Nutrient chapter

L-Threonine

Context-specific entity; species, compartment and exposure are stated on each claim.

68 recorded mechanisms · 13 availability situations · 4 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.

Cloned human ASCT1 transported alanine, serine, cysteine and threonine rather than glutamate or aspartate.
Human neutral amino acid exchanger ASCT1 / SLC1A4 → L-Threonine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human cDNA cloning and transporter characterization.
limitations
Substrate overlap alone does not quantify competition during ordinary dietary intake.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Several amino acids share a cellular entry and exchange route.
primary_references
Human neutral amino acid transporter ASCT1: structure of the gene (SLC1A4) and localization to chromosome 2p13-p15. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7896285/ · DOI 10.1006/geno.1994.1577
transport_effect
depends A substrate-selectivity record. ASCT1 is an obligatory exchanger and no direction is stated.
transport_pool
the cytosol across the plasma membrane A substrate-selectivity record. ASCT1 is an obligatory exchanger and no direction is stated.
L-Threonine: translation, intestinal barrier, metabolism 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 · Human cDNA cloning and transporter characterization. · source_derived_draft · unverified_draft
## l-threonine-asct1-substrate Several amino acids share a cellular entry and exchange route. Cloned human ASCT1 transported alanine, serine, cysteine and threonine rather than glutamate or aspartate. Model: Human cDNA cloning and transporter characterization. Limitations: Substrate overlap alone does not quantify competition during ordinary dietary intake. Evidence access: Primary abstract Human neutral amino acid transporter ASCT1: structure of the gene (SLC1A4) and localization to chromosome 2p13-p15. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7896285/ · DOI 10.1006/geno.1994.1577
Complete structured claim and evidence
L-threonine inhibited radiolabeled L-serine uptake in HEK cells expressing human ASCT1, with an IC50 of 181 ± 75 micromolar.
L-Threonine → Human neutral amino acid exchanger ASCT1 / SLC1A4 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full-text Table 5, publisher PDF
experimental_model
Table 5: three observations per transporter; heterologous human-transporter HEK cell assays.
limitations
An inhibition concentration in culture is not a dietary threshold or proof of reduced brain serine.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Threonine can compete with serine in a defined transporter assay.
primary_references
D-Serine Is a Substrate for Neutral Amino Acid Transporters ASCT1/SLC1A4 and ASCT2/SLC1A5, and Is Transported by Both Subtypes in Rat Hippocampal Astrocyte Cultures. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27272177/ · DOI 10.1371/journal.pone.0156551
L-Threonine: translation, intestinal barrier, metabolism 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 · Table 5: three observations per transporter; heterologous human-transporter HEK cell assays. · source_derived_draft · unverified_draft
## l-threonine-serine-competition-slc1a4 Threonine can compete with serine in a defined transporter assay. L-threonine inhibited radiolabeled L-serine uptake in HEK cells expressing human ASCT1, with an IC50 of 181 ± 75 micromolar. Model: Table 5: three observations per transporter; heterologous human-transporter HEK cell assays. Limitations: An inhibition concentration in culture is not a dietary threshold or proof of reduced brain serine. Evidence access: Primary full-text Table 5, publisher PDF D-Serine Is a Substrate for Neutral Amino Acid Transporters ASCT1/SLC1A4 and ASCT2/SLC1A5, and Is Transported by Both Subtypes in Rat Hippocampal Astrocyte Cultures. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27272177/ · DOI 10.1371/journal.pone.0156551
Complete structured claim and evidence
L-threonine inhibited radiolabeled L-serine uptake in HEK cells expressing human ASCT2, with an IC50 of 228 ± 83 micromolar.
L-Threonine → Human neutral amino acid exchanger ASCT2 / SLC1A5 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full-text Table 5, publisher PDF
experimental_model
Table 5: three observations per transporter; heterologous human-transporter HEK cell assays.
limitations
An inhibition concentration in culture is not a dietary threshold or proof of reduced brain serine.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Threonine can compete with serine in a defined transporter assay.
primary_references
D-Serine Is a Substrate for Neutral Amino Acid Transporters ASCT1/SLC1A4 and ASCT2/SLC1A5, and Is Transported by Both Subtypes in Rat Hippocampal Astrocyte Cultures. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27272177/ · DOI 10.1371/journal.pone.0156551
L-Threonine: translation, intestinal barrier, metabolism 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 · Table 5: three observations per transporter; heterologous human-transporter HEK cell assays. · source_derived_draft · unverified_draft
## l-threonine-serine-competition-slc1a5 Threonine can compete with serine in a defined transporter assay. L-threonine inhibited radiolabeled L-serine uptake in HEK cells expressing human ASCT2, with an IC50 of 228 ± 83 micromolar. Model: Table 5: three observations per transporter; heterologous human-transporter HEK cell assays. Limitations: An inhibition concentration in culture is not a dietary threshold or proof of reduced brain serine. Evidence access: Primary full-text Table 5, publisher PDF D-Serine Is a Substrate for Neutral Amino Acid Transporters ASCT1/SLC1A4 and ASCT2/SLC1A5, and Is Transported by Both Subtypes in Rat Hippocampal Astrocyte Cultures. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27272177/ · DOI 10.1371/journal.pone.0156551
Complete structured claim and evidence
Ex vivo pig jejunal L-threonine flux was sodium dependent in assays using 50 micromolar and 5 millimolar amino-acid concentrations.
Sodium ion → Pig jejunal mucosal-to-serosal threonine flux source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Jejunum from male castrated Pietrain × Danbred pigs receiving different methionine supplements.
limitations
Tissue flux integrates several transporters; it does not identify one exclusive threonine carrier.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
An ion gradient contributes to intestinal amino-acid movement.
primary_references
Transport of Neutral Amino Acids in the Jejunum of Pigs with Special Consideration of L-Methionine. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39408384/ · DOI 10.3390/nu16193418
L-Threonine: translation, intestinal barrier, metabolism 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 · Jejunum from male castrated Pietrain × Danbred pigs receiving different methionine supplements. · source_derived_draft · unverified_draft
## l-threonine-pig-sodium-uptake An ion gradient contributes to intestinal amino-acid movement. Ex vivo pig jejunal L-threonine flux was sodium dependent in assays using 50 micromolar and 5 millimolar amino-acid concentrations. Model: Jejunum from male castrated Pietrain × Danbred pigs receiving different methionine supplements. Limitations: Tissue flux integrates several transporters; it does not identify one exclusive threonine carrier. Evidence access: Primary abstract Transport of Neutral Amino Acids in the Jejunum of Pigs with Special Consideration of L-Methionine. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39408384/ · DOI 10.3390/nu16193418
Complete structured claim and evidence
Mucosal L-methionine inhibited threonine uptake in the pig jejunal transport experiments.
L-Methionine → Pig jejunal apical threonine uptake source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Ex vivo pig tissue; amino-acid uptake inhibition experiment.
limitations
This does not show that normal methionine intake causes human threonine deficiency.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
A different essential amino acid can compete at the intestinal transport step.
primary_references
Transport of Neutral Amino Acids in the Jejunum of Pigs with Special Consideration of L-Methionine. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39408384/ · DOI 10.3390/nu16193418
L-Threonine: translation, intestinal barrier, metabolism 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 · Ex vivo pig tissue; amino-acid uptake inhibition experiment. · source_derived_draft · unverified_draft
## l-threonine-methionine-competition A different essential amino acid can compete at the intestinal transport step. Mucosal L-methionine inhibited threonine uptake in the pig jejunal transport experiments. Model: Ex vivo pig tissue; amino-acid uptake inhibition experiment. Limitations: This does not show that normal methionine intake causes human threonine deficiency. Evidence access: Primary abstract Transport of Neutral Amino Acids in the Jejunum of Pigs with Special Consideration of L-Methionine. · 2024 · https://pubmed.ncbi.nlm.nih.gov/39408384/ · DOI 10.3390/nu16193418
Complete structured claim and evidence
Human cytosolic TARS aminoacylation assays measured threonine loading onto tRNA and competitive inhibition by borrelidin-class compounds.
Human cytosolic threonyl-tRNA synthetase / TARS1 → Human cytosolic threonyl-tRNA Thr source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human enzyme biochemistry alongside inhibitor structures and cellular studies.
limitations
The charging reaction and extracellular signaling by the enzyme are separate functions.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
The amino acid must be attached to its matching tRNA before translation.
primary_references
Aminoacyl-tRNA synthetase dependent angiogenesis revealed by a bioengineered macrolide inhibitor. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26271225/ · DOI 10.1038/srep13160
L-Threonine: translation, intestinal barrier, metabolism 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 enzyme biochemistry alongside inhibitor structures and cellular studies. · source_derived_draft · unverified_draft
## l-threonine-tars1-charging The amino acid must be attached to its matching tRNA before translation. Human cytosolic TARS aminoacylation assays measured threonine loading onto tRNA and competitive inhibition by borrelidin-class compounds. Model: Human enzyme biochemistry alongside inhibitor structures and cellular studies. Limitations: The charging reaction and extracellular signaling by the enzyme are separate functions. Evidence access: Primary abstract Aminoacyl-tRNA synthetase dependent angiogenesis revealed by a bioengineered macrolide inhibitor. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26271225/ · DOI 10.1038/srep13160
Complete structured claim and evidence
Human TARS2 generates mitochondrial Thr-tRNA Thr for mitochondrial translation.
Human mitochondrial threonyl-tRNA synthetase / TARS2 → Human mitochondrial threonyl-tRNA Thr source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human TARS2 functional characterization and disease-variant assays.
limitations
Cytosolic TARS1 does not replace this mitochondrial record.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Mitochondria have their own threonine-loading enzyme.
primary_references
Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease. · 2022 · https://pubmed.ncbi.nlm.nih.gov/34508595/ · DOI 10.1093/hmg/ddab257
L-Threonine: translation, intestinal barrier, metabolism 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 · Human TARS2 functional characterization and disease-variant assays. · source_derived_draft · unverified_draft
## l-threonine-tars2-charging Mitochondria have their own threonine-loading enzyme. Human TARS2 generates mitochondrial Thr-tRNA Thr for mitochondrial translation. Model: Human TARS2 functional characterization and disease-variant assays. Limitations: Cytosolic TARS1 does not replace this mitochondrial record. Evidence access: Primary abstract Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease. · 2022 · https://pubmed.ncbi.nlm.nih.gov/34508595/ · DOI 10.1093/hmg/ddab257
Complete structured claim and evidence
Human TARS2 clears mischarged Ser-tRNA Thr during mitochondrial translation.
Human mitochondrial threonyl-tRNA synthetase / TARS2 → Mischarged human mitochondrial Ser-tRNA Thr source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human mitochondrial aminoacyl-tRNA synthetase biochemistry.
limitations
This is tRNA-bound substrate discrimination, not evidence that serine supplements cause mistranslation.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Proofreading removes serine accidentally attached to threonine tRNA.
primary_references
Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease. · 2022 · https://pubmed.ncbi.nlm.nih.gov/34508595/ · DOI 10.1093/hmg/ddab257
L-Threonine: translation, intestinal barrier, metabolism 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 · Human mitochondrial aminoacyl-tRNA synthetase biochemistry. · source_derived_draft · unverified_draft
## l-threonine-tars2-editing Proofreading removes serine accidentally attached to threonine tRNA. Human TARS2 clears mischarged Ser-tRNA Thr during mitochondrial translation. Model: Human mitochondrial aminoacyl-tRNA synthetase biochemistry. Limitations: This is tRNA-bound substrate discrimination, not evidence that serine supplements cause mistranslation. Evidence access: Primary abstract Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease. · 2022 · https://pubmed.ncbi.nlm.nih.gov/34508595/ · DOI 10.1093/hmg/ddab257
Complete structured claim and evidence
Seven newly reported TARS2 variants were linked to mitochondrial disease, with functional studies demonstrating impaired protein stability or function.
Human mitochondrial threonyl-tRNA synthetase / TARS2 → Human TARS2 stability and catalytic function source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Five unrelated patients; one nonsense and six missense variants; biochemical and functional analysis.
limitations
Disease mechanisms differ by variant; response to threonine supplementation was not established.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Enough amino acid cannot by itself guarantee a working loading enzyme.
primary_references
Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease. · 2022 · https://pubmed.ncbi.nlm.nih.gov/34508595/ · DOI 10.1093/hmg/ddab257
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 · Five unrelated patients; one nonsense and six missense variants; biochemical and functional analysis. · source_derived_draft · unverified_draft
## l-threonine-tars2-variants Enough amino acid cannot by itself guarantee a working loading enzyme. Seven newly reported TARS2 variants were linked to mitochondrial disease, with functional studies demonstrating impaired protein stability or function. Model: Five unrelated patients; one nonsense and six missense variants; biochemical and functional analysis. Limitations: Disease mechanisms differ by variant; response to threonine supplementation was not established. Evidence access: Primary abstract Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease. · 2022 · https://pubmed.ncbi.nlm.nih.gov/34508595/ · DOI 10.1093/hmg/ddab257
Complete structured claim and evidence
GSNO treatment S-nitrosated human mitochondrial ThrRS and reduced both aminoacylation and editing activity in vitro.
S-Nitrosoglutathione / GSNO → Human mitochondrial threonyl-tRNA synthetase / TARS2 source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Purified human enzyme; four modified cysteine residues; corroborating S-nitrosation detection in human cells and mouse tissues.
limitations
GSNO is not reduced glutathione; this exposure does not predict effects of oral glutathione. H2O2 resistance and GSNO sensitivity were distinct in this study.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Chemical modification of the enzyme can disrupt loading and proofreading.
primary_references
Nitrosative stress inhibits aminoacylation and editing activities of mitochondrial threonyl-tRNA synthetase by S-nitrosation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32484546/ · DOI 10.1093/nar/gkaa471
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 · Purified human enzyme; four modified cysteine residues; corroborating S-nitrosation detection in human cells and mouse tissues. · source_derived_draft · unverified_draft
## l-threonine-tars2-nitrosation Chemical modification of the enzyme can disrupt loading and proofreading. GSNO treatment S-nitrosated human mitochondrial ThrRS and reduced both aminoacylation and editing activity in vitro. Model: Purified human enzyme; four modified cysteine residues; corroborating S-nitrosation detection in human cells and mouse tissues. Limitations: GSNO is not reduced glutathione; this exposure does not predict effects of oral glutathione. H2O2 resistance and GSNO sensitivity were distinct in this study. Evidence access: Primary abstract Nitrosative stress inhibits aminoacylation and editing activities of mitochondrial threonyl-tRNA synthetase by S-nitrosation. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32484546/ · DOI 10.1093/nar/gkaa471
Complete structured claim and evidence
TARS2 interacted with inactive Rag complexes, especially GTP-bound RagC, and promoted RagA GTP loading.
Human mitochondrial threonyl-tRNA synthetase / TARS2 → Human RagA GTP loading source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Cellular interaction and mTORC1 signaling experiments.
limitations
GTP-bound RagC here belongs to the inactive Rag configuration; GTP status has different implications for RagA and RagC.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
A threonine-processing protein also links nutrient availability to a growth-control switch.
primary_references
Mitochondrial Threonyl-tRNA Synthetase TARS2 Is Required for Threonine-Sensitive mTORC1 Activation. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33340489/ · DOI 10.1016/j.molcel.2020.11.036
L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 98–104
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cellular interaction and mTORC1 signaling experiments. · source_derived_draft · unverified_draft
## l-threonine-tars2-rag A threonine-processing protein also links nutrient availability to a growth-control switch. TARS2 interacted with inactive Rag complexes, especially GTP-bound RagC, and promoted RagA GTP loading. Model: Cellular interaction and mTORC1 signaling experiments. Limitations: GTP-bound RagC here belongs to the inactive Rag configuration; GTP status has different implications for RagA and RagC. Evidence access: Primary abstract Mitochondrial Threonyl-tRNA Synthetase TARS2 Is Required for Threonine-Sensitive mTORC1 Activation. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33340489/ · DOI 10.1016/j.molcel.2020.11.036
Complete structured claim and evidence
Cells lacking TARS2 failed to restore mTORC1 activation in response to threonine repletion; cytosolic TARS was not required for this signaling effect.
Human mitochondrial threonyl-tRNA synthetase / TARS2 → Threonine-responsive human cellular mTORC1 activation source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
TARS2 loss and threonine repletion in cultured cells.
limitations
This is a signaling endpoint, not a clinical threonine-repletion trial.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Restoring the nutrient did not restore the signal when its machinery was missing.
primary_references
Mitochondrial Threonyl-tRNA Synthetase TARS2 Is Required for Threonine-Sensitive mTORC1 Activation. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33340489/ · DOI 10.1016/j.molcel.2020.11.036
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism and cross-nutrient mechanisms (2026-09-19) · lines 106–112
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · TARS2 loss and threonine repletion in cultured cells. · source_derived_draft · unverified_draft
## l-threonine-tars2-repletion-failure Restoring the nutrient did not restore the signal when its machinery was missing. Cells lacking TARS2 failed to restore mTORC1 activation in response to threonine repletion; cytosolic TARS was not required for this signaling effect. Model: TARS2 loss and threonine repletion in cultured cells. Limitations: This is a signaling endpoint, not a clinical threonine-repletion trial. Evidence access: Primary abstract Mitochondrial Threonyl-tRNA Synthetase TARS2 Is Required for Threonine-Sensitive mTORC1 Activation. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33340489/ · DOI 10.1016/j.molcel.2020.11.036
Complete structured claim and evidence
Disease-associated variants within TARS2 residues 301–381 reduced Rag binding in vitro; the associated mTORC1 mechanism was also investigated in zebrafish.
Human mitochondrial threonyl-tRNA synthetase / TARS2 → Human TARS2 binding to Rag GTPases source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
18 newly reported individuals from 15 families, prior cases reviewed, in vitro assays and zebrafish modeling.
limitations
Likely mechanistic contribution, not proof that this pathway explains every patient feature.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Some variants can affect signaling as well as the usual translation function.
primary_references
Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37454282/ · DOI 10.1016/j.gim.2023.100938
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 · 18 newly reported individuals from 15 families, prior cases reviewed, in vitro assays and zebrafish modeling. · source_derived_draft · unverified_draft
## l-threonine-tars2-rag-variants Some variants can affect signaling as well as the usual translation function. Disease-associated variants within TARS2 residues 301–381 reduced Rag binding in vitro; the associated mTORC1 mechanism was also investigated in zebrafish. Model: 18 newly reported individuals from 15 families, prior cases reviewed, in vitro assays and zebrafish modeling. Limitations: Likely mechanistic contribution, not proof that this pathway explains every patient feature. Evidence access: Primary abstract Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder. · 2023 · https://pubmed.ncbi.nlm.nih.gov/37454282/ · DOI 10.1016/j.gim.2023.100938
Complete structured claim and evidence
Human YRDC and OSGEPL1 supported mitochondrial t6A37 formation using L-threonine, ATP and CO2/bicarbonate as substrates.
Human threonylcarbamoyladenylate synthase / YRDC → Human mitochondrial tRNA threonylcarbamoyltransferase / OSGEPL1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human mitochondrial tRNA-modification reconstitution and cellular experiments.
limitations
The mark occurs on multiple tRNAs; it is not restricted to the tRNA that carries threonine.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Threonine helps make a decoding mark on tRNA, separate from being loaded for protein synthesis.
primary_references
CO2-sensitive tRNA modification associated with human mitochondrial disease. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29760464/ · DOI 10.1038/s41467-018-04250-4
L-Threonine: translation, intestinal barrier, metabolism 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 mitochondrial tRNA-modification reconstitution and cellular experiments. · source_derived_draft · unverified_draft
## l-threonine-trna-mark-substrates Threonine helps make a decoding mark on tRNA, separate from being loaded for protein synthesis. Human YRDC and OSGEPL1 supported mitochondrial t6A37 formation using L-threonine, ATP and CO2/bicarbonate as substrates. Model: Human mitochondrial tRNA-modification reconstitution and cellular experiments. Limitations: The mark occurs on multiple tRNAs; it is not restricted to the tRNA that carries threonine. Evidence access: Primary abstract CO2-sensitive tRNA modification associated with human mitochondrial disease. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29760464/ · DOI 10.1038/s41467-018-04250-4
Complete structured claim and evidence
The t6A pathway first forms threonylcarbamoyladenylate from threonine, bicarbonate and ATP; OSGEPL1 then transfers the threonylcarbamoyl group to mitochondrial tRNA A37.
Human threonylcarbamoyladenylate synthase / YRDC → L-Threonylcarbamoyladenylate / TC-AMP source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract and accessible primary-paper pathway description
experimental_model
Primary paper pathway description supporting human mitochondrial experiments.
limitations
The reaction sequence is described in the primary paper introduction; the 2024 study primarily tests loss of the downstream enzyme.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
An activated intermediate links nutrient supply to an RNA modification.
primary_references
Multifaceted roles of t6A biogenesis in efficiency and fidelity of mitochondrial gene expression. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38227555/ · DOI 10.1093/nar/gkae013
L-Threonine: translation, intestinal barrier, metabolism 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 · Primary paper pathway description supporting human mitochondrial experiments. · source_derived_draft · unverified_draft
## l-threonine-trna-intermediate An activated intermediate links nutrient supply to an RNA modification. The t6A pathway first forms threonylcarbamoyladenylate from threonine, bicarbonate and ATP; OSGEPL1 then transfers the threonylcarbamoyl group to mitochondrial tRNA A37. Model: Primary paper pathway description supporting human mitochondrial experiments. Limitations: The reaction sequence is described in the primary paper introduction; the 2024 study primarily tests loss of the downstream enzyme. Evidence access: Primary abstract and accessible primary-paper pathway description Multifaceted roles of t6A biogenesis in efficiency and fidelity of mitochondrial gene expression. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38227555/ · DOI 10.1093/nar/gkae013
Complete structured claim and evidence
The measured bicarbonate/CO2 Km for t6A37 formation was 31 millimolar; human cells cultured without bicarbonate had less t6A37 in mitochondrial tRNAs.
Bicarbonate ion → tRNA-bound N6-threonylcarbamoyladenosine / t6A37 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Reconstituted enzyme kinetics and bicarbonate-deprived human cell culture.
limitations
The culture manipulation is not a bicarbonate supplementation trial or a clinical intracellular threshold.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
An additional substrate can limit the threonine-dependent reaction.
primary_references
CO2-sensitive tRNA modification associated with human mitochondrial disease. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29760464/ · DOI 10.1038/s41467-018-04250-4
L-Threonine: translation, intestinal barrier, metabolism 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 · Reconstituted enzyme kinetics and bicarbonate-deprived human cell culture. · source_derived_draft · unverified_draft
## l-threonine-bicarbonate-limitation An additional substrate can limit the threonine-dependent reaction. The measured bicarbonate/CO2 Km for t6A37 formation was 31 millimolar; human cells cultured without bicarbonate had less t6A37 in mitochondrial tRNAs. Model: Reconstituted enzyme kinetics and bicarbonate-deprived human cell culture. Limitations: The culture manipulation is not a bicarbonate supplementation trial or a clinical intracellular threshold. Evidence access: Primary abstract CO2-sensitive tRNA modification associated with human mitochondrial disease. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29760464/ · DOI 10.1038/s41467-018-04250-4
Complete structured claim and evidence
OSGEPL1 knockout reduced mitochondrial translation and impaired respiration in human cells.
Human mitochondrial tRNA threonylcarbamoyltransferase / OSGEPL1 → Human mitochondrial translation dependent on t6A37 source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human knockout cell experiments.
limitations
Loss of the enzyme is not equivalent to inadequate dietary threonine.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
An amino-acid-derived RNA mark depends on its own installing enzyme.
primary_references
CO2-sensitive tRNA modification associated with human mitochondrial disease. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29760464/ · DOI 10.1038/s41467-018-04250-4
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 knockout cell experiments. · source_derived_draft · unverified_draft
## l-threonine-osgepl1-loss An amino-acid-derived RNA mark depends on its own installing enzyme. OSGEPL1 knockout reduced mitochondrial translation and impaired respiration in human cells. Model: Human knockout cell experiments. Limitations: Loss of the enzyme is not equivalent to inadequate dietary threonine. Evidence access: Primary abstract CO2-sensitive tRNA modification associated with human mitochondrial disease. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29760464/ · DOI 10.1038/s41467-018-04250-4
Complete structured claim and evidence
OSGEPL1 deletion in HEK293T cells reduced aminoacylation of mitochondrial tRNA Thr and tRNA Lys and altered other tRNA modifications.
Human mitochondrial tRNA threonylcarbamoyltransferase / OSGEPL1 → Human mitochondrial threonine and lysine tRNA charging source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human HEK293T knockout and tRNA modification/aminoacylation measurements.
limitations
The result identifies a tRNA-modification requirement, not a dietary lysine shortage.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Threonine-derived chemistry supports the handling of another amino acid too.
primary_references
Multifaceted roles of t6A biogenesis in efficiency and fidelity of mitochondrial gene expression. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38227555/ · DOI 10.1093/nar/gkae013
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 HEK293T knockout and tRNA modification/aminoacylation measurements. · source_derived_draft · unverified_draft
## l-threonine-osgepl1-charging Threonine-derived chemistry supports the handling of another amino acid too. OSGEPL1 deletion in HEK293T cells reduced aminoacylation of mitochondrial tRNA Thr and tRNA Lys and altered other tRNA modifications. Model: Human HEK293T knockout and tRNA modification/aminoacylation measurements. Limitations: The result identifies a tRNA-modification requirement, not a dietary lysine shortage. Evidence access: Primary abstract Multifaceted roles of t6A biogenesis in efficiency and fidelity of mitochondrial gene expression. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38227555/ · DOI 10.1093/nar/gkae013
Complete structured claim and evidence
Mitochondrial t6A37 hypomodification after OSGEPL1 deletion caused near-cognate codon misreading and amino-acid misincorporation.
Human mitochondrial tRNA threonylcarbamoyltransferase / OSGEPL1 → Human mitochondrial near-cognate codon misreading source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human HEK293T knockout; mitochondrial protein and translation analyses.
limitations
Knockout cells remained viable; physiological consequences cannot be inferred from mistranslation alone.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Loss of an RNA mark can change translation accuracy as well as speed.
primary_references
Multifaceted roles of t6A biogenesis in efficiency and fidelity of mitochondrial gene expression. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38227555/ · DOI 10.1093/nar/gkae013
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 HEK293T knockout; mitochondrial protein and translation analyses. · source_derived_draft · unverified_draft
## l-threonine-osgepl1-fidelity Loss of an RNA mark can change translation accuracy as well as speed. Mitochondrial t6A37 hypomodification after OSGEPL1 deletion caused near-cognate codon misreading and amino-acid misincorporation. Model: Human HEK293T knockout; mitochondrial protein and translation analyses. Limitations: Knockout cells remained viable; physiological consequences cannot be inferred from mistranslation alone. Evidence access: Primary abstract Multifaceted roles of t6A biogenesis in efficiency and fidelity of mitochondrial gene expression. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38227555/ · DOI 10.1093/nar/gkae013
Complete structured claim and evidence
Wild-type OSGEPL1 restored mitochondrial function, whereas a tRNA-binding-defective OSGEPL1 construct did not.
Human mitochondrial tRNA threonylcarbamoyltransferase / OSGEPL1 → Mitochondrial function in OSGEPL1-deficient human cells source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Genetic complementation of knockout cells.
limitations
The same study observed translation disruption without overt baseline heart deficiency in Osgepl1-deleted mice; tissue and challenge matter.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Restoring a protein helps only if it retains the required molecular function.
primary_references
Multifaceted roles of t6A biogenesis in efficiency and fidelity of mitochondrial gene expression. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38227555/ · DOI 10.1093/nar/gkae013
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 · Genetic complementation of knockout cells. · source_derived_draft · unverified_draft
## l-threonine-osgepl1-rescue Restoring a protein helps only if it retains the required molecular function. Wild-type OSGEPL1 restored mitochondrial function, whereas a tRNA-binding-defective OSGEPL1 construct did not. Model: Genetic complementation of knockout cells. Limitations: The same study observed translation disruption without overt baseline heart deficiency in Osgepl1-deleted mice; tissue and challenge matter. Evidence access: Primary abstract Multifaceted roles of t6A biogenesis in efficiency and fidelity of mitochondrial gene expression. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38227555/ · DOI 10.1093/nar/gkae013
Complete structured claim and evidence
Threonyl-tRNA synthetase interacted with 4EHP and recruited initiation components into a translation-initiation machinery that selected target mRNAs.
Human cytosolic threonyl-tRNA synthetase / TARS1 → Human eIF4E homologous protein / 4EHP / EIF4E2 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Biochemical interaction and RNA immunoprecipitation/sequencing analyses in vertebrate models.
limitations
This scaffold function is not evidence that adding free threonine increases translation of the same targets.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
A tRNA-loading enzyme can also help organize translation initiation.
primary_references
A threonyl-tRNA synthetase-mediated translation initiation machinery. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30902983/ · DOI 10.1038/s41467-019-09086-0
L-Threonine: translation, intestinal barrier, metabolism 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 · Biochemical interaction and RNA immunoprecipitation/sequencing analyses in vertebrate models. · source_derived_draft · unverified_draft
## l-threonine-tars1-translation-scaffold A tRNA-loading enzyme can also help organize translation initiation. Threonyl-tRNA synthetase interacted with 4EHP and recruited initiation components into a translation-initiation machinery that selected target mRNAs. Model: Biochemical interaction and RNA immunoprecipitation/sequencing analyses in vertebrate models. Limitations: This scaffold function is not evidence that adding free threonine increases translation of the same targets. Evidence access: Primary abstract A threonyl-tRNA synthetase-mediated translation initiation machinery. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30902983/ · DOI 10.1038/s41467-019-09086-0
Complete structured claim and evidence
GalNAc-T2 initiates mucin-type O-glycosylation by transferring GalNAc from UDP-GalNAc to serine or threonine residues within proteins.
Human polypeptide GalNAc transferase 2 / GALNT2 → Protein-bound L-threonine residue source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human GalNAc-T2 structural and NMR enzymology.
limitations
Free dietary threonine is not the glycosyltransferase acceptor used in this protein-modification reaction.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
A threonine residue already built into a protein can carry a sugar.
primary_references
Structural Analysis of a GalNAc-T2 Mutant Reveals an Induced-Fit Catalytic Mechanism for GalNAc-Ts. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29601100/ · DOI 10.1002/chem.201800701
L-Threonine: translation, intestinal barrier, metabolism 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 GalNAc-T2 structural and NMR enzymology. · source_derived_draft · unverified_draft
## l-threonine-galnt2-sugar A threonine residue already built into a protein can carry a sugar. GalNAc-T2 initiates mucin-type O-glycosylation by transferring GalNAc from UDP-GalNAc to serine or threonine residues within proteins. Model: Human GalNAc-T2 structural and NMR enzymology. Limitations: Free dietary threonine is not the glycosyltransferase acceptor used in this protein-modification reaction. Evidence access: Primary abstract Structural Analysis of a GalNAc-T2 Mutant Reveals an Induced-Fit Catalytic Mechanism for GalNAc-Ts. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29601100/ · DOI 10.1002/chem.201800701
Complete structured claim and evidence
GALNT2 F104S disrupted the UDP-GalNAc-dependent active conformation and peptide-substrate binding.
Human polypeptide GalNAc transferase 2 / GALNT2 → Human GALNT2 peptide-substrate binding source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human mutant crystal structure, NMR and molecular-dynamics analysis.
limitations
No correction of this defect by threonine supplementation was demonstrated.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
A sugar donor and amino-acid-containing protein are insufficient if the modifying enzyme cannot bind correctly.
primary_references
Structural Analysis of a GalNAc-T2 Mutant Reveals an Induced-Fit Catalytic Mechanism for GalNAc-Ts. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29601100/ · DOI 10.1002/chem.201800701
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 mutant crystal structure, NMR and molecular-dynamics analysis. · source_derived_draft · unverified_draft
## l-threonine-galnt2-f104s A sugar donor and amino-acid-containing protein are insufficient if the modifying enzyme cannot bind correctly. GALNT2 F104S disrupted the UDP-GalNAc-dependent active conformation and peptide-substrate binding. Model: Human mutant crystal structure, NMR and molecular-dynamics analysis. Limitations: No correction of this defect by threonine supplementation was demonstrated. Evidence access: Primary abstract Structural Analysis of a GalNAc-T2 Mutant Reveals an Induced-Fit Catalytic Mechanism for GalNAc-Ts. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29601100/ · DOI 10.1002/chem.201800701
Complete structured claim and evidence
Piglet portal-drained viscera used a large fraction of dietary threonine, mainly through incorporation into mucosal proteins; dietary supply was preferentially used over systemic supply under normal-protein feeding.
L-Threonine → Pig intestinal mucosal protein source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
18 piglets, normal or protein-restricted isocaloric feeding; stable-isotope tracing after seven hours of enteral feeding.
limitations
Reported 91% versus 85% dietary utilization is specific to this model and feeding interval, not a human universal fraction.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
The gut uses much of the incoming amino acid before it reaches other tissues.
primary_references
Threonine utilization is high in the intestine of piglets. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15795432/ · DOI 10.1093/jn/135.4.765
L-Threonine: translation, intestinal barrier, metabolism 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 · 18 piglets, normal or protein-restricted isocaloric feeding; stable-isotope tracing after seven hours of enteral feeding. · source_derived_draft · unverified_draft
## l-threonine-intestinal-allocation The gut uses much of the incoming amino acid before it reaches other tissues. Piglet portal-drained viscera used a large fraction of dietary threonine, mainly through incorporation into mucosal proteins; dietary supply was preferentially used over systemic supply under normal-protein feeding. Model: 18 piglets, normal or protein-restricted isocaloric feeding; stable-isotope tracing after seven hours of enteral feeding. Limitations: Reported 91% versus 85% dietary utilization is specific to this model and feeding interval, not a human universal fraction. Evidence access: Primary abstract Threonine utilization is high in the intestine of piglets. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15795432/ · DOI 10.1093/jn/135.4.765
Complete structured claim and evidence
Increasing luminal threonine across 0, 21 and 56 mg/g total amino acids raised measured mucin synthesis in perfused intestinal loops.
L-Threonine → Pig gut-loop mucin synthesis source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Six pigs; isolated loops perfused for 120 minutes with an amino-acid mixture and labeled phenylalanine incorporation.
limitations
An acute local dose response is distinct from chronic whole-diet excess.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
The local amino-acid supply can change how quickly mucus protein is made.
primary_references
Luminal threonine concentration acutely affects intestinal mucosal protein and mucin synthesis in piglets. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18567751/ · DOI 10.1093/jn/138.7.1298
L-Threonine: translation, intestinal barrier, metabolism 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 · Six pigs; isolated loops perfused for 120 minutes with an amino-acid mixture and labeled phenylalanine incorporation. · source_derived_draft · unverified_draft
## l-threonine-gut-local-synthesis The local amino-acid supply can change how quickly mucus protein is made. Increasing luminal threonine across 0, 21 and 56 mg/g total amino acids raised measured mucin synthesis in perfused intestinal loops. Model: Six pigs; isolated loops perfused for 120 minutes with an amino-acid mixture and labeled phenylalanine incorporation. Limitations: An acute local dose response is distinct from chronic whole-diet excess. Evidence access: Primary abstract Luminal threonine concentration acutely affects intestinal mucosal protein and mucin synthesis in piglets. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18567751/ · DOI 10.1093/jn/138.7.1298
Complete structured claim and evidence
Feeding neonatal piglets 0.1 rather than 0.6 g threonine/kg/day for eight days reduced colonic mucosal mass and mucin content and altered acidic mucin-producing goblet cells.
L-Threonine → Neonatal pig intestinal mucin barrier source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Two-day-old piglets; intragastric adequate versus deficient diets.
limitations
Acidic mucin subtypes decreased in small intestine but increased in colon; these different sites must not be collapsed into one uniform response.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
A severe shortfall changed both mucus quantity and its distribution.
primary_references
Adequate oral threonine is critical for mucin production and gut function in neonatal piglets. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17234895/ · DOI 10.1152/ajpgi.00221.2006
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 · Two-day-old piglets; intragastric adequate versus deficient diets. · source_derived_draft · unverified_draft
## l-threonine-gut-deficiency-mucin A severe shortfall changed both mucus quantity and its distribution. Feeding neonatal piglets 0.1 rather than 0.6 g threonine/kg/day for eight days reduced colonic mucosal mass and mucin content and altered acidic mucin-producing goblet cells. Model: Two-day-old piglets; intragastric adequate versus deficient diets. Limitations: Acidic mucin subtypes decreased in small intestine but increased in colon; these different sites must not be collapsed into one uniform response. Evidence access: Primary abstract Adequate oral threonine is critical for mucin production and gut function in neonatal piglets. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17234895/ · DOI 10.1152/ajpgi.00221.2006
Complete structured claim and evidence
The threonine-deficient piglets excreted more nitrogen and had higher plasma urea than adequate groups.
L-Threonine → Neonatal pig nitrogen loss under threonine deficiency source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Same eight-day piglet intervention, not an independent cohort.
limitations
The experiment did not establish a human threshold for threonine-limited protein retention.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Shortage of one amino acid can make other dietary nitrogen less efficiently retained.
primary_references
Adequate oral threonine is critical for mucin production and gut function in neonatal piglets. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17234895/ · DOI 10.1152/ajpgi.00221.2006
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 · Same eight-day piglet intervention, not an independent cohort. · source_derived_draft · unverified_draft
## l-threonine-gut-deficiency-nitrogen Shortage of one amino acid can make other dietary nitrogen less efficiently retained. The threonine-deficient piglets excreted more nitrogen and had higher plasma urea than adequate groups. Model: Same eight-day piglet intervention, not an independent cohort. Limitations: The experiment did not establish a human threshold for threonine-limited protein retention. Evidence access: Primary abstract Adequate oral threonine is critical for mucin production and gut function in neonatal piglets. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17234895/ · DOI 10.1152/ajpgi.00221.2006
Complete structured claim and evidence
Adding 0.5 g/kg/day intravenous threonine to the 0.1 g/kg/day oral supply maintained most measured outcomes, but colonic goblet-cell and mucin differences remained.
L-Threonine → Pig responses to parenteral threonine during oral deficiency source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Parenteral add-back during otherwise intragastric piglet feeding.
limitations
This is not an oral supplement trial; the same animals contribute several outcomes.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Circulating supply compensated for much, but not every feature, of low luminal supply.
primary_references
Adequate oral threonine is critical for mucin production and gut function in neonatal piglets. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17234895/ · DOI 10.1152/ajpgi.00221.2006
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 · Parenteral add-back during otherwise intragastric piglet feeding. · source_derived_draft · unverified_draft
## l-threonine-gut-parenteral-rescue Circulating supply compensated for much, but not every feature, of low luminal supply. Adding 0.5 g/kg/day intravenous threonine to the 0.1 g/kg/day oral supply maintained most measured outcomes, but colonic goblet-cell and mucin differences remained. Model: Parenteral add-back during otherwise intragastric piglet feeding. Limitations: This is not an oral supplement trial; the same animals contribute several outcomes. Evidence access: Primary abstract Adequate oral threonine is critical for mucin production and gut function in neonatal piglets. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17234895/ · DOI 10.1152/ajpgi.00221.2006
Complete structured claim and evidence
In weanling pigs, both 0.37% and 1.11% dietary digestible threonine reduced duodenal mucin and MUC2 expression relative to 0.89% during fourteen-day feeding.
L-Threonine → Weanling pig MUC2 expression and mucosal barrier source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Four groups of eight pigs; 0.37%, 0.74%, 0.89% or 1.11% true ileal digestible threonine.
limitations
Pig diet percentages do not establish human doses. Different duration, preparation and endpoint explain why this need not oppose the acute loop experiment.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
More was not always better in a chronic feeding experiment.
primary_references
Optimal dietary true ileal digestible threonine for supporting the mucosal barrier in small intestine of weanling pigs. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20335627/ · DOI 10.3945/jn.109.118497
L-Threonine: translation, intestinal barrier, metabolism 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 · Four groups of eight pigs; 0.37%, 0.74%, 0.89% or 1.11% true ileal digestible threonine. · source_derived_draft · unverified_draft
## l-threonine-gut-nonlinearity More was not always better in a chronic feeding experiment. In weanling pigs, both 0.37% and 1.11% dietary digestible threonine reduced duodenal mucin and MUC2 expression relative to 0.89% during fourteen-day feeding. Model: Four groups of eight pigs; 0.37%, 0.74%, 0.89% or 1.11% true ileal digestible threonine. Limitations: Pig diet percentages do not establish human doses. Different duration, preparation and endpoint explain why this need not oppose the acute loop experiment. Evidence access: Primary abstract Optimal dietary true ileal digestible threonine for supporting the mucosal barrier in small intestine of weanling pigs. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20335627/ · DOI 10.3945/jn.109.118497
Complete structured claim and evidence
Purified human hepatic serine dehydratase showed L-threonine dehydratase activity in comparison with the human SDH-like isoform.
Human hepatic serine dehydratase / SDS → Alpha-ketobutyrate source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human recombinant enzymes expressed in E. coli and compared biochemically.
limitations
Activity in a purified system does not quantify whole-body human threonine flux. The threonine product is alpha-ketobutyrate, distinct from the serine product pyruvate.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Threonine can enter carbon metabolism through an enzyme it shares with serine.
primary_references
Enzymatic and biochemical properties of a novel human serine dehydratase isoform. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16580895/ · DOI 10.1016/j.bbapap.2006.02.010
L-Threonine: translation, intestinal barrier, metabolism 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 · Human recombinant enzymes expressed in E. coli and compared biochemically. · source_derived_draft · unverified_draft
## l-threonine-human-sds-catabolism Threonine can enter carbon metabolism through an enzyme it shares with serine. Purified human hepatic serine dehydratase showed L-threonine dehydratase activity in comparison with the human SDH-like isoform. Model: Human recombinant enzymes expressed in E. coli and compared biochemically. Limitations: Activity in a purified system does not quantify whole-body human threonine flux. The threonine product is alpha-ketobutyrate, distinct from the serine product pyruvate. Evidence access: Primary abstract Enzymatic and biochemical properties of a novel human serine dehydratase isoform. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16580895/ · DOI 10.1016/j.bbapap.2006.02.010
Complete structured claim and evidence
The recombinant human SDH-like protein also had threonine dehydratase activity, with kinetic constants differing substantially from hepatic SDS.
Human serine dehydratase-like protein / SDSL → Alpha-ketobutyrate source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Comparative human enzyme kinetics and PLP-binding measurements.
limitations
Isoform abundance in cultured cells was low; catalytic capacity does not establish its dominant tissue role.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Closely related enzymes can process the same substrate at different rates.
primary_references
Enzymatic and biochemical properties of a novel human serine dehydratase isoform. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16580895/ · DOI 10.1016/j.bbapap.2006.02.010
L-Threonine: translation, intestinal barrier, metabolism 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 · Comparative human enzyme kinetics and PLP-binding measurements. · source_derived_draft · unverified_draft
## l-threonine-human-sdsl-catabolism Closely related enzymes can process the same substrate at different rates. The recombinant human SDH-like protein also had threonine dehydratase activity, with kinetic constants differing substantially from hepatic SDS. Model: Comparative human enzyme kinetics and PLP-binding measurements. Limitations: Isoform abundance in cultured cells was low; catalytic capacity does not establish its dominant tissue role. Evidence access: Primary abstract Enzymatic and biochemical properties of a novel human serine dehydratase isoform. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16580895/ · DOI 10.1016/j.bbapap.2006.02.010
Complete structured claim and evidence
Deleting Pro128 from human hepatic SDS changed substrate kinetic constants and affinity for pyridoxal phosphate.
PLP → Human hepatic serine dehydratase / SDS source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Purified wild-type and engineered human enzymes.
limitations
This manipulation does not show that additional B6 restores a mutant enzyme or that ordinary dietary B6 is limiting.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
B6-dependent chemistry also depends on the enzyme structure that binds its cofactor.
primary_references
Enzymatic and biochemical properties of a novel human serine dehydratase isoform. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16580895/ · DOI 10.1016/j.bbapap.2006.02.010
L-Threonine: translation, intestinal barrier, metabolism 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 · Purified wild-type and engineered human enzymes. · source_derived_draft · unverified_draft
## l-threonine-human-sds-plp B6-dependent chemistry also depends on the enzyme structure that binds its cofactor. Deleting Pro128 from human hepatic SDS changed substrate kinetic constants and affinity for pyridoxal phosphate. Model: Purified wild-type and engineered human enzymes. Limitations: This manipulation does not show that additional B6 restores a mutant enzyme or that ordinary dietary B6 is limiting. Evidence access: Primary abstract Enzymatic and biochemical properties of a novel human serine dehydratase isoform. · 2006 · https://pubmed.ncbi.nlm.nih.gov/16580895/ · DOI 10.1016/j.bbapap.2006.02.010
Complete structured claim and evidence
Human TDH transcripts encode truncated proteins because of splice-site disruption and a premature stop codon; the gene was classified as an expressed pseudogene.
Human TDH expressed pseudogene → Functional canonical human TDH threonine-oxidation route source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human cDNA/genomic analysis; exon-6 splice-site loss in all 23 genotyped individuals.
limitations
Do not transfer intact mouse Tdh-dependent glycine and acetyl-CoA synthesis to humans.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
An expressed gene is not necessarily a functioning metabolic route.
primary_references
The human L-threonine 3-dehydrogenase gene is an expressed pseudogene. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12361482/ · DOI 10.1186/1471-2156-3-18
L-Threonine: translation, intestinal barrier, metabolism 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 · Human cDNA/genomic analysis; exon-6 splice-site loss in all 23 genotyped individuals. · source_derived_draft · unverified_draft
## l-threonine-human-tdh-boundary An expressed gene is not necessarily a functioning metabolic route. Human TDH transcripts encode truncated proteins because of splice-site disruption and a premature stop codon; the gene was classified as an expressed pseudogene. Model: Human cDNA/genomic analysis; exon-6 splice-site loss in all 23 genotyped individuals. Limitations: Do not transfer intact mouse Tdh-dependent glycine and acetyl-CoA synthesis to humans. Evidence access: Primary abstract The human L-threonine 3-dehydrogenase gene is an expressed pseudogene. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12361482/ · DOI 10.1186/1471-2156-3-18
Complete structured claim and evidence
Human GLY1 contained frameshifting deletions and a premature stop codon; its mRNA was not detected, unlike the transcribed mouse homolog.
Human threonine aldolase / GLY1 pseudogene → Functional canonical human GLY1 threonine-aldolase route source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Comparative human and mouse gene characterization.
limitations
This does not exclude all possible promiscuous enzyme activity; it rejects treating canonical human GLY1 as an established active enzyme.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
A second proposed glycine-producing route also differs across species.
primary_references
Mice have a transcribed L-threonine aldolase/GLY1 gene, but the human GLY1 gene is a non-processed pseudogene. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15757516/ · DOI 10.1186/1471-2164-6-32
L-Threonine: translation, intestinal barrier, metabolism 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 · Comparative human and mouse gene characterization. · source_derived_draft · unverified_draft
## l-threonine-human-aldolase-boundary A second proposed glycine-producing route also differs across species. Human GLY1 contained frameshifting deletions and a premature stop codon; its mRNA was not detected, unlike the transcribed mouse homolog. Model: Comparative human and mouse gene characterization. Limitations: This does not exclude all possible promiscuous enzyme activity; it rejects treating canonical human GLY1 as an established active enzyme. Evidence access: Primary abstract Mice have a transcribed L-threonine aldolase/GLY1 gene, but the human GLY1 gene is a non-processed pseudogene. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15757516/ · DOI 10.1186/1471-2164-6-32
Complete structured claim and evidence
A study in six adult men detected limited threonine-derived glycine labeling, accounting for an estimated 7–11% of threonine catabolism under its model.
L-Threonine → Glycine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Four-hour labeled-threonine/glycine infusions under control and high-threonine diets.
limitations
The paper called this TDG flux before the human TDH pseudogene was characterized. Retain the tracer observation without asserting functional human TDH; alternative routes were not resolved.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Detecting carbon transfer does not identify the enzyme responsible.
primary_references
Threonine dehydrogenase is a minor degradative pathway of threonine catabolism in adult humans. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10780944/ · DOI 10.1152/ajpendo.2000.278.5.E877
L-Threonine: translation, intestinal barrier, metabolism 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 · Four-hour labeled-threonine/glycine infusions under control and high-threonine diets. · source_derived_draft · unverified_draft
## l-threonine-human-glycine-tracer Detecting carbon transfer does not identify the enzyme responsible. A study in six adult men detected limited threonine-derived glycine labeling, accounting for an estimated 7–11% of threonine catabolism under its model. Model: Four-hour labeled-threonine/glycine infusions under control and high-threonine diets. Limitations: The paper called this TDG flux before the human TDH pseudogene was characterized. Retain the tracer observation without asserting functional human TDH; alternative routes were not resolved. Evidence access: Primary abstract Threonine dehydrogenase is a minor degradative pathway of threonine catabolism in adult humans. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10780944/ · DOI 10.1152/ajpendo.2000.278.5.E877
Complete structured claim and evidence
High threonine intake supplied either as free amino acid or protein increased measured threonine oxidation to CO2 approximately threefold.
L-Threonine → Human threonine oxidation to carbon dioxide source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Same six men; control intake 50 versus 126 micromol/kg/hour in the two high-intake conditions.
limitations
Short controlled feeding/tracer study; not a long-term benefit or safety threshold.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Extra intake can increase disposal rather than being retained unchanged.
primary_references
Threonine dehydrogenase is a minor degradative pathway of threonine catabolism in adult humans. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10780944/ · DOI 10.1152/ajpendo.2000.278.5.E877
L-Threonine: translation, intestinal barrier, metabolism 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 · Same six men; control intake 50 versus 126 micromol/kg/hour in the two high-intake conditions. · source_derived_draft · unverified_draft
## l-threonine-human-oxidation-response Extra intake can increase disposal rather than being retained unchanged. High threonine intake supplied either as free amino acid or protein increased measured threonine oxidation to CO2 approximately threefold. Model: Same six men; control intake 50 versus 126 micromol/kg/hour in the two high-intake conditions. Limitations: Short controlled feeding/tracer study; not a long-term benefit or safety threshold. Evidence access: Primary abstract Threonine dehydrogenase is a minor degradative pathway of threonine catabolism in adult humans. · 2000 · https://pubmed.ncbi.nlm.nih.gov/10780944/ · DOI 10.1152/ajpendo.2000.278.5.E877
Complete structured claim and evidence
Purified BCOADC oxidized 2-oxobutyrate with a reported Km of 18 micromolar; purified PDC also accepted it, whereas OGDH did not.
Purified BCOADC in the 1986 ketoacid study, source species unverified → Alpha-ketobutyrate source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Purified-enzyme comparison; source species is not specified in the accessible abstract.
limitations
This is not recorded as direct human enzyme evidence or an exclusive BCKDH route. Correction record: PubMed indexes an erratum in Biochemical Journal 1987;242(3):935. The notice text was inaccessible during this curation; its specific scope and impact remain unverified. The purified-enzyme findings are retained provisionally with this flag, and the abstract does not identify the source species. https://pubmed.ncbi.nlm.nih.gov/3800905/
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
More than one ketoacid complex can handle this carbon skeleton in vitro.
primary_references
Oxidative decarboxylation of 4-methylthio-2-oxobutyrate by branched-chain 2-oxo acid dehydrogenase complex. · 1986 · https://pubmed.ncbi.nlm.nih.gov/3800905/ · DOI 10.1042/bj2370621
L-Threonine: translation, intestinal barrier, metabolism 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 · Purified-enzyme comparison; source species is not specified in the accessible abstract. · source_derived_draft · unverified_draft
## l-threonine-ketoacid-oxidation More than one ketoacid complex can handle this carbon skeleton in vitro. Purified BCOADC oxidized 2-oxobutyrate with a reported Km of 18 micromolar; purified PDC also accepted it, whereas OGDH did not. Model: Purified-enzyme comparison; source species is not specified in the accessible abstract. Limitations: This is not recorded as direct human enzyme evidence or an exclusive BCKDH route. Correction record: PubMed indexes an erratum in Biochemical Journal 1987;242(3):935. The notice text was inaccessible during this curation; its specific scope and impact remain unverified. The purified-enzyme findings are retained provisionally with this flag, and the abstract does not identify the source species. https://pubmed.ncbi.nlm.nih.gov/3800905/ Evidence access: Primary abstract Oxidative decarboxylation of 4-methylthio-2-oxobutyrate by branched-chain 2-oxo acid dehydrogenase complex. · 1986 · https://pubmed.ncbi.nlm.nih.gov/3800905/ · DOI 10.1042/bj2370621
Complete structured claim and evidence
2-Oxobutyrate inhibited BCOADC kinase, and reduced BCOADC phosphorylation was observed in isolated adipocytes.
Alpha-ketobutyrate → BCOADC kinase in the 1986 study, source species unverified source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Purified kinase and isolated-adipocyte assays; species unverified from abstract.
limitations
This does not prove that a threonine supplement changes BCAA oxidation in humans. Correction record: PubMed indexes an erratum in Biochemical Journal 1987;242(3):935. The notice text was inaccessible during this curation; its specific scope and impact remain unverified. The purified-enzyme findings are retained provisionally with this flag, and the abstract does not identify the source species. https://pubmed.ncbi.nlm.nih.gov/3800905/
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
A catabolic intermediate can influence the regulatory brake on its disposal machinery.
primary_references
Oxidative decarboxylation of 4-methylthio-2-oxobutyrate by branched-chain 2-oxo acid dehydrogenase complex. · 1986 · https://pubmed.ncbi.nlm.nih.gov/3800905/ · DOI 10.1042/bj2370621
L-Threonine: translation, intestinal barrier, metabolism 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 · Purified kinase and isolated-adipocyte assays; species unverified from abstract. · source_derived_draft · unverified_draft
## l-threonine-ketoacid-feedback A catabolic intermediate can influence the regulatory brake on its disposal machinery. 2-Oxobutyrate inhibited BCOADC kinase, and reduced BCOADC phosphorylation was observed in isolated adipocytes. Model: Purified kinase and isolated-adipocyte assays; species unverified from abstract. Limitations: This does not prove that a threonine supplement changes BCAA oxidation in humans. Correction record: PubMed indexes an erratum in Biochemical Journal 1987;242(3):935. The notice text was inaccessible during this curation; its specific scope and impact remain unverified. The purified-enzyme findings are retained provisionally with this flag, and the abstract does not identify the source species. https://pubmed.ncbi.nlm.nih.gov/3800905/ Evidence access: Primary abstract Oxidative decarboxylation of 4-methylthio-2-oxobutyrate by branched-chain 2-oxo acid dehydrogenase complex. · 1986 · https://pubmed.ncbi.nlm.nih.gov/3800905/ · DOI 10.1042/bj2370621
Complete structured claim and evidence
Mouse embryonic stem cells expressed abundant Tdh and used mitochondrial threonine catabolism to support glycine and acetyl-CoA generation.
Mouse L-threonine dehydrogenase / Tdh → Mouse embryonic stem-cell threonine-derived glycine and acetyl-CoA source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse embryonic stem-cell metabolism and amino-acid withdrawal experiments.
limitations
Canonical human TDH is nonfunctional; this route is explicitly mouse-specific.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
A specialized mouse cell uses threonine as both carbon and one-carbon support.
primary_references
Dependence of mouse embryonic stem cells on threonine catabolism. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19589965/ · DOI 10.1126/science.1173288
L-Threonine: translation, intestinal barrier, metabolism 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 · Mouse embryonic stem-cell metabolism and amino-acid withdrawal experiments. · source_derived_draft · unverified_draft
## l-threonine-mouse-tdh-flux A specialized mouse cell uses threonine as both carbon and one-carbon support. Mouse embryonic stem cells expressed abundant Tdh and used mitochondrial threonine catabolism to support glycine and acetyl-CoA generation. Model: Mouse embryonic stem-cell metabolism and amino-acid withdrawal experiments. Limitations: Canonical human TDH is nonfunctional; this route is explicitly mouse-specific. Evidence access: Primary abstract Dependence of mouse embryonic stem cells on threonine catabolism. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19589965/ · DOI 10.1126/science.1173288
Complete structured claim and evidence
Threonine withdrawal reduced SAM accumulation and H3K4 trimethylation in mouse embryonic stem cells, with slower growth and increased differentiation.
L-Threonine → Mouse embryonic stem-cell SAM and H3K4 trimethylation source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse stem-cell isotope tracing and culture-medium withdrawal.
limitations
Do not generalize to all methylation marks, adult human tissues or a threonine treatment for methylation problems.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
A nutrient supply change altered a specific epigenetic mark in this cell model.
primary_references
Influence of threonine metabolism on S-adenosylmethionine and histone methylation. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23118012/ · DOI 10.1126/science.1226603
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 · Mouse stem-cell isotope tracing and culture-medium withdrawal. · source_derived_draft · unverified_draft
## l-threonine-mouse-threonine-methylation A nutrient supply change altered a specific epigenetic mark in this cell model. Threonine withdrawal reduced SAM accumulation and H3K4 trimethylation in mouse embryonic stem cells, with slower growth and increased differentiation. Model: Mouse stem-cell isotope tracing and culture-medium withdrawal. Limitations: Do not generalize to all methylation marks, adult human tissues or a threonine treatment for methylation problems. Evidence access: Primary abstract Influence of threonine metabolism on S-adenosylmethionine and histone methylation. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23118012/ · DOI 10.1126/science.1226603
Complete structured claim and evidence
Depleting Tdh also lowered SAM and H3K4 trimethylation in the mouse stem-cell experiments.
Mouse L-threonine dehydrogenase / Tdh → Mouse embryonic stem-cell SAM and H3K4 trimethylation source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse embryonic stem-cell Tdh depletion, alongside dietary-substrate tracing in the same study.
limitations
The experiment and threonine withdrawal are complementary tests from one paper, not independent laboratories.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
The precursor requires an active metabolic pathway to affect the downstream mark.
primary_references
Influence of threonine metabolism on S-adenosylmethionine and histone methylation. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23118012/ · DOI 10.1126/science.1226603
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 · Mouse embryonic stem-cell Tdh depletion, alongside dietary-substrate tracing in the same study. · source_derived_draft · unverified_draft
## l-threonine-mouse-tdh-methylation The precursor requires an active metabolic pathway to affect the downstream mark. Depleting Tdh also lowered SAM and H3K4 trimethylation in the mouse stem-cell experiments. Model: Mouse embryonic stem-cell Tdh depletion, alongside dietary-substrate tracing in the same study. Limitations: The experiment and threonine withdrawal are complementary tests from one paper, not independent laboratories. Evidence access: Primary abstract Influence of threonine metabolism on S-adenosylmethionine and histone methylation. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23118012/ · DOI 10.1126/science.1226603
Complete structured claim and evidence
Dietary threonine restriction produced systemic metabolic remodeling in mice that required liver-derived FGF21.
L-Threonine → Mouse threonine-restriction metabolic remodeling source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse dietary essential-amino-acid restriction and FGF21-dependency experiments.
limitations
Mouse metabolic responses are not evidence that restriction is appropriate for humans or developing animals.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
A liver hormone mediates part of the organism-level response to restricted supply.
primary_references
Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32518324/ · DOI 10.1038/s41467-020-16568-z
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 dietary essential-amino-acid restriction and FGF21-dependency experiments. · source_derived_draft · unverified_draft
## l-threonine-fgf21-restriction A liver hormone mediates part of the organism-level response to restricted supply. Dietary threonine restriction produced systemic metabolic remodeling in mice that required liver-derived FGF21. Model: Mouse dietary essential-amino-acid restriction and FGF21-dependency experiments. Limitations: Mouse metabolic responses are not evidence that restriction is appropriate for humans or developing animals. Evidence access: Primary abstract Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32518324/ · DOI 10.1038/s41467-020-16568-z
Complete structured claim and evidence
Engineering threonine biosynthetic capacity selectively in hepatocytes reversed the systemic response to dietary threonine restriction.
L-Threonine → Mouse threonine-restriction metabolic remodeling source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Engineered mouse hepatocyte threonine synthesis during dietary restriction.
limitations
This experimentally installed pathway is not a normal mammalian threonine-synthesis route.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Restoring supply in one organ changed a whole-body nutritional signal.
primary_references
Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32518324/ · DOI 10.1038/s41467-020-16568-z
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 · Engineered mouse hepatocyte threonine synthesis during dietary restriction. · source_derived_draft · unverified_draft
## l-threonine-liver-supply-rescue Restoring supply in one organ changed a whole-body nutritional signal. Engineering threonine biosynthetic capacity selectively in hepatocytes reversed the systemic response to dietary threonine restriction. Model: Engineered mouse hepatocyte threonine synthesis during dietary restriction. Limitations: This experimentally installed pathway is not a normal mammalian threonine-synthesis route. Evidence access: Primary abstract Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32518324/ · DOI 10.1038/s41467-020-16568-z
Complete structured claim and evidence
Targeting YRDC reduced t6A, translation and tumor growth in glioblastoma stem-cell cultures and in vivo tumor models.
Human threonylcarbamoyladenylate synthase / YRDC → Human glioblastoma stem-cell t6A and translation source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
CRISPR screen, cultured glioblastoma stem cells and xenografts.
limitations
Genetic targeting of YRDC is distinct from nutritional restriction and from a demonstrated human cancer treatment.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
A tumor model depended on the machinery that uses threonine to modify tRNA.
primary_references
Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38519786/ · DOI 10.1038/s43018-024-00748-7
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 · CRISPR screen, cultured glioblastoma stem cells and xenografts. · source_derived_draft · unverified_draft
## l-threonine-yrdc-glioblastoma A tumor model depended on the machinery that uses threonine to modify tRNA. Targeting YRDC reduced t6A, translation and tumor growth in glioblastoma stem-cell cultures and in vivo tumor models. Model: CRISPR screen, cultured glioblastoma stem cells and xenografts. Limitations: Genetic targeting of YRDC is distinct from nutritional restriction and from a demonstrated human cancer treatment. Evidence access: Primary abstract Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38519786/ · DOI 10.1038/s43018-024-00748-7
Complete structured claim and evidence
Dietary threonine restriction reduced tumor t6A and slowed glioblastoma xenograft growth, augmenting tested chemotherapy and anti-mitotic therapy.
L-Threonine → Glioblastoma xenograft t6A and growth in mice source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse xenografts linked to human glioblastoma stem-cell experiments.
limitations
This study does not establish a safe or effective threonine-restricted diet for patients. Exact dietary protocol and drug schedules require full-text clinical translation review.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Tumor dependency led to an experimental dietary intervention in animals.
primary_references
Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38519786/ · DOI 10.1038/s43018-024-00748-7
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 xenografts linked to human glioblastoma stem-cell experiments. · source_derived_draft · unverified_draft
## l-threonine-tumor-threonine-restriction Tumor dependency led to an experimental dietary intervention in animals. Dietary threonine restriction reduced tumor t6A and slowed glioblastoma xenograft growth, augmenting tested chemotherapy and anti-mitotic therapy. Model: Mouse xenografts linked to human glioblastoma stem-cell experiments. Limitations: This study does not establish a safe or effective threonine-restricted diet for patients. Exact dietary protocol and drug schedules require full-text clinical translation review. Evidence access: Primary abstract Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38519786/ · DOI 10.1038/s43018-024-00748-7
Complete structured claim and evidence
Human endothelial cells secreted TARS after TNF-alpha or VEGF exposure.
Human cytosolic threonyl-tRNA synthetase / TARS1 → Human endothelial TNF-alpha or VEGF stimulation source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human vascular endothelial cell culture.
limitations
This is secretion of the enzyme, not secretion of threonine or proof that dietary threonine triggers the process.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
A protein that loads threonine can also leave the cell under signaling conditions.
primary_references
Secreted Threonyl-tRNA synthetase stimulates endothelial cell migration and angiogenesis. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23425968/ · DOI 10.1038/srep01317
L-Threonine: translation, intestinal barrier, metabolism 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 · Human vascular endothelial cell culture. · source_derived_draft · unverified_draft
## l-threonine-tars1-secretion A protein that loads threonine can also leave the cell under signaling conditions. Human endothelial cells secreted TARS after TNF-alpha or VEGF exposure. Model: Human vascular endothelial cell culture. Limitations: This is secretion of the enzyme, not secretion of threonine or proof that dietary threonine triggers the process. Evidence access: Primary abstract Secreted Threonyl-tRNA synthetase stimulates endothelial cell migration and angiogenesis. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23425968/ · DOI 10.1038/srep01317
Complete structured claim and evidence
Exogenous TARS promoted endothelial migration and angiogenesis in culture and chick chorioallantoic membrane assays.
Human cytosolic threonyl-tRNA synthetase / TARS1 → Endothelial migration and angiogenesis following extracellular TARS source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human endothelial assays and chick membrane model.
limitations
Enzyme exposure is not amino-acid supplementation; no claim of dietary cancer causation is made.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
The same enzyme has an extracellular signaling role.
primary_references
Secreted Threonyl-tRNA synthetase stimulates endothelial cell migration and angiogenesis. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23425968/ · DOI 10.1038/srep01317
L-Threonine: translation, intestinal barrier, metabolism 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 · Human endothelial assays and chick membrane model. · source_derived_draft · unverified_draft
## l-threonine-tars1-extracellular The same enzyme has an extracellular signaling role. Exogenous TARS promoted endothelial migration and angiogenesis in culture and chick chorioallantoic membrane assays. Model: Human endothelial assays and chick membrane model. Limitations: Enzyme exposure is not amino-acid supplementation; no claim of dietary cancer causation is made. Evidence access: Primary abstract Secreted Threonyl-tRNA synthetase stimulates endothelial cell migration and angiogenesis. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23425968/ · DOI 10.1038/srep01317
Complete structured claim and evidence
Borrelidin-class inhibitor toxicity was linked to competition with threonine at TARS, provoking amino-acid-starvation responses and apoptosis in the studied systems.
Borrelidin → Human cytosolic threonyl-tRNA synthetase / TARS1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Enzyme biochemistry, structures, cellular assays and zebrafish work.
limitations
Anti-angiogenic action could be separated from toxicity with selected derivatives; these are experimental agents, not routine nutrient interactions.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Blocking amino-acid processing can mimic inadequate supply inside a cell.
primary_references
Aminoacyl-tRNA synthetase dependent angiogenesis revealed by a bioengineered macrolide inhibitor. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26271225/ · DOI 10.1038/srep13160
L-Threonine: translation, intestinal barrier, metabolism 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 · Enzyme biochemistry, structures, cellular assays and zebrafish work. · source_derived_draft · unverified_draft
## l-threonine-borrelidin-competition Blocking amino-acid processing can mimic inadequate supply inside a cell. Borrelidin-class inhibitor toxicity was linked to competition with threonine at TARS, provoking amino-acid-starvation responses and apoptosis in the studied systems. Model: Enzyme biochemistry, structures, cellular assays and zebrafish work. Limitations: Anti-angiogenic action could be separated from toxicity with selected derivatives; these are experimental agents, not routine nutrient interactions. Evidence access: Primary abstract Aminoacyl-tRNA synthetase dependent angiogenesis revealed by a bioengineered macrolide inhibitor. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26271225/ · DOI 10.1038/srep13160
Complete structured claim and evidence
Acsf3 depletion increased labeled-threonine conversion to methylmalonic acid in mouse primary hepatocytes.
Mouse acyl-CoA synthetase family member 3 / Acsf3 → Mouse threonine-derived methylmalonate flux source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full-text Figure 3 results excerpt
experimental_model
Primary-paper Figure 3 isotope tracing and Acsf3-deficient mouse hepatocytes.
limitations
This mouse experiment must not be summarized as proven human threonine depletion or a clinical treatment.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
A downstream metabolic defect changed how threonine carbon accumulated.
primary_references
An ancient regulatory variant of ACSF3 influences the coevolution of increased human height and basal metabolic rate via metabolic homeostasis. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40403731/ · DOI 10.1016/j.xgen.2025.100855
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 · Primary-paper Figure 3 isotope tracing and Acsf3-deficient mouse hepatocytes. · source_derived_draft · unverified_draft
## l-threonine-acsf3-methylmalonate A downstream metabolic defect changed how threonine carbon accumulated. Acsf3 depletion increased labeled-threonine conversion to methylmalonic acid in mouse primary hepatocytes. Model: Primary-paper Figure 3 isotope tracing and Acsf3-deficient mouse hepatocytes. Limitations: This mouse experiment must not be summarized as proven human threonine depletion or a clinical treatment. Evidence access: Primary full-text Figure 3 results excerpt An ancient regulatory variant of ACSF3 influences the coevolution of increased human height and basal metabolic rate via metabolic homeostasis. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40403731/ · DOI 10.1016/j.xgen.2025.100855
Complete structured claim and evidence
Threonine in drinking water increased serum methylmalonic acid in Acsf3-null mice on a ketogenic diet, but not significantly in controls.
L-Threonine → Serum methylmalonic acid in Acsf3-null mice source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full-text Figure 3 results excerpt
experimental_model
Mouse genotype-by-diet experiment; ketogenic diet with amino-acid supplementation.
limitations
Not a human supplementation trial or evidence that serum MMA exclusively reports B12 status.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
More substrate affected a blocked metabolic setting differently from controls.
primary_references
An ancient regulatory variant of ACSF3 influences the coevolution of increased human height and basal metabolic rate via metabolic homeostasis. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40403731/ · DOI 10.1016/j.xgen.2025.100855
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 · Mouse genotype-by-diet experiment; ketogenic diet with amino-acid supplementation. · source_derived_draft · unverified_draft
## l-threonine-acsf3-threonine-addition More substrate affected a blocked metabolic setting differently from controls. Threonine in drinking water increased serum methylmalonic acid in Acsf3-null mice on a ketogenic diet, but not significantly in controls. Model: Mouse genotype-by-diet experiment; ketogenic diet with amino-acid supplementation. Limitations: Not a human supplementation trial or evidence that serum MMA exclusively reports B12 status. Evidence access: Primary full-text Figure 3 results excerpt An ancient regulatory variant of ACSF3 influences the coevolution of increased human height and basal metabolic rate via metabolic homeostasis. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40403731/ · DOI 10.1016/j.xgen.2025.100855
Complete structured claim and evidence
Compared with age-adjusted controls, NKH patients had higher CSF threonine, lower serine and higher glycine.
L-Threonine → CSF threonine in genetically confirmed nonketotic hyperglycinemia source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
61 genetically confirmed patients versus reference data from 274 controls; stereoselective serine analysis in a smaller subset.
limitations
Association does not identify a unique transport mechanism or justify treating an isolated CSF ratio.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
A high amino-acid measurement can accompany a defect in a neighboring pathway.
primary_references
Cerebrospinal fluid amino acids glycine, serine, and threonine in nonketotic hyperglycinemia. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35357708/ · DOI 10.1002/jimd.12500
trigger_kind
biomarker_context Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 · 61 genetically confirmed patients versus reference data from 274 controls; stereoselective serine analysis in a smaller subset. · source_derived_draft · unverified_draft
## l-threonine-nkh-amino-acid-pattern A high amino-acid measurement can accompany a defect in a neighboring pathway. Compared with age-adjusted controls, NKH patients had higher CSF threonine, lower serine and higher glycine. Model: 61 genetically confirmed patients versus reference data from 274 controls; stereoselective serine analysis in a smaller subset. Limitations: Association does not identify a unique transport mechanism or justify treating an isolated CSF ratio. Evidence access: Primary abstract Cerebrospinal fluid amino acids glycine, serine, and threonine in nonketotic hyperglycinemia. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35357708/ · DOI 10.1002/jimd.12500
Complete structured claim and evidence
E. coli mutant and enzyme studies showed TdcE conversion of threonine-derived 2-ketobutyrate into propionyl-CoA during anaerobic growth.
Escherichia coli 2-ketobutyrate formate-lyase / TdcE → Propionyl-CoA source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
E. coli operon analysis, mutants, enzyme assays and culture-supernatant NMR.
limitations
This is not a human enzyme reaction or a measurement of net propionate production in the human gut.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
Microbes have a separate route for fermenting threonine carbon.
primary_references
Novel keto acid formate-lyase and propionate kinase enzymes are components of an anaerobic pathway in Escherichia coli that degrades L-threonine to propionate. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9484901/ · DOI 10.1046/j.1365-2958.1998.00696.x
L-Threonine: translation, intestinal barrier, metabolism 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 · E. coli operon analysis, mutants, enzyme assays and culture-supernatant NMR. · source_derived_draft · unverified_draft
## l-threonine-microbial-ketoacid Microbes have a separate route for fermenting threonine carbon. E. coli mutant and enzyme studies showed TdcE conversion of threonine-derived 2-ketobutyrate into propionyl-CoA during anaerobic growth. Model: E. coli operon analysis, mutants, enzyme assays and culture-supernatant NMR. Limitations: This is not a human enzyme reaction or a measurement of net propionate production in the human gut. Evidence access: Primary abstract Novel keto acid formate-lyase and propionate kinase enzymes are components of an anaerobic pathway in Escherichia coli that degrades L-threonine to propionate. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9484901/ · DOI 10.1046/j.1365-2958.1998.00696.x
Complete structured claim and evidence
E. coli TdcD or AckA converted propionyl phosphate to propionate with ATP generation in the anaerobic threonine-degradation pathway.
Escherichia coli propionate kinase / TdcD → Propionate source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mutant pathway analysis and enzyme characterization.
limitations
Whether this pathway changes human host exposure depends on community, substrate supply and environmental conditions.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
A microbial fermentation step releases energy as well as a short-chain fatty acid.
primary_references
Novel keto acid formate-lyase and propionate kinase enzymes are components of an anaerobic pathway in Escherichia coli that degrades L-threonine to propionate. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9484901/ · DOI 10.1046/j.1365-2958.1998.00696.x
L-Threonine: translation, intestinal barrier, metabolism 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 · Mutant pathway analysis and enzyme characterization. · source_derived_draft · unverified_draft
## l-threonine-microbial-atp A microbial fermentation step releases energy as well as a short-chain fatty acid. E. coli TdcD or AckA converted propionyl phosphate to propionate with ATP generation in the anaerobic threonine-degradation pathway. Model: Mutant pathway analysis and enzyme characterization. Limitations: Whether this pathway changes human host exposure depends on community, substrate supply and environmental conditions. Evidence access: Primary abstract Novel keto acid formate-lyase and propionate kinase enzymes are components of an anaerobic pathway in Escherichia coli that degrades L-threonine to propionate. · 1998 · https://pubmed.ncbi.nlm.nih.gov/9484901/ · DOI 10.1046/j.1365-2958.1998.00696.x
Complete structured claim and evidence
Cytosolic t6A formation uses sequential YRDC and OSGEP activities, with OSGEP operating within the KEOPS complex.
Human threonylcarbamoyladenylate synthase / YRDC → Human KEOPS catalytic subunit / OSGEP source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Primary human genetics and structural study of the t6A pathway.
limitations
OSGEP and mitochondrial OSGEPL1 are distinct proteins; threonyl-tRNA loading is a separate reaction.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
The cytosol uses a different downstream machine from the mitochondrial pathway.
primary_references
Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31481669/ · DOI 10.1038/s41467-019-11951-x
L-Threonine: translation, intestinal barrier, metabolism 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 · Primary human genetics and structural study of the t6A pathway. · source_derived_draft · unverified_draft
## l-threonine-cytosolic-keops The cytosol uses a different downstream machine from the mitochondrial pathway. Cytosolic t6A formation uses sequential YRDC and OSGEP activities, with OSGEP operating within the KEOPS complex. Model: Primary human genetics and structural study of the t6A pathway. Limitations: OSGEP and mitochondrial OSGEPL1 are distinct proteins; threonyl-tRNA loading is a separate reaction. Evidence access: Primary abstract Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31481669/ · DOI 10.1038/s41467-019-11951-x
Complete structured claim and evidence
Human GON7 became partly structured upon binding LAGE3 in the GON7/LAGE3/OSGEP subcomplex, supporting its proposed role in KEOPS stability and organization.
Human KEOPS subunit / GON7 → Human KEOPS subunit / LAGE3 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Crystal structure and cellular characterization of human KEOPS components.
limitations
The structural observation supports a stabilizing role; it does not establish that extra threonine repairs a subunit defect.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
An organizing subunit helps assemble the RNA-modifying machine.
primary_references
Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31481669/ · DOI 10.1038/s41467-019-11951-x
L-Threonine: translation, intestinal barrier, metabolism 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 · Crystal structure and cellular characterization of human KEOPS components. · source_derived_draft · unverified_draft
## l-threonine-gon7-complex An organizing subunit helps assemble the RNA-modifying machine. Human GON7 became partly structured upon binding LAGE3 in the GON7/LAGE3/OSGEP subcomplex, supporting its proposed role in KEOPS stability and organization. Model: Crystal structure and cellular characterization of human KEOPS components. Limitations: The structural observation supports a stabilizing role; it does not establish that extra threonine repairs a subunit defect. Evidence access: Primary abstract Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31481669/ · DOI 10.1038/s41467-019-11951-x
Complete structured claim and evidence
Inherited YRDC mutations were associated with severe Galloway–Mowat syndrome, linking t6A machinery impairment with microcephaly and early-onset nephrotic disease.
Human threonylcarbamoyladenylate synthase / YRDC → YRDC-associated Galloway–Mowat syndrome source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human genetic disease study with functional analyses; GON7-associated cases were milder in the reported series.
limitations
This is an inherited machinery disorder, not demonstrated dietary threonine deficiency or a proven supplementation-responsive syndrome.
nutrient_topic
L-Threonine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Threonine
plain_language
A threonine-using RNA pathway matters in human brain and kidney development.
primary_references
Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31481669/ · DOI 10.1038/s41467-019-11951-x
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Threonine: translation, intestinal barrier, metabolism 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 · Human genetic disease study with functional analyses; GON7-associated cases were milder in the reported series. · source_derived_draft · unverified_draft
## l-threonine-yrdc-inherited-disease A threonine-using RNA pathway matters in human brain and kidney development. Inherited YRDC mutations were associated with severe Galloway–Mowat syndrome, linking t6A machinery impairment with microcephaly and early-onset nephrotic disease. Model: Human genetic disease study with functional analyses; GON7-associated cases were milder in the reported series. Limitations: This is an inherited machinery disorder, not demonstrated dietary threonine deficiency or a proven supplementation-responsive syndrome. Evidence access: Primary abstract Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31481669/ · DOI 10.1038/s41467-019-11951-x
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
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
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
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
HLCS rapidly biotinylated the biotin-acceptor fragment of human PCCA, with transfer limited by enzyme-substrate association.
Human holocarboxylase synthetase / HLCS → Human propionyl-CoA carboxylase alpha subunit / PCCA source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/biotin-research/22123817.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "559afe20b6f8601a2d055d42fb121c89eaf1ece76afaa5cc0817c20787893233", "start_char": 0, "end_char": 1502, "text_sha256": "559afe20b6f8601a2d055d42fb121c89eaf1ece76afaa5cc0817c20787893233"}
experimental_model
Single-turnover biotin transfer to minimal BCCP fragments from all five human carboxylases
exposure
Stopped-flow and quench-flow transfer kinetics
limitations
Fragment kinetics support differential recognition, not a universal nutrient-deficiency survival order in humans.
nutrient_topic
Biotin research collection; topical membership is not evidence of a direct dietary effect. · Biotin
organism
Homo sapiens
plain_language
This mitochondrial enzyme has a biotin attachment domain recognized by HLCS.
primary_references
[b7-p22123817] Selectivity in post-translational biotin addition to five human carboxylases. (2012). https://pubmed.ncbi.nlm.nih.gov/22123817/ DOI: 10.1074/jbc.m111.275982
tissue_or_cell_type
Purified HLCS and acceptor fragments
Biotin: carboxylases, recycling, deficiency and nutrient interactions (2026-09-17) · lines 403–414
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Single-turnover biotin transfer to minimal BCCP fragments from all five human carboxylases · source_derived_draft · unverified_draft
### b7-hlcs-pcc-acceptor HLCS rapidly biotinylated the biotin-acceptor fragment of human PCCA, with transfer limited by enzyme-substrate association. Condition category: normal nutrient_topic: Biotin research collection; topical membership is not evidence of a direct dietary effect. plain_language: This mitochondrial enzyme has a biotin attachment domain recognized by HLCS. organism: Homo sapiens tissue_or_cell_type: Purified HLCS and acceptor fragments experimental_model: Single-turnover biotin transfer to minimal BCCP fragments from all five human carboxylases limitations: Fragment kinetics support differential recognition, not a universal nutrient-deficiency survival order in humans. exposure: Stopped-flow and quench-flow transfer kinetics evidence_span: {"source_cache": "artifacts/biotin-research/22123817.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "559afe20b6f8601a2d055d42fb121c89eaf1ece76afaa5cc0817c20787893233", "start_char": 0, "end_char": 1502, "text_sha256": "559afe20b6f8601a2d055d42fb121c89eaf1ece76afaa5cc0817c20787893233"} [b7-p22123817] Selectivity in post-translational biotin addition to five human carboxylases. (2012). https://pubmed.ncbi.nlm.nih.gov/22123817/ DOI: 10.1074/jbc.m111.275982
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
{"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"}
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
PCCB provides the carboxyltransferase activity of human PCC.
Human propionyl-CoA carboxylase beta subunit / PCCB → Human propionyl-CoA carboxylase / PCC source_derived_draftungraded
Experimental context and source evidence
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"}
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 beta subunit performs the transfer onto the carbon substrate.
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 611–622
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-pccb PCCB provides the carboxyltransferase activity of human PCC. Condition category: normal nutrient_topic: Biotin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The beta subunit performs the transfer onto the carbon substrate. 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
In seven adults, 28-day egg-white-induced biotin depletion reduced mean lymphocyte PCC activity to 23% of baseline.
Biotin → Human lymphocyte propionyl-CoA carboxylase activity source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
true
evidence_location
Primary abstract and indexed Results: PCC activity
experimental_model
Seven healthy adults
exposure
28-day egg-white-rich biotin-depletion diet
limitations
Lymphocyte enzyme activity; no concurrent B12 intervention or systemic pathway flux measurement.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
In this small depletion study, low biotin weakened a human enzyme upstream of B12-dependent metabolism.
primary_references
[stratton-2006-biotin] Lymphocyte propionyl-CoA carboxylase and its activation by biotin are sensitive indicators of marginal biotin deficiency in humans. (2006). https://pubmed.ncbi.nlm.nih.gov/16895887/ DOI: 10.1093/ajcn/84.1.384
tissue_or_cell_type
Peripheral blood lymphocytes
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1202–1214
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Seven healthy adults · source_derived_draft · unverified_draft
### biotin-depletion-lowers-pcc In seven adults, 28-day egg-white-induced biotin depletion reduced mean lymphocyte PCC activity to 23% of baseline. Condition category: nutrient_deficiency nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: In this small depletion study, low biotin weakened a human enzyme upstream of B12-dependent metabolism. organism: Homo sapiens tissue_or_cell_type: Peripheral blood lymphocytes experimental_model: Seven healthy adults limitations: Lymphocyte enzyme activity; no concurrent B12 intervention or systemic pathway flux measurement. exposure: 28-day egg-white-rich biotin-depletion diet cross_nutrient: true evidence_location: Primary abstract and indexed Results: PCC activity [stratton-2006-biotin] Lymphocyte propionyl-CoA carboxylase and its activation by biotin are sensitive indicators of marginal biotin deficiency in humans. (2006). https://pubmed.ncbi.nlm.nih.gov/16895887/ DOI: 10.1093/ajcn/84.1.384
Complete structured claim and evidence
Human MCEE I53R lacked measured activity in the coupled patient-fibroblast assay with overexpressed MMUT and added adenosylcobalamin.
Human MCEE p.Ile53Arg → Human MCEE-dependent coupled propionyl-CoA pathway activity source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Full text Methods 2.6 and Results 3.6; Figure 5
experimental_model
MCEE-null human fibroblasts expressing MCEE I53R
exposure
I53R expression; MMUT coexpression; 50 micromolar AdoCbl
limitations
Overexpression assay; not a clinical test of B12 treatment.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Adding activated B12 did not make this defective epimerase work in the human-cell assay.
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
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1188–1200
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · MCEE-null human fibroblasts expressing MCEE I53R · source_derived_draft · unverified_draft
### mcee-i53r-reduces-coupled-activity Human MCEE I53R lacked measured activity in the coupled patient-fibroblast assay with overexpressed MMUT and added adenosylcobalamin. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding activated B12 did not make this defective epimerase work in the human-cell assay. organism: Homo sapiens tissue_or_cell_type: Fibroblasts experimental_model: MCEE-null human fibroblasts expressing MCEE I53R limitations: Overexpression assay; not a clinical test of B12 treatment. exposure: I53R expression; MMUT coexpression; 50 micromolar 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
Adding MMAA after 60 minutes restored activity in an inactivated human MMUT reaction through GTP hydrolysis.
Human MMAA GTPase → Human methylmalonyl-CoA mutase / MMUT source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Indexed primary abstract
experimental_model
Purified human proteins
exposure
MMAA added after 60-minute catalytic inactivation
limitations
In-vitro reactivation; abstract interprets damaged-cofactor exchange rather than measuring every intermediate.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
MMAA restarted an inactive purified human MMUT reaction in a GTP-dependent assay.
primary_references
[takahashi-2010-mmaa-repair] Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein. (2011). https://pubmed.ncbi.nlm.nih.gov/21138732/ DOI: 10.1016/j.bbrc.2010.11.141
tissue_or_cell_type
Purified protein assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1089–1101
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
### mmaa-reactivates-mmut Adding MMAA after 60 minutes restored activity in an inactivated human MMUT reaction through GTP hydrolysis. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: MMAA restarted an inactive purified human MMUT reaction in a GTP-dependent assay. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human proteins limitations: In-vitro reactivation; abstract interprets damaged-cofactor exchange rather than measuring every intermediate. exposure: MMAA added after 60-minute catalytic inactivation cross_nutrient: false evidence_location: Indexed primary abstract [takahashi-2010-mmaa-repair] Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein. (2011). https://pubmed.ncbi.nlm.nih.gov/21138732/ DOI: 10.1016/j.bbrc.2010.11.141
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

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.

Threonine loading, proofreading and sensing require functional TARS2

Condition: machinery_impairment · Inherited variants or engineered TARS2 loss.

Normal role: Cells import indispensable threonine, load it for translation and allocate it to compartment-specific reactions; each route requires its own machinery.

Recorded consequence: Impaired enzyme stability/activity or threonine-responsive mTORC1 activation; adding substrate does not replace missing machinery.