Nutrient chapter

L-Isoleucine

Branched-chain essential amino acid.

78 recorded mechanisms · 19 availability situations · 7 preserved sources. Draft and verified records are labeled separately.

Read recorded mechanisms Open recursive mind map

The mechanisms

What the sources say this nutrient does, one relationship at a time. Plain wording comes first; the technical statement follows.

Replacing sodium during mouse ileum uptake assays removed the sodium-dependent component of radiolabeled L-isoleucine uptake.
Sodium ion → Isoleucine uptake in mouse ileum source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Ace2 deletion removed intestinal B0AT1 expression and abolished sodium-dependent isoleucine uptake in mouse ileum segments.
Mouse angiotensin-converting enzyme 2 / Ace2 → Isoleucine uptake in mouse ileum source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Human neutral amino acid transporter B0AT1 / SLC6A19 → Accessory-protein response of human B0AT1 variants source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human LAT1 with SLC3A2 transported large neutral amino acids and exchanged intracellular leucine or glutamine with extracellular substrates.
Human L-type amino acid transporter 1 / LAT1 / SLC7A5 → Large neutral amino-acid exchange through human LAT1 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Slc25a44 loss reduced mitochondrial valine and leucine uptake; ectopic expression and reconstituted liposomes supported transporter function.
Mouse mitochondrial BCAA carrier / Slc25a44 → Mitochondrial BCAA uptake in mouse cells source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human supraclavicular BAT SLC25A44 mRNA increased after cold exposure and correlated with UCP1 and BCKDHA expression.
Controlled cold exposure in the human BAT study → Human mitochondrial BCAA carrier / SLC25A44 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
BAT-specific BCAA catabolic impairment reduced BCAA clearance and thermogenic fuel oxidation and promoted glucose intolerance in the tested mice.
Mouse branched-chain alpha-ketoacid dehydrogenase complex → Systemic BCAA clearance supported by mouse BAT source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
BAT-specific Slc25a44 deletion blunted BCAA oxidation and non-shivering thermogenesis following intracerebroventricular PGE2.
Mouse mitochondrial BCAA carrier / Slc25a44 → PGE2-evoked BAT thermogenesis in mice source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Nitrogen-labeled valine and leucine supplied glutamate and alanine rapidly in brown-adipocyte tracing experiments.
BCAA nitrogen flux in mouse brown adipocytes → L-Glutamate source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Impaired mitochondrial BCAA nitrogen flux reduced synthesis of downstream metabolites including glutathione and increased oxidative stress in the tested BAT system.
Mouse mitochondrial BCAA carrier / Slc25a44 → Glutathione synthesis in mouse brown adipocytes source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
BAT-specific Slc25a44 knockout impaired BCAA clearance and insulin tolerance without a significant difference in energy expenditure or body weight in this study.
Mouse mitochondrial BCAA carrier / Slc25a44 → Systemic insulin tolerance supported by mouse BAT source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human IARS1 aminoacylates tRNA-Ile with isoleucine for cytosolic translation; purified-protein aminoacylation assays were used to study this reaction.
Human cytosolic isoleucyl-tRNA synthetase / IARS1 → Human cytosolic isoleucyl-tRNA source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Under isoleucine restriction, healthy human fibroblasts incorporated valine at isoleucine codons; biochemical assays implicated IARS1-mediated valine misacylation.
Human cytosolic isoleucyl-tRNA synthetase / IARS1 → Isoleucine-to-valine protein substitution in human fibroblasts source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Valine supplementation restored translation and proliferation during severe isoleucine deprivation in healthy fibroblasts but not in the tested IARS1-deficient fibroblasts.
L-Valine → Protein translation in human fibroblasts source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
IARS-deficient patient fibroblasts had reduced residual aminoacylation activity and greater growth sensitivity to low isoleucine.
Human cytosolic isoleucyl-tRNA synthetase / IARS1 → Growth of IARS1-deficient human fibroblasts source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The IARS patients within a small personalized ARS-treatment series received cognate amino-acid supplementation and showed reported clinical benefit during follow-up.
L-Isoleucine → Personalized isoleucine treatment in IARS deficiency source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Three individuals with biallelic IARS variants had zinc deficiency; one showed improved growth with zinc supplementation.
Biallelic human IARS1 variants → Zinc deficiency in reported IARS1 patients source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Human mitochondrial isoleucyl-tRNA synthetase / IARS2 → Mitochondrial respiratory function dependent on human IARS2 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human BCAT2 transfers the isoleucine amino group through the PLP/PMP cycle, linking isoleucine/branched ketoacid interconversion to 2-oxoglutarate/glutamate.
Human mitochondrial branched-chain aminotransferase / BCAT2 → 3-Methyl-2-oxopentanoate source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The isoleucine pathway in the primary biochemical study places BCKDH-mediated oxidative decarboxylation of the branched ketoacid upstream of 2-methylbutyryl-CoA.
Human branched-chain alpha-ketoacid dehydrogenase complex → 2-Methylbutyryl-CoA source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human ACADSB supported oxidation of 2-methylbutyryl-CoA; patient fibroblast assays and expression studies distinguished this isoleucine enzyme from valine-related ACAD8.
Human short/branched-chain acyl-CoA dehydrogenase / ACADSB → 2-Methylbutyryl-CoA source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
An ACADSB splice defect caused exon skipping, impaired 2-methylbutyryl-CoA oxidation and isolated 2-methylbutyrylglycinuria in the reported patient.
Human ACADSB exon-10-skipping defect → Human short/branched-chain acyl-CoA dehydrogenase / ACADSB source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human fibroblast and liver assays measured tiglyl-CoA hydration in the isoleucine branch; residual activity persisted despite ECHS1 deficiency, indicating overlapping hydratase capacity.
Short-chain enoyl-CoA hydratase / ECHS1 → Tiglyl-CoA source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
ECHS1-deficient patients showed a dominant valine-metabolism defect rather than the expected isolated isoleucine block; liver retained tiglyl-CoA hydration capacity.
Short-chain enoyl-CoA hydratase / ECHS1 → Tiglyl-CoA processing capacity in human tissues source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
HSD17B10 encodes the 2-methyl-3-hydroxybutyryl-CoA dehydrogenase step of isoleucine metabolism.
Human hydroxysteroid dehydrogenase 10 / HSD17B10 → 2-Methyl-3-hydroxybutyryl-CoA source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Mouse HSD10 / Hsd17b10 → Mitochondrial integrity in Hsd17b10-deficient mouse cells source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human mitochondrial ACAT1/T2 degraded 2-methylacetoacetyl-CoA by CoA-dependent thiolysis, yielding the isoleucine-branch acetyl-CoA and propionyl-CoA products.
Mitochondrial acetyl-CoA acetyltransferase / ACAT1 → 2-Methylacetoacetyl-CoA source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Increasing KCl from 0 to 40 mM increased purified human T2 turnover approximately threefold for both acetoacetyl-CoA and 2-methylacetoacetyl-CoA.
Potassium ion → Mitochondrial acetyl-CoA acetyltransferase / ACAT1 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human T2 structures identified a copurified chloride ion at a high-affinity site near catalytic loops at the dimer interface.
Chloride ion → Mitochondrial acetyl-CoA acetyltransferase / ACAT1 source_derived_draftungraded
Experimental context and source evidence
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
L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 242–248
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
Complete structured claim and evidence
Two HSD10 and four ACAT1 deficiency cases shared elevated 2-methyl-3-hydroxybutyrate/tiglylglycine patterns but had different clinical courses.
Comparison of human HSD10 and ACAT1 deficiencies → Overlapping isoleucine-related urinary organic-acid pattern source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
BCKDK phosphorylates BCKDH E1-alpha; inactivating human BCKDK variants reduced E1-alpha phosphorylation and circulating BCAAs.
Human branched-chain ketoacid dehydrogenase kinase / BCKDK → Human branched-chain alpha-ketoacid dehydrogenase complex source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Dietary BCAA supplementation improved neurobehavioral abnormalities in Bckdk-knockout mice.
Dietary BCAA supplementation in Bckdk-deficient mice → Neurobehavioral phenotype in Bckdk-deficient mice source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
PP2Cm bound the BCKDH complex and promoted substrate-dependent dephosphorylation of E1-alpha Ser293.
Mouse BCKDH phosphatase PP2Cm / Ppm1k → Mouse branched-chain alpha-ketoacid dehydrogenase complex source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Ppm1k loss abolished substrate-induced E1-alpha dephosphorylation and impaired BCAA catabolism in mice.
Mouse BCKDH phosphatase PP2Cm / Ppm1k → Substrate-induced BCKDH activation in mice source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Isoleucine at 80-200 micromolar and valine at 250-500 micromolar reduced leucine transamination/oxidation by up to 25% in human peripheral lymphocytes.
L-Isoleucine → Leucine transamination and oxidation in human lymphocytes source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Phenylbutyrate inhibited recombinant BCKDH kinase, reduced E1-alpha phosphorylation and increased overall BCKDH activity in the reported assays.
Sodium phenylbutyrate → Recombinant BCKDH-kinase preparation, species unresolved in accessed abstract source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Sodium phenylbutyrate → Circulating BCAAs during sodium phenylbutyrate exposure source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Sodium phenylbutyrate → BCAA and branched-ketoacid pools in selected MSUD patients source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Isoleucine shortage during human MSUD dietary treatment → Epithelial injury during isoleucine shortage source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
A critically ill newborn with MSUD developed corneal epithelial loss with skin and intestinal symptoms during isolated isoleucine deficiency.
Isoleucine shortage during human MSUD dietary treatment → Corneal epithelial loss during isoleucine shortage source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
L-Isoleucine → Rat plasma glucose after oral glucose challenge source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Isoleucine at 1-10 mM increased 2-deoxyglucose uptake in insulin-free C2C12 myotube assays.
L-Isoleucine → Glucose uptake in mouse C2C12 myotubes source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Pharmacological experiments implicated PI3K, while mTOR inhibition did not account for the isoleucine glucose-uptake response.
L-Isoleucine → PI3K-sensitive glucose response in mouse C2C12 cells source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Oral isoleucine increased tracer-measured muscle glucose uptake by 73% in food-deprived rats without increased AMPK activity; AMPK-alpha2 activity decreased.
L-Isoleucine → Glucose uptake in rat skeletal muscle source_derived_draftungraded
Experimental context and source evidence
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
L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 362–368
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
Complete structured claim and evidence
A 67% isoleucine reduction in formulated diets increased glucose infusion requirements and hepatic insulin sensitivity during clamps in mice.
Experimentally reduced-isoleucine mouse diet → Hepatic insulin response in the low-isoleucine diet study source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The reduced-isoleucine diet increased hepatic FGF21 expression and circulating FGF21, with adipose UCP1-associated changes and increased energy expenditure.
Experimentally reduced-isoleucine mouse diet → Mouse fibroblast growth factor 21 / Fgf21 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Whole-body Fgf21 deletion blunted low-isoleucine-induced energy expenditure and hyperphagia but did not abolish improved glucose tolerance.
Mouse fibroblast growth factor 21 / Fgf21 → Energy-expenditure response to low-isoleucine diet source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Low isoleucine improved glucose tolerance and body composition despite liver-specific Tsc1 deletion and constitutive hepatic mTORC1 activity.
Experimentally reduced-isoleucine mouse diet → Constitutive hepatic mTORC1 activity in Tsc1-knockout mice source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Liver-specific Gcn2 deletion did not prevent low-isoleucine improvements in glucose tolerance or body-composition measures.
Experimentally reduced-isoleucine mouse diet → Mouse GCN2 / Eif2ak4 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Higher dietary isoleucine content was associated with higher BMI in the study human dietary analysis.
L-Isoleucine → Dietary isoleucine and BMI association source_derived_draftungraded
Experimental context and source evidence
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
L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 410–416
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
Complete structured claim and evidence
Isoleucine-restricted feeding beginning at six months extended lifespan in male and female genetically heterogeneous UM-HET3 mice, more strongly in males.
Experimentally reduced-isoleucine mouse diet → Lifespan in the UM-HET3 isoleucine-restriction study source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Experimentally reduced-isoleucine mouse diet → Functional outcomes of late-life isoleucine restriction source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
L-isoleucine and selected analogs induced epithelial beta-defensin transcription with NF-kappaB/Rel activation in the study assays.
L-Isoleucine → Epithelial beta-defensin expression in the tested preparation source_derived_draftungraded
Experimental context and source evidence
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
L-Isoleucine: transport, translation, catabolism and cross-nutrient mechanisms (2026-09-19) · lines 434–440
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
Complete structured claim and evidence
L-isoleucine induced human beta-defensin-2 expression in A549 cells; the D-isoleucine comparison did not reproduce induction.
L-Isoleucine → Human beta-defensin 2 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Intratracheal isoleucine at 250 micrograms every forty-eight hours increased beta-defensins 3/4 in mice with established pulmonary tuberculosis.
L-Isoleucine → Pulmonary beta-defensin 3/4 in infected mice source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The same local isoleucine regimen reduced lung bacillary load and tissue injury alongside defensin induction.
L-Isoleucine → Bacillary load in the mouse intratracheal-isoleucine study source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
L-Isoleucine → Nuclear propionyl-CoA in studied cancer cells source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
L-Isoleucine → Propionyl-CoA source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
In the preprint, propionate rescued propionyl-CoA and selected histone propionylation after combined isoleucine/valine deprivation, but did not restore proliferation.
Propionate → Histone propionylation in PDA cell models source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The preprint reported that excluding BCKDH machinery from nuclei suppressed histone propionylation and associated gene-expression responses in PDA models.
Mouse dihydrolipoyl branched-chain transacylase / Dbt → Nuclear isoleucine catabolism in mouse PDA cells source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
A 2026 prostate-cancer study identified isoleucine and valine catabolism as major sources of intracellular propionyl-CoA in its experimental models.
L-Isoleucine → Propionyl-CoA source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Propionyl-CoA-dependent site-specific lysine propionylation stabilized nuclear SREBP2 and increased its transcriptional activity in the reported prostate-cancer models.
Propionyl-CoA → SREBP2 in the prostate-cancer study, species unresolved here source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The reported SREBP2 activation promoted cholesterol biosynthesis and supported de novo androgen production and androgen-receptor signaling under metabolic/androgen-deprivation stress.
SREBP2 in the prostate-cancer study, species unresolved here → Cholesterol synthesis and androgen signaling in prostate-cancer models source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human BCAT2 crystal structures show PLP covalently linked to the active-site lysine in active enzyme forms.
PLP → Human mitochondrial branched-chain aminotransferase / BCAT2 source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
B6 participates in essential branched-chain amino-acid metabolism.
experimental_model
Purified recombinant human BCAT2 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
Mitochondrial branched-chain amino-acid metabolism uses bound active B6.
primary_references
[b6-bcat2-2001] The structure of human mitochondrial branched-chain aminotransferase (2001). https://doi.org/10.1107/S0907444901001925 DOI: 10.1107/S0907444901001925
tissue_or_cell_type
Purified recombinant protein; no intact tissue
Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 694–704
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant human BCAT2 crystallography · source_derived_draft · unverified_draft
### b6-met-bcat2-plp Human BCAT2 crystal structures show PLP covalently linked to the active-site lysine in active enzyme forms. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Mitochondrial branched-chain amino-acid metabolism uses bound active B6. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified recombinant human BCAT2 crystallography limitations: Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds. cross_nutrient: B6 participates in essential branched-chain amino-acid metabolism. [b6-bcat2-2001] The structure of human mitochondrial branched-chain aminotransferase (2001). https://doi.org/10.1107/S0907444901001925 DOI: 10.1107/S0907444901001925
Complete structured claim and evidence
Human BCAT2 structures capture the isoleucine ketimine and PMP forms of its amino-transfer cycle.
Human mitochondrial branched-chain aminotransferase / BCAT2 → Pyridoxamine 5-prime-phosphate source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human BCKDH E1 decarboxylates a branched-chain alpha-ketoacid using ThDP and reductively acylates the lipoylated DBT domain.
Human branched-chain ketoacid dehydrogenase E1 → Dihydrolipoyl branched-chain transacylase / DBT source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Thiamine and protein-bound lipoate connect branched-chain amino-acid catabolism; CoA and DLD act later.
evidence
[{"paper_key": "li-2004-bckdh", "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
Recombinant human E1b and E2b lipoyl domain assays.
limitations
Purified-system evidence; nutritional response was not tested.
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
Homo sapiens
plain_language
B1 helps process ketoacids formed from branched-chain amino acids; the acyl fragment then moves to a lipoyl carrier on E2.
primary_references
[li-2004-bckdh] Cross-talk between thiamin diphosphate binding and phosphorylation loop conformation in human branched-chain alpha-keto acid decarboxylase/dehydrogenase (2004). https://pubmed.ncbi.nlm.nih.gov/15166214/ DOI: 10.1074/jbc.m403611200
tissue_or_cell_type
Purified proteins
Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 773–785
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human E1b and E2b lipoyl domain assays. · source_derived_draft · unverified_draft
### b1-bckdh-ketoacid-acylation Human BCKDH E1 decarboxylates a branched-chain alpha-ketoacid using ThDP and reductively acylates the lipoylated DBT domain. Condition category: normal nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: B1 helps process ketoacids formed from branched-chain amino acids; the acyl fragment then moves to a lipoyl carrier on E2. organism: Homo sapiens tissue_or_cell_type: Purified proteins experimental_model: Recombinant human E1b and E2b lipoyl domain assays. limitations: Purified-system evidence; nutritional response was not tested. evidence: [{"paper_key": "li-2004-bckdh", "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: Thiamine and protein-bound lipoate connect branched-chain amino-acid catabolism; CoA and DLD act later. nutrient: Thiamine (vitamin B1) [li-2004-bckdh] Cross-talk between thiamin diphosphate binding and phosphorylation loop conformation in human branched-chain alpha-keto acid decarboxylase/dehydrogenase (2004). https://pubmed.ncbi.nlm.nih.gov/15166214/ DOI: 10.1074/jbc.m403611200
Complete structured claim and evidence
Human DLD uses bound FAD and transiently bound NAD+ to oxidize dihydrolipoamide; NADH-bound structures place its nicotinamide ring beside FAD.
DLD → Protein-bound reduced dihydrolipoyl-lysine source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
B1 performs E1 carbon chemistry; B2-derived FAD and the niacin-related NAD cofactor participate in the separate shared E3 reaction.
evidence
[{"paper_key": "brautigam-2005-dld", "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
Human DLD crystallography with NAD+ and NADH.
limitations
Cofactor chemistry does not establish dietary B2/B3 limitation or prove rescue of B1 deficiency.
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
Homo sapiens
plain_language
The shared E3 protein resets reduced lipoyl carriers using the B2-derived flavin and B3-related NAD system, allowing another round of B1-dependent turnover.
primary_references
[brautigam-2005-dld] Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations (2005). https://pubmed.ncbi.nlm.nih.gov/15946682/ DOI: 10.1016/j.jmb.2005.05.014
tissue_or_cell_type
Purified enzyme
Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 717–729
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human DLD crystallography with NAD+ and NADH. · source_derived_draft · unverified_draft
### b1-dld-fad-nad-lipoyl-regeneration Human DLD uses bound FAD and transiently bound NAD+ to oxidize dihydrolipoamide; NADH-bound structures place its nicotinamide ring beside FAD. Condition category: normal nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: The shared E3 protein resets reduced lipoyl carriers using the B2-derived flavin and B3-related NAD system, allowing another round of B1-dependent turnover. organism: Homo sapiens tissue_or_cell_type: Purified enzyme experimental_model: Human DLD crystallography with NAD+ and NADH. limitations: Cofactor chemistry does not establish dietary B2/B3 limitation or prove rescue of B1 deficiency. evidence: [{"paper_key": "brautigam-2005-dld", "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: B1 performs E1 carbon chemistry; B2-derived FAD and the niacin-related NAD cofactor participate in the separate shared E3 reaction. nutrient: Thiamine (vitamin B1) [brautigam-2005-dld] Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations (2005). https://pubmed.ncbi.nlm.nih.gov/15946682/ DOI: 10.1016/j.jmb.2005.05.014
Complete structured claim and evidence
Adenosylcobalamin-loaded human MMUT converts (R)-methylmalonyl-CoA to succinyl-CoA in the coupled enzyme assay.
Human methylmalonyl-CoA mutase / MMUT → (R)-Methylmalonyl-CoA source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Full text Results; Figures 2-4; cofactor off-loading and MMUT activity Methods
experimental_model
Purified human proteins
exposure
AdoCbl-loaded MMUT and methylmalonyl-CoA; thiokinase-coupled readout
limitations
Product formation is a coupled assay; cellular net flux was not measured.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Purified human MMUT used activated B12 to make succinyl-CoA from the matching methylmalonyl-CoA epimer.
primary_references
[mascarenhas-2023-nanoassembly] Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B12 delivery and repair. (2023). https://pubmed.ncbi.nlm.nih.gov/37468522/ DOI: 10.1038/s41467-023-40077-4
tissue_or_cell_type
Purified protein assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1103–1115
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human proteins · source_derived_draft · unverified_draft
### mmut-isomerizes-r-methylmalonyl-coa Adenosylcobalamin-loaded human MMUT converts (R)-methylmalonyl-CoA to succinyl-CoA in the coupled enzyme assay. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Purified human MMUT used activated B12 to make succinyl-CoA from the matching methylmalonyl-CoA epimer. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human proteins limitations: Product formation is a coupled assay; cellular net flux was not measured. exposure: AdoCbl-loaded MMUT and methylmalonyl-CoA; thiokinase-coupled readout cross_nutrient: false evidence_location: Full text Results; Figures 2-4; cofactor off-loading and MMUT activity Methods [mascarenhas-2023-nanoassembly] Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B12 delivery and repair. (2023). https://pubmed.ncbi.nlm.nih.gov/37468522/ DOI: 10.1038/s41467-023-40077-4
Complete structured claim and evidence
Human PCC supplies (S)-methylmalonyl-CoA by propionyl-CoA carboxylation upstream of the MCEE-MMUT sequence examined in fibroblast assays.
Human propionyl-CoA carboxylase / PCC → Propionyl-CoA source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Indexed primary abstract; Full text Methods 2.6 and Results 3.6; Figure 5
experimental_model
Human fibroblast PCC and coupled-pathway assays
exposure
Propionyl-CoA, ATP and bicarbonate in enzyme pathway
limitations
Pathway assignment combines human PCC characterization with coupled assays; it is not a simultaneous dietary biotin/B12 intervention.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Biotin-dependent PCC makes the precursor that must be rearranged before human MMUT can use B12 on it.
primary_references
[hsia-1979-pcc] Human propionyl CoA carboxylase: some properties of the partially purified enzyme in fibroblasts from controls and patients with propionic acidemia. (1979). https://pubmed.ncbi.nlm.nih.gov/481943/ DOI: 10.1203/00006450-197906000-00005 [heuberger-2019-mcee] Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency. (2019). https://pubmed.ncbi.nlm.nih.gov/30682498/ DOI: 10.1016/j.bbadis.2019.01.021
tissue_or_cell_type
Fibroblasts
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1159–1172
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human fibroblast PCC and coupled-pathway assays · source_derived_draft · unverified_draft
### pcc-carboxylation-upstream-b12 Human PCC supplies (S)-methylmalonyl-CoA by propionyl-CoA carboxylation upstream of the MCEE-MMUT sequence examined in fibroblast assays. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Biotin-dependent PCC makes the precursor that must be rearranged before human MMUT can use B12 on it. organism: Homo sapiens tissue_or_cell_type: Fibroblasts experimental_model: Human fibroblast PCC and coupled-pathway assays limitations: Pathway assignment combines human PCC characterization with coupled assays; it is not a simultaneous dietary biotin/B12 intervention. exposure: Propionyl-CoA, ATP and bicarbonate in enzyme pathway cross_nutrient: true evidence_location: Indexed primary abstract; Full text Methods 2.6 and Results 3.6; Figure 5 [hsia-1979-pcc] Human propionyl CoA carboxylase: some properties of the partially purified enzyme in fibroblasts from controls and patients with propionic acidemia. (1979). https://pubmed.ncbi.nlm.nih.gov/481943/ DOI: 10.1203/00006450-197906000-00005 [heuberger-2019-mcee] Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency. (2019). https://pubmed.ncbi.nlm.nih.gov/30682498/ DOI: 10.1016/j.bbadis.2019.01.021
Complete structured claim and evidence
Human MCEE interconverts methylmalonyl-CoA epimers, supplying the (R) form for MMUT; MCEE expression increased coupled succinate production.
Human methylmalonyl-CoA epimerase / MCEE → (S)-Methylmalonyl-CoA source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Full text Methods 2.6 and Results 3.6; Figure 5
experimental_model
Human fibroblast lysates overexpressing MCEE and/or MMUT
exposure
Radiolabeled propionyl-CoA; MCEE/MMUT expression and AdoCbl
limitations
Coupled labeled hydrolysis-product assay; MCEE being limiting here is not a universal in-vivo rate limitation.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Human fibroblast assays showed why the epimerase step matters before the B12 enzyme.
primary_references
[heuberger-2019-mcee] Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency. (2019). https://pubmed.ncbi.nlm.nih.gov/30682498/ DOI: 10.1016/j.bbadis.2019.01.021
tissue_or_cell_type
Fibroblasts
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1174–1186
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human fibroblast lysates overexpressing MCEE and/or MMUT · source_derived_draft · unverified_draft
### mcee-epimerizes-methylmalonyl-coa Human MCEE interconverts methylmalonyl-CoA epimers, supplying the (R) form for MMUT; MCEE expression increased coupled succinate production. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Human fibroblast assays showed why the epimerase step matters before the B12 enzyme. organism: Homo sapiens tissue_or_cell_type: Fibroblasts experimental_model: Human fibroblast lysates overexpressing MCEE and/or MMUT limitations: Coupled labeled hydrolysis-product assay; MCEE being limiting here is not a universal in-vivo rate limitation. exposure: Radiolabeled propionyl-CoA; MCEE/MMUT expression and AdoCbl cross_nutrient: false evidence_location: Full text Methods 2.6 and Results 3.6; Figure 5 [heuberger-2019-mcee] Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency. (2019). https://pubmed.ncbi.nlm.nih.gov/30682498/ DOI: 10.1016/j.bbadis.2019.01.021
Complete structured claim and evidence
PCC partially purified from control human fibroblasts contained biotin.
Human propionyl-CoA carboxylase / PCC → Biotin source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Indexed primary abstract
experimental_model
Partially purified human fibroblast PCC
exposure
Control fibroblast enzyme fraction
limitations
Biotin content in an enzyme preparation; does not establish whole-body biotin thresholds.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Human fibroblast PCC carried biotin, a different vitamin required upstream of the B12-dependent step.
primary_references
[hsia-1979-pcc] Human propionyl CoA carboxylase: some properties of the partially purified enzyme in fibroblasts from controls and patients with propionic acidemia. (1979). https://pubmed.ncbi.nlm.nih.gov/481943/ DOI: 10.1203/00006450-197906000-00005
tissue_or_cell_type
Fibroblasts
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1145–1157
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Partially purified human fibroblast PCC · source_derived_draft · unverified_draft
### human-pcc-biotin PCC partially purified from control human fibroblasts contained biotin. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Human fibroblast PCC carried biotin, a different vitamin required upstream of the B12-dependent step. organism: Homo sapiens tissue_or_cell_type: Fibroblasts experimental_model: Partially purified human fibroblast PCC limitations: Biotin content in an enzyme preparation; does not establish whole-body biotin thresholds. exposure: Control fibroblast enzyme fraction cross_nutrient: true evidence_location: Indexed primary abstract [hsia-1979-pcc] Human propionyl CoA carboxylase: some properties of the partially purified enzyme in fibroblasts from controls and patients with propionic acidemia. (1979). https://pubmed.ncbi.nlm.nih.gov/481943/ DOI: 10.1203/00006450-197906000-00005
Complete structured claim and evidence
PCCA contains the biotin-carboxylase and biotin-carrier domains of human PCC.
Human propionyl-CoA carboxylase alpha subunit / PCCA → Human propionyl-CoA carboxylase / PCC source_derived_draftungraded
Experimental context and source evidence
evidence_span
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experimental_model
Bacterial PCC crystallography and separate 15-angstrom human PCC cryo-EM reconstruction
exposure
Structural analysis
limitations
Atomic bacterial positions are not high-resolution human measurements. Human cryo-EM establishes the overall assembly at lower resolution.
nutrient_topic
Biotin research collection; topical membership is not evidence of a direct dietary effect. · Biotin
organism
Homo sapiens; bacterial PCC comparison
plain_language
The alpha subunit handles biotin loading with the carboxyl group and carries that group onward.
primary_references
[b7-p20725044] Crystal structure of the alpha(6)beta(6) holoenzyme of propionyl-coenzyme A carboxylase. (2010). https://pubmed.ncbi.nlm.nih.gov/20725044/ DOI: 10.1038/nature09302
tissue_or_cell_type
Purified PCC complexes
Biotin: carboxylases, recycling, deficiency and nutrient interactions (2026-09-17) · lines 598–609
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bacterial PCC crystallography and separate 15-angstrom human PCC cryo-EM reconstruction · source_derived_draft · unverified_draft
### b7-pcc-pcca PCCA contains the biotin-carboxylase and biotin-carrier domains of human PCC. Condition category: normal nutrient_topic: Biotin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The alpha subunit handles biotin loading with the carboxyl group and carries that group onward. organism: Homo sapiens; bacterial PCC comparison tissue_or_cell_type: Purified PCC complexes experimental_model: Bacterial PCC crystallography and separate 15-angstrom human PCC cryo-EM reconstruction limitations: Atomic bacterial positions are not high-resolution human measurements. Human cryo-EM establishes the overall assembly at lower resolution. exposure: Structural analysis evidence_span: {"source_cache": "artifacts/biotin-research/20725044.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "825bf28b9f35a8d45f8d08d883fa200bd430336b0558db035ce4fd1c5ef19053", "start_char": 0, "end_char": 1921, "text_sha256": "825bf28b9f35a8d45f8d08d883fa200bd430336b0558db035ce4fd1c5ef19053"} [b7-p20725044] Crystal structure of the alpha(6)beta(6) holoenzyme of propionyl-coenzyme A carboxylase. (2010). https://pubmed.ncbi.nlm.nih.gov/20725044/ DOI: 10.1038/nature09302
Complete structured claim and evidence
Carbon-13 isoleucine supplied lipogenic propionyl-CoA in cultured 3T3-L1 adipocytes.
L-Isoleucine → Propionyl-CoA source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Fatty-acid fragment labeling identified propionyl-CoA as the primer for odd-chain fatty-acid synthesis in 3T3-L1 adipocytes.
Propionyl-CoA → Odd-chain fatty acid synthesis source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Full text Results; Figures 6-8 and isotope model
experimental_model
Differentiated mouse 3T3-L1 adipocytes
exposure
Parallel carbon-13 tracer and GC-MS fragment analysis
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
These mouse fat cells could divert the B12-pathway precursor into odd-chain fats.
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 1244–1256
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
### propionyl-primes-odd-chain-fatty-acids Fatty-acid fragment labeling identified propionyl-CoA as the primer for odd-chain fatty-acid synthesis in 3T3-L1 adipocytes. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: These mouse fat cells could divert the B12-pathway precursor into odd-chain fats. 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: Parallel carbon-13 tracer and GC-MS fragment analysis cross_nutrient: false 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
Complete structured claim and evidence
Adding 2.5 micromolar B12 during ECHDC1-knockout L929 adipocyte differentiation lowered whole-cell methylmalonyl-CoA approximately 20-fold.
Vitamin B12 (cobalamins) → Whole-cell methylmalonyl-CoA pool source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Full text Results: vitamin B12 supplementation; Figure 4g-u
experimental_model
Differentiating ECHDC1-knockout mouse L929 adipocytes (Figure 4g-u)
exposure
ECHDC1 knockout; 2.5 micromolar supplementary B12 during differentiation
limitations
Whole-cell LC-MS pools; no compartment or epimer resolution and no direct pathway flux measurement.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Mus musculus
plain_language
B12 addition sharply lowered this measured precursor pool in cultured mouse adipocytes. The cells had ECHDC1 deleted.
primary_references
[dewulf-2019-l929-b12] The synthesis of branched-chain fatty acids is limited by enzymatic decarboxylation of ethyl- and methylmalonyl-CoA. (2019). https://pubmed.ncbi.nlm.nih.gov/31416829/ DOI: 10.1042/bcj20190500
tissue_or_cell_type
Adipocytes
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1258–1270
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Differentiating ECHDC1-knockout mouse L929 adipocytes (Figure 4g-u) · source_derived_draft · unverified_draft
### l929-b12-lowers-methylmalonyl-pool Adding 2.5 micromolar B12 during ECHDC1-knockout L929 adipocyte differentiation lowered whole-cell methylmalonyl-CoA approximately 20-fold. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: B12 addition sharply lowered this measured precursor pool in cultured mouse adipocytes. The cells had ECHDC1 deleted. organism: Mus musculus tissue_or_cell_type: Adipocytes experimental_model: Differentiating ECHDC1-knockout mouse L929 adipocytes (Figure 4g-u) limitations: Whole-cell LC-MS pools; no compartment or epimer resolution and no direct pathway flux measurement. exposure: ECHDC1 knockout; 2.5 micromolar supplementary B12 during differentiation cross_nutrient: false evidence_location: Full text Results: vitamin B12 supplementation; Figure 4g-u [dewulf-2019-l929-b12] The synthesis of branched-chain fatty acids is limited by enzymatic decarboxylation of ethyl- and methylmalonyl-CoA. (2019). https://pubmed.ncbi.nlm.nih.gov/31416829/ DOI: 10.1042/bcj20190500
Complete structured claim and evidence
B12 supplementation lowered the measured propionyl-CoA pool approximately fourfold in differentiating ECHDC1-knockout L929 adipocytes.
Vitamin B12 (cobalamins) → Propionyl-CoA source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Full text Results: vitamin B12 supplementation; Figure 4g-u
experimental_model
Differentiating ECHDC1-knockout mouse L929 adipocytes (Figure 4g-u)
exposure
ECHDC1 knockout; 2.5 micromolar supplementary B12 during differentiation
limitations
Whole-cell LC-MS pools; no compartment or epimer resolution and no direct pathway flux measurement.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Mus musculus
plain_language
In the same mouse-cell experiment, B12 also lowered the upstream propionyl-CoA pool. The cells had ECHDC1 deleted.
primary_references
[dewulf-2019-l929-b12] The synthesis of branched-chain fatty acids is limited by enzymatic decarboxylation of ethyl- and methylmalonyl-CoA. (2019). https://pubmed.ncbi.nlm.nih.gov/31416829/ DOI: 10.1042/bcj20190500
tissue_or_cell_type
Adipocytes
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1272–1284
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Differentiating ECHDC1-knockout mouse L929 adipocytes (Figure 4g-u) · source_derived_draft · unverified_draft
### l929-b12-lowers-propionyl-pool B12 supplementation lowered the measured propionyl-CoA pool approximately fourfold in differentiating ECHDC1-knockout L929 adipocytes. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: In the same mouse-cell experiment, B12 also lowered the upstream propionyl-CoA pool. The cells had ECHDC1 deleted. organism: Mus musculus tissue_or_cell_type: Adipocytes experimental_model: Differentiating ECHDC1-knockout mouse L929 adipocytes (Figure 4g-u) limitations: Whole-cell LC-MS pools; no compartment or epimer resolution and no direct pathway flux measurement. exposure: ECHDC1 knockout; 2.5 micromolar supplementary B12 during differentiation cross_nutrient: false evidence_location: Full text Results: vitamin B12 supplementation; Figure 4g-u [dewulf-2019-l929-b12] The synthesis of branched-chain fatty acids is limited by enzymatic decarboxylation of ethyl- and methylmalonyl-CoA. (2019). https://pubmed.ncbi.nlm.nih.gov/31416829/ DOI: 10.1042/bcj20190500
Complete structured claim and evidence
In those LIPT1-deficient fibroblasts, PDH activity increased only moderately, OGDH showed no increase, and the leucine-flux assay showed no BCKDH rescue.
Lipoic acid → Human pyruvate dehydrogenase complex source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/ala-research/24341803.fulltext.txt", "locator": "Exact primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "44f3fc89f065e58c1deb82f02c93a3654504f002fbc051d00a7703d3fbe6764b", "start_char": 19977, "end_char": 20689, "text_sha256": "3a495a2251965512793b341794c86b5caedc8525754344b8bba51281e7802a79"}
experimental_model
LIPT1 patient fibroblasts with supplementation and genetic complementation
exposure
Lipoic acid 10 or 100 micromolar for three weeks
limitations
Partial biochemical changes do not establish restored lipoylation or clinical efficacy. Historical pathway speculation is not imported as current enzymology.
nutrient_topic
Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid
organism
Human
plain_language
A lower lactate measurement did not mean all affected enzyme systems were repaired.
primary_references
[ala-p24341803] Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase. (2013). https://pubmed.ncbi.nlm.nih.gov/24341803/ DOI: 10.1186/1750-1172-8-192
tissue_or_cell_type
Patient and control fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 494–505
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · LIPT1 patient fibroblasts with supplementation and genetic complementation · source_derived_draft · unverified_draft
### ala-lipt1-enzyme-partial-response In those LIPT1-deficient fibroblasts, PDH activity increased only moderately, OGDH showed no increase, and the leucine-flux assay showed no BCKDH rescue. Condition category: machinery_impairment nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A lower lactate measurement did not mean all affected enzyme systems were repaired. organism: Human tissue_or_cell_type: Patient and control fibroblasts experimental_model: LIPT1 patient fibroblasts with supplementation and genetic complementation limitations: Partial biochemical changes do not establish restored lipoylation or clinical efficacy. Historical pathway speculation is not imported as current enzymology. exposure: Lipoic acid 10 or 100 micromolar for three weeks evidence_span: {"source_cache": "artifacts/ala-research/24341803.fulltext.txt", "locator": "Exact primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "44f3fc89f065e58c1deb82f02c93a3654504f002fbc051d00a7703d3fbe6764b", "start_char": 19977, "end_char": 20689, "text_sha256": "3a495a2251965512793b341794c86b5caedc8525754344b8bba51281e7802a79"} [ala-p24341803] Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase. (2013). https://pubmed.ncbi.nlm.nih.gov/24341803/ DOI: 10.1186/1750-1172-8-192
Complete structured claim and evidence
Hypusination disruption lowered expression of methylmalonyl-CoA mutase; its mitochondrial targeting sequence increased reporter dependence on eIF5A.
Mouse eIF5A translation factor → Mouse methylmalonyl-CoA mutase / MMUT source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Mouse macrophage/MEF protein experiments and targeting-sequence reporters.
limitations
This is protein expression, not proof of riboflavin, CoA or B12 deficiency; the relevant cofactor requires separate evidence.
nutrient_topic
Spermidine collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Spermidine
plain_language
Making a cofactor-dependent enzyme is another potential bottleneck.
primary_references
Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31130465/ · DOI 10.1016/j.cmet.2019.05.003
Spermidine: biosynthesis, hypusination, transport and cross-nutrient mechanisms (2026-09-19) · lines 286–292
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse macrophage/MEF protein experiments and targeting-sequence reporters. · source_derived_draft · unverified_draft
## spermidine-mitochondrial-target-mmut Making a cofactor-dependent enzyme is another potential bottleneck. Hypusination disruption lowered expression of methylmalonyl-CoA mutase; its mitochondrial targeting sequence increased reporter dependence on eIF5A. Model: Mouse macrophage/MEF protein experiments and targeting-sequence reporters. Limitations: This is protein expression, not proof of riboflavin, CoA or B12 deficiency; the relevant cofactor requires separate evidence. Evidence access: Primary full text Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31130465/ · DOI 10.1016/j.cmet.2019.05.003
Complete structured claim and evidence

Availability and dependencies

Each situation shows the normal role first, then what the sources report under a specific condition. A shortfall in the diet, a fault in the machinery, and a low blood reading are kept separate because they are not the same thing.

Transport can fail despite an available substrate

Condition: machinery_impairment · Accessory-protein deletion or transporter variants.