dose not resolved in accessed abstract. · source_derived_draft · unverified_draft

## isoleucine-rat-ampk-boundary Glucose uptake increased without the often-assumed AMPK activation. Oral isoleucine increased tracer-measured muscle glucose uptake by 73% in food-deprived rats without increased AMPK activity; AMPK-alpha2 activity decreased. Model: Rat oral exposure and tissue tracer/kinase assays; dose not resolved in accessed abstract. Limitations: Acute food-deprived rat context, not a human dose-response or long-term outcome. Evidence access: Primary abstract Isoleucine, a blood glucose-lowering amino acid, increases glucose uptake in rat skeletal muscle in the absence of increases in AMP-activated protein kinase activity. · 2005 · https://pubmed.ncbi.nlm.nih.gov/16140883/ · DOI 10.1093/jn/135.9.2103

cross_nutrient

true

evidence_location

Full text Results; Figures 6-8 and isotope model

experimental_model

Differentiated mouse 3T3-L1 adipocytes

exposure

24-hour [U-13C]isoleucine tracing

limitations

Mouse cell culture; isotope labeling and model assumptions do not establish human dietary carbon fractions.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Mus musculus

plain_language

Mouse fat-cell tracing identified isoleucine as another source of the B12-pathway precursor.

primary_references

[crown-2015-bcaa-fatty-acids] Catabolism of Branched Chain Amino Acids Contributes Significantly to Synthesis of Odd-Chain and Even-Chain Fatty Acids in 3T3-L1 Adipocytes. (2015). https://pubmed.ncbi.nlm.nih.gov/26710334/ DOI: 10.1371/journal.pone.0145850

tissue_or_cell_type

Adipocytes

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1230–1242

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Differentiated mouse 3T3-L1 adipocytes · source_derived_draft · unverified_draft

### isoleucine-propionyl-coa-lipogenesis Carbon-13 isoleucine supplied lipogenic propionyl-CoA in cultured 3T3-L1 adipocytes. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Mouse fat-cell tracing identified isoleucine as another source of the B12-pathway precursor. organism: Mus musculus tissue_or_cell_type: Adipocytes experimental_model: Differentiated mouse 3T3-L1 adipocytes limitations: Mouse cell culture; isotope labeling and model assumptions do not establish human dietary carbon fractions. exposure: 24-hour [U-13C]isoleucine tracing cross_nutrient: true evidence_location: Full text Results; Figures 6-8 and isotope model [crown-2015-bcaa-fatty-acids] Catabolism of Branched Chain Amino Acids Contributes Significantly to Synthesis of Odd-Chain and Even-Chain Fatty Acids in 3T3-L1 Adipocytes. (2015). https://pubmed.ncbi.nlm.nih.gov/26710334/ DOI: 10.1371/journal.pone.0145850

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human patient fibroblast assays plus expression validation.

limitations

Single-patient mechanistic discovery does not determine severity for all screen-detected variants.

nutrient_topic

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

plain_language

A breakdown block can be detected through an alternative excreted product.

primary_references

Isolated 2-methylbutyrylglycinuria caused by short/branched-chain acyl-CoA dehydrogenase deficiency: identification of a new enzyme defect, resolution of its molecular basis, and evidence for distinct acyl-CoA dehydrogenases in isoleucine and valine metabolism. · 2000 · https://pubmed.ncbi.nlm.nih.gov/11013134/ · DOI 10.1086/303105

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism 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 fibroblast assays plus expression validation. · source_derived_draft · unverified_draft

## isoleucine-acadsb-loss A breakdown block can be detected through an alternative excreted product. An ACADSB splice defect caused exon skipping, impaired 2-methylbutyryl-CoA oxidation and isolated 2-methylbutyrylglycinuria in the reported patient. Model: Human patient fibroblast assays plus expression validation. Limitations: Single-patient mechanistic discovery does not determine severity for all screen-detected variants. Evidence access: Primary abstract Isolated 2-methylbutyrylglycinuria caused by short/branched-chain acyl-CoA dehydrogenase deficiency: identification of a new enzyme defect, resolution of its molecular basis, and evidence for distinct acyl-CoA dehydrogenases in isoleucine and valine metabolism. · 2000 · https://pubmed.ncbi.nlm.nih.gov/11013134/ · DOI 10.1086/303105

evidence_access

Primary abstract

experimental_model

Human fibroblasts, sequence analysis and recombinant expression.

limitations

Does not make ACADSB and ACAD8 interchangeable.

nutrient_topic

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

plain_language

Isoleucine and valine split into different enzyme routes after their shared early steps.

primary_references

Isolated 2-methylbutyrylglycinuria caused by short/branched-chain acyl-CoA dehydrogenase deficiency: identification of a new enzyme defect, resolution of its molecular basis, and evidence for distinct acyl-CoA dehydrogenases in isoleucine and valine metabolism. · 2000 · https://pubmed.ncbi.nlm.nih.gov/11013134/ · DOI 10.1086/303105

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 178–184

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human fibroblasts, sequence analysis and recombinant expression. · source_derived_draft · unverified_draft

## isoleucine-acadsb-reaction Isoleucine and valine split into different enzyme routes after their shared early steps. Human ACADSB supported oxidation of 2-methylbutyryl-CoA; patient fibroblast assays and expression studies distinguished this isoleucine enzyme from valine-related ACAD8. Model: Human fibroblasts, sequence analysis and recombinant expression. Limitations: Does not make ACADSB and ACAD8 interchangeable. Evidence access: Primary abstract Isolated 2-methylbutyrylglycinuria caused by short/branched-chain acyl-CoA dehydrogenase deficiency: identification of a new enzyme defect, resolution of its molecular basis, and evidence for distinct acyl-CoA dehydrogenases in isoleucine and valine metabolism. · 2000 · https://pubmed.ncbi.nlm.nih.gov/11013134/ · DOI 10.1086/303105

evidence_access

Primary abstract

experimental_model

Human T2 crystallography.

limitations

Binding-site evidence does not establish dietary chloride limitation or clinical repletion effects.

nutrient_topic

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

plain_language

A second ion occupies a structural site in the same enzyme.

primary_references

Crystallographic and kinetic studies of human mitochondrial acetoacetyl-CoA thiolase: the importance of potassium and chloride ions for its structure and function. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17371050/ · DOI 10.1021/bi6026192

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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human T2 crystallography. · source_derived_draft · unverified_draft

## isoleucine-acat1-chloride A second ion occupies a structural site in the same enzyme. Human T2 structures identified a copurified chloride ion at a high-affinity site near catalytic loops at the dimer interface. Model: Human T2 crystallography. Limitations: Binding-site evidence does not establish dietary chloride limitation or clinical repletion effects. Evidence access: Primary abstract Crystallographic and kinetic studies of human mitochondrial acetoacetyl-CoA thiolase: the importance of potassium and chloride ions for its structure and function. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17371050/ · DOI 10.1021/bi6026192

evidence_access

Primary abstract

experimental_model

Purified human enzyme and potassium-bound structures.

limitations

Assay activation is not proof that extra potassium accelerates isoleucine breakdown in a potassium-replete person.

nutrient_topic

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

plain_language

Potassium changed the activity of an enzyme shared by isoleucine and ketone processing.

primary_references

Crystallographic and kinetic studies of human mitochondrial acetoacetyl-CoA thiolase: the importance of potassium and chloride ions for its structure and function. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17371050/ · DOI 10.1021/bi6026192

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 234–240

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human enzyme and potassium-bound structures. · source_derived_draft · unverified_draft

## isoleucine-acat1-potassium Potassium changed the activity of an enzyme shared by isoleucine and ketone processing. Increasing KCl from 0 to 40 mM increased purified human T2 turnover approximately threefold for both acetoacetyl-CoA and 2-methylacetoacetyl-CoA. Model: Purified human enzyme and potassium-bound structures. Limitations: Assay activation is not proof that extra potassium accelerates isoleucine breakdown in a potassium-replete person. Evidence access: Primary abstract Crystallographic and kinetic studies of human mitochondrial acetoacetyl-CoA thiolase: the importance of potassium and chloride ions for its structure and function. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17371050/ · DOI 10.1021/bi6026192

evidence_access

Primary abstract

experimental_model

Purified human T2 structural/kinetic study; established product chemistry.

limitations

ACAT1 here is acetyl-CoA acetyltransferase, not the cholesterol-esterifying SOAT1 enzyme sometimes called ACAT.

nutrient_topic

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

plain_language

One carbon skeleton feeds both an acetyl branch and a propionyl branch.

primary_references

Crystallographic and kinetic studies of human mitochondrial acetoacetyl-CoA thiolase: the importance of potassium and chloride ions for its structure and function. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17371050/ · DOI 10.1021/bi6026192

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 226–232

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human T2 structural/kinetic study; established product chemistry. · source_derived_draft · unverified_draft

## isoleucine-acat1-split One carbon skeleton feeds both an acetyl branch and a propionyl branch. Human mitochondrial ACAT1/T2 degraded 2-methylacetoacetyl-CoA by CoA-dependent thiolysis, yielding the isoleucine-branch acetyl-CoA and propionyl-CoA products. Model: Purified human T2 structural/kinetic study; established product chemistry. Limitations: ACAT1 here is acetyl-CoA acetyltransferase, not the cholesterol-esterifying SOAT1 enzyme sometimes called ACAT. Evidence access: Primary abstract Crystallographic and kinetic studies of human mitochondrial acetoacetyl-CoA thiolase: the importance of potassium and chloride ions for its structure and function. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17371050/ · DOI 10.1021/bi6026192

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

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

evidence_access

Primary abstract; reaction-intermediate structural study

experimental_model

Human BCAT2 intermediate structures and established reaction chemistry.

limitations

Reversible enzyme chemistry; concentration and compartment determine net flux.

nutrient_topic

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

plain_language

The first breakdown step passes nitrogen to another metabolite.

primary_references

Crystal structures of human mitochondrial branched chain aminotransferase reaction intermediates: ketimine and pyridoxamine phosphate forms. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12269802/ · DOI 10.1021/bi020221c

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 162–168

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human BCAT2 intermediate structures and established reaction chemistry. · source_derived_draft · unverified_draft

## isoleucine-bcat-reaction The first breakdown step passes nitrogen to another metabolite. Human BCAT2 transfers the isoleucine amino group through the PLP/PMP cycle, linking isoleucine/branched ketoacid interconversion to 2-oxoglutarate/glutamate. Model: Human BCAT2 intermediate structures and established reaction chemistry. Limitations: Reversible enzyme chemistry; concentration and compartment determine net flux. Evidence access: Primary abstract; reaction-intermediate structural study Crystal structures of human mitochondrial branched chain aminotransferase reaction intermediates: ketimine and pyridoxamine phosphate forms. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12269802/ · DOI 10.1021/bi020221c

evidence_access

Primary full text, pathway background

experimental_model

Established pathway shown in a human ECHS1 disease/biochemistry study; not a new BCKDH assay in that paper.

limitations

Cofactor and catalytic evidence is separately linked from existing ThDP/DLD records.

nutrient_topic

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

plain_language

A shared BCAA enzyme commits the carbon skeleton to further breakdown.

primary_references

Clinical and biochemical characterization of four patients with mutations in ECHS1. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26081110/ · DOI 10.1186/s13023-015-0290-1

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 170–176

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Established pathway shown in a human ECHS1 disease/biochemistry study; not a new BCKDH assay in that paper. · source_derived_draft · unverified_draft

## isoleucine-bckdh-carbon-step A shared BCAA enzyme commits the carbon skeleton to further breakdown. The isoleucine pathway in the primary biochemical study places BCKDH-mediated oxidative decarboxylation of the branched ketoacid upstream of 2-methylbutyryl-CoA. Model: Established pathway shown in a human ECHS1 disease/biochemistry study; not a new BCKDH assay in that paper. Limitations: Cofactor and catalytic evidence is separately linked from existing ThDP/DLD records. Evidence access: Primary full text, pathway background Clinical and biochemical characterization of four patients with mutations in ECHS1. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26081110/ · DOI 10.1186/s13023-015-0290-1

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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Six-patient human clinical and molecular study.

limitations

Small series; the suggested neurosteroid explanation was not experimentally proven by these comparisons.

nutrient_topic

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

plain_language

Similar metabolite readings can arise from different machinery failures.

primary_references

Clinical and molecular analysis of 6 Chinese patients with isoleucine metabolism defects: identification of 3 novel mutations in the HSD17B10 and ACAT1 gene. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28875337/ · DOI 10.1007/s11011-017-0097-y

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 250–256

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Six-patient human clinical and molecular study. · source_derived_draft · unverified_draft

## isoleucine-catabolic-differential Similar metabolite readings can arise from different machinery failures. Two HSD10 and four ACAT1 deficiency cases shared elevated 2-methyl-3-hydroxybutyrate/tiglylglycine patterns but had different clinical courses. Model: Six-patient human clinical and molecular study. Limitations: Small series; the suggested neurosteroid explanation was not experimentally proven by these comparisons. Evidence access: Primary abstract Clinical and molecular analysis of 6 Chinese patients with isoleucine metabolism defects: identification of 3 novel mutations in the HSD17B10 and ACAT1 gene. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28875337/ · DOI 10.1007/s11011-017-0097-y

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Four-patient biochemical study with tissue enzyme comparisons.

limitations

Does not establish the same backup capacity in every cell type.

nutrient_topic

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

plain_language

A pathway diagram alone can overstate an enzyme as an unavoidable gate.

primary_references

Clinical and biochemical characterization of four patients with mutations in ECHS1. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26081110/ · DOI 10.1186/s13023-015-0290-1

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 202–208

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Four-patient biochemical study with tissue enzyme comparisons. · source_derived_draft · unverified_draft

## isoleucine-echs1-boundary A pathway diagram alone can overstate an enzyme as an unavoidable gate. ECHS1-deficient patients showed a dominant valine-metabolism defect rather than the expected isolated isoleucine block; liver retained tiglyl-CoA hydration capacity. Model: Four-patient biochemical study with tissue enzyme comparisons. Limitations: Does not establish the same backup capacity in every cell type. Evidence access: Primary full text Clinical and biochemical characterization of four patients with mutations in ECHS1. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26081110/ · DOI 10.1186/s13023-015-0290-1

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse conditional knockout; PGE2 1.4 micrograms per mouse; valine oxidation readout.

limitations

Not an isoleucine-specific tracer result or a supplement treatment for fever.

nutrient_topic

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

plain_language

The shared mitochondrial gate mattered during a defined fever response.

primary_references

Metabolic flexibility via mitochondrial BCAA carrier SLC25A44 is required for optimal fever. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33944778/ · DOI 10.7554/eLife.66865

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 74–80

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse conditional knockout; PGE2 1.4 micrograms per mouse; valine oxidation readout. · source_derived_draft · unverified_draft

## isoleucine-fever-carrier The shared mitochondrial gate mattered during a defined fever response. BAT-specific Slc25a44 deletion blunted BCAA oxidation and non-shivering thermogenesis following intracerebroventricular PGE2. Model: Mouse conditional knockout; PGE2 1.4 micrograms per mouse; valine oxidation readout. Limitations: Not an isoleucine-specific tracer result or a supplement treatment for fever. Evidence access: Primary full text Metabolic flexibility via mitochondrial BCAA carrier SLC25A44 is required for optimal fever. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33944778/ · DOI 10.7554/eLife.66865

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human transporter variants in Xenopus oocytes with mouse ACE2 or human collectrin.

limitations

Mixed-species expression system; not a direct measurement of each patient intestine or kidney.

nutrient_topic

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

plain_language

The same transporter mutation can behave differently with different helper proteins.

primary_references

Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with hartnup mutations. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19185582/ · DOI 10.1053/j.gastro.2008.10.055

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 34–40

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human transporter variants in Xenopus oocytes with mouse ACE2 or human collectrin. · source_derived_draft · unverified_draft

## isoleucine-hartnup-partners The same transporter mutation can behave differently with different helper proteins. Human B0AT1 D173N and P265L variants retained activation by coexpressed mouse ACE2 but not human collectrin; A69T and R240Q were not activated by either partner. Model: Human transporter variants in Xenopus oocytes with mouse ACE2 or human collectrin. Limitations: Mixed-species expression system; not a direct measurement of each patient intestine or kidney. Evidence access: Primary full text Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with hartnup mutations. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19185582/ · DOI 10.1053/j.gastro.2008.10.055

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse-derived cells and separate Xenopus embryo experiments; human clinical activity comparisons.

limitations

Does not justify treating the entire HSD10 disorder by restricting isoleucine.

nutrient_topic

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

plain_language

A protein can be essential even when its named metabolic reaction is not the relevant failure.

primary_references

A non-enzymatic function of 17beta-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20077426/ · DOI 10.1002/emmm.200900055

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 218–224

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse-derived cells and separate Xenopus embryo experiments; human clinical activity comparisons. · source_derived_draft · unverified_draft

## isoleucine-hsd10-noncatabolic A protein can be essential even when its named metabolic reaction is not the relevant failure. Loss and rescue experiments in conditional mouse-derived cells showed an HSD10 property independent of dehydrogenase activity was required for mitochondrial integrity and cell survival. Model: Mouse-derived cells and separate Xenopus embryo experiments; human clinical activity comparisons. Limitations: Does not justify treating the entire HSD10 disorder by restricting isoleucine. Evidence access: Primary abstract A non-enzymatic function of 17beta-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20077426/ · DOI 10.1002/emmm.200900055

evidence_access

Primary abstract

experimental_model

Established biochemical function in a primary loss-of-function/rescue study.

limitations

The protein also has essential functions beyond this reaction; metabolic activity alone does not explain its disease phenotype.

nutrient_topic

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

plain_language

Another enzyme changes the intermediate before the final carbon split.

primary_references

A non-enzymatic function of 17beta-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20077426/ · DOI 10.1002/emmm.200900055

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 210–216

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Established biochemical function in a primary loss-of-function/rescue study. · source_derived_draft · unverified_draft

## isoleucine-hsd10-reaction Another enzyme changes the intermediate before the final carbon split. HSD17B10 encodes the 2-methyl-3-hydroxybutyryl-CoA dehydrogenase step of isoleucine metabolism. Model: Established biochemical function in a primary loss-of-function/rescue study. Limitations: The protein also has essential functions beyond this reaction; metabolic activity alone does not explain its disease phenotype. Evidence access: Primary abstract A non-enzymatic function of 17beta-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20077426/ · DOI 10.1002/emmm.200900055

evidence_access

Primary full text

experimental_model

Human cold-exposure BAT samples; expression correlations.

limitations

Observational expression evidence, not transporter gene manipulation or proof of isoleucine-specific clearance in humans.

nutrient_topic

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

plain_language

Human tissue showed a coordinated change in the shared catabolic system.

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

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 58–64

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cold-exposure BAT samples; expression correlations. · source_derived_draft · unverified_draft

## isoleucine-human-bat-carrier Human tissue showed a coordinated change in the shared catabolic system. Human supraclavicular BAT SLC25A44 mRNA increased after cold exposure and correlated with UCP1 and BCKDHA expression. Model: Human cold-exposure BAT samples; expression correlations. Limitations: Observational expression evidence, not transporter gene manipulation or proof of isoleucine-specific clearance in humans. 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 full text

experimental_model

Human IARS1/tRNA assays and primary human fibroblasts.

limitations

Reaction role is distinct from the study-specific shortage substitution experiments.

nutrient_topic

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

plain_language

A charging enzyme links free isoleucine to protein synthesis.

primary_references

Isoleucine-to-valine substitutions support cellular physiology during isoleucine deprivation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39657787/ · DOI 10.1093/nar/gkae1184

L-Isoleucine: transport, translation, catabolism 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 · Human IARS1/tRNA assays and primary human fibroblasts. · source_derived_draft · unverified_draft

## isoleucine-iars-charging A charging enzyme links free isoleucine to protein synthesis. Human IARS1 aminoacylates tRNA-Ile with isoleucine for cytosolic translation; purified-protein aminoacylation assays were used to study this reaction. Model: Human IARS1/tRNA assays and primary human fibroblasts. Limitations: Reaction role is distinct from the study-specific shortage substitution experiments. Evidence access: Primary full text Isoleucine-to-valine substitutions support cellular physiology during isoleucine deprivation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39657787/ · DOI 10.1093/nar/gkae1184

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Patient-derived human fibroblasts tested across isoleucine concentrations.

limitations

Do not assign the study temperature sensitivity in LARS/FARSB to IARS without evidence.

nutrient_topic

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

plain_language

Low substrate can expose the limited reserve of a faulty enzyme.

primary_references

Treatment of ARS deficiencies with specific amino acids. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34194004/ · DOI 10.1038/s41436-021-01249-z

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 130–136

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Patient-derived human fibroblasts tested across isoleucine concentrations. · source_derived_draft · unverified_draft

## isoleucine-iars-low-substrate Low substrate can expose the limited reserve of a faulty enzyme. IARS-deficient patient fibroblasts had reduced residual aminoacylation activity and greater growth sensitivity to low isoleucine. Model: Patient-derived human fibroblasts tested across isoleucine concentrations. Limitations: Do not assign the study temperature sensitivity in LARS/FARSB to IARS without evidence. Evidence access: Primary abstract Treatment of ARS deficiencies with specific amino acids. · 2021 · https://pubmed.ncbi.nlm.nih.gov/34194004/ · DOI 10.1038/s41436-021-01249-z

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human family/variant study; yeast functional validation of variants.

limitations

An association and one treatment observation do not establish how IARS dysfunction caused low zinc or that all isoleucine shortages deplete zinc.

nutrient_topic

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

plain_language

A coexisting nutrient shortage was documented in this rare genetic disorder.

primary_references

Biallelic IARS Mutations Cause Growth Retardation with Prenatal Onset, Intellectual Disability, Muscular Hypotonia, and Infantile Hepatopathy. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27426735/ · DOI 10.1016/j.ajhg.2016.05.027

trigger_kind

biomarker_context Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 146–152

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human family/variant study; yeast functional validation of variants. · source_derived_draft · unverified_draft

## isoleucine-iars-zinc-context A coexisting nutrient shortage was documented in this rare genetic disorder. Three individuals with biallelic IARS variants had zinc deficiency; one showed improved growth with zinc supplementation. Model: Human family/variant study; yeast functional validation of variants. Limitations: An association and one treatment observation do not establish how IARS dysfunction caused low zinc or that all isoleucine shortages deplete zinc. Evidence access: Primary abstract Biallelic IARS Mutations Cause Growth Retardation with Prenatal Onset, Intellectual Disability, Muscular Hypotonia, and Infantile Hepatopathy. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27426735/ · DOI 10.1016/j.ajhg.2016.05.027

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human patient lymphocytes and IARS2-knockdown HEK293T cells with genetic rescue.

limitations

No dietary isoleucine rescue was demonstrated. Protein replacement is not equivalent to substrate supplementation.

nutrient_topic

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

plain_language

Mitochondria need their own isoleucine-charging machinery.

primary_references

IARS2 mutations lead to Leigh syndrome with a combined oxidative phosphorylation deficiency. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39169373/ · DOI 10.1186/s13023-024-03310-x

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism 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 patient lymphocytes and IARS2-knockdown HEK293T cells with genetic rescue. · source_derived_draft · unverified_draft

## isoleucine-iars2-respiration Mitochondria need their own isoleucine-charging machinery. IARS2 knockdown and patient variants impaired respiratory complexes I and III; wild-type, but not tested mutant, IARS2 rescued respiration and ATP in knockdown cells. Model: Human patient lymphocytes and IARS2-knockdown HEK293T cells with genetic rescue. Limitations: No dietary isoleucine rescue was demonstrated. Protein replacement is not equivalent to substrate supplementation. Evidence access: Primary abstract IARS2 mutations lead to Leigh syndrome with a combined oxidative phosphorylation deficiency. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39169373/ · DOI 10.1186/s13023-024-03310-x

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Ace2-null mouse intestine; expression, interaction and uptake assays.

limitations

Kidney accessory-protein dependence differs; not evidence that every change in ACE2 produces dietary isoleucine deficiency.

nutrient_topic

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

plain_language

A working transporter also needs its accessory protein in this tissue.

primary_references

Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with hartnup mutations. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19185582/ · DOI 10.1053/j.gastro.2008.10.055

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 26–32

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Ace2-null mouse intestine; expression, interaction and uptake assays. · source_derived_draft · unverified_draft

## isoleucine-intestinal-ace2 A working transporter also needs its accessory protein in this tissue. Ace2 deletion removed intestinal B0AT1 expression and abolished sodium-dependent isoleucine uptake in mouse ileum segments. Model: Ace2-null mouse intestine; expression, interaction and uptake assays. Limitations: Kidney accessory-protein dependence differs; not evidence that every change in ACE2 produces dietary isoleucine deficiency. Evidence access: Primary full text Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with hartnup mutations. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19185582/ · DOI 10.1053/j.gastro.2008.10.055

evidence_access

Primary full text

experimental_model

Everted mouse ileum; 1 mM L-isoleucine, five-minute uptake assay.

limitations

Does not imply extra dietary sodium improves absorption in sodium-replete people.

nutrient_topic

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

plain_language

An ion gradient helps the intestine take up this amino acid.

primary_references

Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with hartnup mutations. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19185582/ · DOI 10.1053/j.gastro.2008.10.055

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 18–24

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Everted mouse ileum; 1 mM L-isoleucine, five-minute uptake assay. · source_derived_draft · unverified_draft

## isoleucine-intestinal-sodium An ion gradient helps the intestine take up this amino acid. Replacing sodium during mouse ileum uptake assays removed the sodium-dependent component of radiolabeled L-isoleucine uptake. Model: Everted mouse ileum; 1 mM L-isoleucine, five-minute uptake assay. Limitations: Does not imply extra dietary sodium improves absorption in sodium-replete people. Evidence access: Primary full text Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with hartnup mutations. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19185582/ · DOI 10.1053/j.gastro.2008.10.055

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 abstract

experimental_model

Aged male and female C57BL/6J.Nia mice.

limitations

Not evidence that severe restriction is desirable in older humans; differs from the six-month-start longevity experiment.

nutrient_topic

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

plain_language

A diet can improve some endpoints while worsening others.

primary_references

Late-life protein or isoleucine restriction impacts physiological and molecular signatures of aging. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39604703/ · DOI 10.1038/s43587-024-00744-7

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 426–432

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Aged male and female C57BL/6J.Nia mice. · source_derived_draft · unverified_draft

## isoleucine-late-life-tradeoff A diet can improve some endpoints while worsening others. Starting 67% isoleucine restriction at twenty months improved selected metabolic/frailty measures but reduced grip strength in both sexes and produced mixed sex-dependent cardiac effects. Model: Aged male and female C57BL/6J.Nia mice. Limitations: Not evidence that severe restriction is desirable in older humans; differs from the six-month-start longevity experiment. Evidence access: Primary abstract Late-life protein or isoleucine restriction impacts physiological and molecular signatures of aging. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39604703/ · DOI 10.1038/s43587-024-00744-7

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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary preprint full text; not peer reviewed

experimental_model

Engineered mouse KPC PDA cells; nuclear-exclusion/localization experiments.

limitations

Preprint and compartment-engineering result; not established as a general nuclear pathway in healthy human tissue.

nutrient_topic

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

plain_language

The location of an enzyme complex influenced which cellular process used its products.

primary_references

A nuclear branched-chain amino acid catabolism pathway controls histone propionylation in pancreatic cancer. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40568091/ · DOI 10.1101/2025.04.23.650241

trigger_kind

machinery_impairment Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 490–496

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Engineered mouse KPC PDA cells; nuclear-exclusion/localization experiments. · source_derived_draft · unverified_draft

## isoleucine-pancreatic-preprint-nuclear The location of an enzyme complex influenced which cellular process used its products. The preprint reported that excluding BCKDH machinery from nuclei suppressed histone propionylation and associated gene-expression responses in PDA models. Model: Engineered mouse KPC PDA cells; nuclear-exclusion/localization experiments. Limitations: Preprint and compartment-engineering result; not established as a general nuclear pathway in healthy human tissue. Evidence access: Primary preprint full text; not peer reviewed A nuclear branched-chain amino acid catabolism pathway controls histone propionylation in pancreatic cancer. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40568091/ · DOI 10.1101/2025.04.23.650241

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary preprint full text; not peer reviewed

experimental_model

Mouse KPC and human PDA cell assays; combined Ile/Val removal, twenty-four hours.

limitations

Preprint; deprivation of two amino acids cannot be attributed exclusively to one.

nutrient_topic

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

plain_language

Restoring one carbon product did not replace essential amino-acid supply.

primary_references

A nuclear branched-chain amino acid catabolism pathway controls histone propionylation in pancreatic cancer. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40568091/ · DOI 10.1101/2025.04.23.650241

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 482–488

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse KPC and human PDA cell assays; combined Ile/Val removal, twenty-four hours. · source_derived_draft · unverified_draft

## isoleucine-pancreatic-preprint-rescue Restoring one carbon product did not replace essential amino-acid supply. In the preprint, propionate rescued propionyl-CoA and selected histone propionylation after combined isoleucine/valine deprivation, but did not restore proliferation. Model: Mouse KPC and human PDA cell assays; combined Ile/Val removal, twenty-four hours. Limitations: Preprint; deprivation of two amino acids cannot be attributed exclusively to one. Evidence access: Primary preprint full text; not peer reviewed A nuclear branched-chain amino acid catabolism pathway controls histone propionylation in pancreatic cancer. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40568091/ · DOI 10.1101/2025.04.23.650241

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

Prostate-cancer experimental models.

limitations

Does not imply a testosterone-boosting effect of supplements or a human dietary cancer treatment.

nutrient_topic

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

plain_language

The pathway linked amino-acid carbon handling to lipid and hormone-related tumor adaptation.

primary_references

Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol metabolism. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42625032/ · DOI 10.1038/s42255-026-01583-z

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 514–520

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

## isoleucine-prostate-cholesterol The pathway linked amino-acid carbon handling to lipid and hormone-related tumor adaptation. The reported SREBP2 activation promoted cholesterol biosynthesis and supported de novo androgen production and androgen-receptor signaling under metabolic/androgen-deprivation stress. Model: Prostate-cancer experimental models. Limitations: Does not imply a testosterone-boosting effect of supplements or a human dietary cancer treatment. Evidence access: Primary abstract Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol metabolism. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42625032/ · DOI 10.1038/s42255-026-01583-z

evidence_access

Primary abstract

experimental_model

Primary prostate-cancer mechanistic study; exact construct and lysine site not resolved in accessed abstract.

limitations

Site identity is not guessed; clinical target engagement was not established.

nutrient_topic

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

plain_language

A breakdown product changed the stability of a lipid-regulating transcription factor.

primary_references

Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol metabolism. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42625032/ · DOI 10.1038/s42255-026-01583-z

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 506–512

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary prostate-cancer mechanistic study; exact construct and lysine site not resolved in accessed abstract. · source_derived_draft · unverified_draft

## isoleucine-prostate-srebp2 A breakdown product changed the stability of a lipid-regulating transcription factor. Propionyl-CoA-dependent site-specific lysine propionylation stabilized nuclear SREBP2 and increased its transcriptional activity in the reported prostate-cancer models. Model: Primary prostate-cancer mechanistic study; exact construct and lysine site not resolved in accessed abstract. Limitations: Site identity is not guessed; clinical target engagement was not established. Evidence access: Primary abstract Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol metabolism. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42625032/ · DOI 10.1038/s42255-026-01583-z

evidence_access

Primary full text

experimental_model

Mouse isocaloric amino-acid-defined diets; other amino acids adjusted to maintain amino-acid calories.

limitations

Restriction is not complete deprivation; human isolated-isoleucine restriction efficacy was not tested.

nutrient_topic

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

plain_language

Reduced chronic supply changed liver glucose regulation in this dietary context.

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

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 370–376

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse isocaloric amino-acid-defined diets; other amino acids adjusted to maintain amino-acid calories. · source_derived_draft · unverified_draft

## isoleucine-restriction-clamp Reduced chronic supply changed liver glucose regulation in this dietary context. A 67% isoleucine reduction in formulated diets increased glucose infusion requirements and hepatic insulin sensitivity during clamps in mice. Model: Mouse isocaloric amino-acid-defined diets; other amino acids adjusted to maintain amino-acid calories. Limitations: Restriction is not complete deprivation; human isolated-isoleucine restriction efficacy was not tested. 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

evidence_access

Primary full text

experimental_model

Mouse formulated-diet and tissue studies.

limitations

Co-change alone does not show that every metabolic benefit depends on FGF21.

nutrient_topic

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

plain_language

Dietary composition elicited a liver-to-adipose hormonal response.

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

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 378–384

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse formulated-diet and tissue studies. · source_derived_draft · unverified_draft

## isoleucine-restriction-fgf21 Dietary composition elicited a liver-to-adipose hormonal response. The reduced-isoleucine diet increased hepatic FGF21 expression and circulating FGF21, with adipose UCP1-associated changes and increased energy expenditure. Model: Mouse formulated-diet and tissue studies. Limitations: Co-change alone does not show that every metabolic benefit depends on FGF21. 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

Fgf21-knockout mice and littermate diet comparisons.

limitations

Do not label FGF21 a required mediator of all isoleucine-restriction effects.

nutrient_topic

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

plain_language

Different outcomes used partly different routes.

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 386–392

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Fgf21-knockout mice and littermate diet comparisons. · source_derived_draft · unverified_draft

## isoleucine-restriction-fgf21-loss Different outcomes used partly different routes. Whole-body Fgf21 deletion blunted low-isoleucine-induced energy expenditure and hyperphagia but did not abolish improved glucose tolerance. Model: Fgf21-knockout mice and littermate diet comparisons. Limitations: Do not label FGF21 a required mediator of all isoleucine-restriction effects. 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

Mouse liver-specific Gcn2 knockout, twelve-day and three-week glucose tests.

limitations

Not equivalent to complete cellular starvation or loss of GCN2 in every tissue.

nutrient_topic

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

plain_language

A common amino-acid stress sensor was dispensable in this liver/diet experiment.

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 402–408

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse liver-specific Gcn2 knockout, twelve-day and three-week glucose tests. · source_derived_draft · unverified_draft

## isoleucine-restriction-gcn2-boundary A common amino-acid stress sensor was dispensable in this liver/diet experiment. Liver-specific Gcn2 deletion did not prevent low-isoleucine improvements in glucose tolerance or body-composition measures. Model: Mouse liver-specific Gcn2 knockout, twelve-day and three-week glucose tests. Limitations: Not equivalent to complete cellular starvation or loss of GCN2 in every tissue. 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

evidence_access

Primary full text

experimental_model

UM-HET3 mice; 67% dietary isoleucine reduction with controlled diet formulation.

limitations

Not a human lifespan finding, and not an independent laboratory replication of all prior Lamming-group diet findings.

nutrient_topic

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

plain_language

A controlled mouse study found an age- and sex-dependent longevity effect.

primary_references

Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37939658/ · DOI 10.1016/j.cmet.2023.10.005

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 418–424

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · UM-HET3 mice; 67% dietary isoleucine reduction with controlled diet formulation. · source_derived_draft · unverified_draft

## isoleucine-restriction-lifespan A controlled mouse study found an age- and sex-dependent longevity effect. Isoleucine-restricted feeding beginning at six months extended lifespan in male and female genetically heterogeneous UM-HET3 mice, more strongly in males. Model: UM-HET3 mice; 67% dietary isoleucine reduction with controlled diet formulation. Limitations: Not a human lifespan finding, and not an independent laboratory replication of all prior Lamming-group diet findings. Evidence access: Primary full text Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37939658/ · DOI 10.1016/j.cmet.2023.10.005

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

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Single infant case during intensive metabolic dietary treatment.

limitations

Case attribution does not define a universal plasma threshold or the molecular epithelial mechanism.

nutrient_topic

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

plain_language

Inadequate supply can affect more than muscle or growth.

primary_references

Corneal deepithelialization caused by acute deficiency of isoleucine during treatment of a patient with maple syrup urine disease. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8741119/ · DOI 10.1111/j.1600-0420.1996.tb00386.x

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 330–336

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Single infant case during intensive metabolic dietary treatment. · source_derived_draft · unverified_draft

## isoleucine-shortage-cornea Inadequate supply can affect more than muscle or growth. A critically ill newborn with MSUD developed corneal epithelial loss with skin and intestinal symptoms during isolated isoleucine deficiency. Model: Single infant case during intensive metabolic dietary treatment. Limitations: Case attribution does not define a universal plasma threshold or the molecular epithelial mechanism. Evidence access: Primary abstract Corneal deepithelialization caused by acute deficiency of isoleucine during treatment of a patient with maple syrup urine disease. · 1996 · https://pubmed.ncbi.nlm.nih.gov/8741119/ · DOI 10.1111/j.1600-0420.1996.tb00386.x

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Human case report; isoleucine replacement, leucine restriction and topical mometasone used together.

limitations

Combined treatment prevents assigning the entire response to one intervention; not a general dermatitis diagnosis.

nutrient_topic

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

plain_language

Restricting a breakdown substrate too far can damage tissues that still need it.

primary_references

Acrodermatitis dysmetabolica secondary to isoleucine deficiency in infant with maple syrup urine disease. · 2023 · https://pubmed.ncbi.nlm.nih.gov/38327590/ · DOI 10.4081/dr.2023.9750

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 322–328

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human case report; isoleucine replacement, leucine restriction and topical mometasone used together. · source_derived_draft · unverified_draft

## isoleucine-shortage-skin Restricting a breakdown substrate too far can damage tissues that still need it. An infant on MSUD treatment developed dermatitis, diarrhea and hair loss associated with isoleucine deficiency; skin lesions resolved after combined dietary correction and topical treatment. Model: Human case report; isoleucine replacement, leucine restriction and topical mometasone used together. Limitations: Combined treatment prevents assigning the entire response to one intervention; not a general dermatitis diagnosis. Evidence access: Primary abstract Acrodermatitis dysmetabolica secondary to isoleucine deficiency in infant with maple syrup urine disease. · 2023 · https://pubmed.ncbi.nlm.nih.gov/38327590/ · DOI 10.4081/dr.2023.9750

evidence_access

Primary full text

experimental_model

Human ECHS1-deficient fibroblasts and liver; substrate-selective enzyme assays.

limitations

ECHS1 activity does not establish that it is the sole required isoleucine hydratase.

nutrient_topic

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

plain_language

A reaction can have backup enzyme capacity in a tissue.

primary_references

Clinical and biochemical characterization of four patients with mutations in ECHS1. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26081110/ · DOI 10.1186/s13023-015-0290-1

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 194–200

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human ECHS1-deficient fibroblasts and liver; substrate-selective enzyme assays. · source_derived_draft · unverified_draft

## isoleucine-tiglyl-hydration A reaction can have backup enzyme capacity in a tissue. Human fibroblast and liver assays measured tiglyl-CoA hydration in the isoleucine branch; residual activity persisted despite ECHS1 deficiency, indicating overlapping hydratase capacity. Model: Human ECHS1-deficient fibroblasts and liver; substrate-selective enzyme assays. Limitations: ECHS1 activity does not establish that it is the sole required isoleucine hydratase. Evidence access: Primary full text Clinical and biochemical characterization of four patients with mutations in ECHS1. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26081110/ · DOI 10.1186/s13023-015-0290-1

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Primary human fibroblasts, mass spectrometry and tRNA charging assays.

limitations

Amino-acid substitution is not proof of normal function for every affected protein or nutritional interchangeability.

nutrient_topic

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

plain_language

Some cells preserve translation by sacrificing amino-acid accuracy.

primary_references

Isoleucine-to-valine substitutions support cellular physiology during isoleucine deprivation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39657787/ · DOI 10.1093/nar/gkae1184

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 114–120

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary human fibroblasts, mass spectrometry and tRNA charging assays. · source_derived_draft · unverified_draft

## isoleucine-valine-substitution Some cells preserve translation by sacrificing amino-acid accuracy. Under isoleucine restriction, healthy human fibroblasts incorporated valine at isoleucine codons; biochemical assays implicated IARS1-mediated valine misacylation. Model: Primary human fibroblasts, mass spectrometry and tRNA charging assays. Limitations: Amino-acid substitution is not proof of normal function for every affected protein or nutritional interchangeability. Evidence access: Primary full text Isoleucine-to-valine substitutions support cellular physiology during isoleucine deprivation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39657787/ · DOI 10.1093/nar/gkae1184

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human fibroblast experiments; representative low isoleucine 1.02 micromolar and high valine 2330 micromolar conditions.

limitations

Culture conditions are not a recommended dietary ratio; two patient lines shared the investigated variants.

nutrient_topic

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

plain_language

The rescue required functioning charging machinery.

primary_references

Isoleucine-to-valine substitutions support cellular physiology during isoleucine deprivation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39657787/ · DOI 10.1093/nar/gkae1184

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 122–128

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human fibroblast experiments; representative low isoleucine 1.02 micromolar and high valine 2330 micromolar conditions. · source_derived_draft · unverified_draft

## isoleucine-valine-translation-rescue The rescue required functioning charging machinery. Valine supplementation restored translation and proliferation during severe isoleucine deprivation in healthy fibroblasts but not in the tested IARS1-deficient fibroblasts. Model: Human fibroblast experiments; representative low isoleucine 1.02 micromolar and high valine 2330 micromolar conditions. Limitations: Culture conditions are not a recommended dietary ratio; two patient lines shared the investigated variants. Evidence access: Primary full text Isoleucine-to-valine substitutions support cellular physiology during isoleucine deprivation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39657787/ · DOI 10.1093/nar/gkae1184

experimental_model

Human BCAT2 reaction-intermediate crystallography

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

The cofactor cycles between PLP and PMP as it carries an amino group.

primary_references

[b6-bcat2-2002] Crystal structures of human mitochondrial branched chain aminotransferase reaction intermediates: ketimine and pyridoxamine phosphate forms (2002). https://pubmed.ncbi.nlm.nih.gov/12269802/ DOI: 10.1021/bi020221c

tissue_or_cell_type

Purified recombinant protein; no intact tissue

Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 706–715

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human BCAT2 reaction-intermediate crystallography · source_derived_draft · unverified_draft

### b6-met-bcat2-pmp Human BCAT2 structures capture the isoleucine ketimine and PMP forms of its amino-transfer cycle. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The cofactor cycles between PLP and PMP as it carries an amino group. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Human BCAT2 reaction-intermediate crystallography limitations: Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds. [b6-bcat2-2002] Crystal structures of human mitochondrial branched chain aminotransferase reaction intermediates: ketimine and pyridoxamine phosphate forms (2002). https://pubmed.ncbi.nlm.nih.gov/12269802/ DOI: 10.1021/bi020221c

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 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