Nutrient chapter

Aspartame

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

63 recorded mechanisms · 5 availability situations · 8 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.

The intestinal study describes ester-bond hydrolysis of aspartame to Asp-Phe before further dipeptide digestion.
Aspartame → Alpha-L-aspartyl-L-phenylalanine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Reaction background and human intestinal mucosal enzyme experiments.
limitations
This record does not assign the initial esterase to an unverified gene.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Removing the methyl ester is separate from splitting the peptide.
primary_references
Intestinal hydrolysis of aspartylphenylalanine--the metabolic product of aspartame. · 1986 · https://pubmed.ncbi.nlm.nih.gov/3743970/ · DOI 10.1016/0016-5085(86)90697-9
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 18–24
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Reaction background and human intestinal mucosal enzyme experiments. · source_derived_draft · unverified_draft
## aspartame-ester-cleavage Removing the methyl ester is separate from splitting the peptide. The intestinal study describes ester-bond hydrolysis of aspartame to Asp-Phe before further dipeptide digestion. Model: Reaction background and human intestinal mucosal enzyme experiments. Limitations: This record does not assign the initial esterase to an unverified gene. Evidence access: Primary abstract Intestinal hydrolysis of aspartylphenylalanine--the metabolic product of aspartame. · 1986 · https://pubmed.ncbi.nlm.nih.gov/3743970/ · DOI 10.1016/0016-5085(86)90697-9
Complete structured claim and evidence
Brush-border and cytosolic preparations hydrolyzed Asp-Phe; cytosolic fractionation identified one activity peak distinct from seven previously described peptidases.
Alpha-L-aspartyl-L-phenylalanine → Human intestinal Asp-Phe dipeptide hydrolysis source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human intestinal mucosa and red-cell lysate fractionation.
limitations
Intact dipeptide transport was proposed; the cytosolic enzyme was not molecularly identified.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
The amino-acid pair can be processed after reaching a different cell compartment.
primary_references
Intestinal hydrolysis of aspartylphenylalanine--the metabolic product of aspartame. · 1986 · https://pubmed.ncbi.nlm.nih.gov/3743970/ · DOI 10.1016/0016-5085(86)90697-9
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 26–32
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human intestinal mucosa and red-cell lysate fractionation. · source_derived_draft · unverified_draft
## aspartame-dipeptide-cleavage The amino-acid pair can be processed after reaching a different cell compartment. Brush-border and cytosolic preparations hydrolyzed Asp-Phe; cytosolic fractionation identified one activity peak distinct from seven previously described peptidases. Model: Human intestinal mucosa and red-cell lysate fractionation. Limitations: Intact dipeptide transport was proposed; the cytosolic enzyme was not molecularly identified. Evidence access: Primary abstract Intestinal hydrolysis of aspartylphenylalanine--the metabolic product of aspartame. · 1986 · https://pubmed.ncbi.nlm.nih.gov/3743970/ · DOI 10.1016/0016-5085(86)90697-9
Complete structured claim and evidence
Diseased intestinal mucosa showed reduced brush-border and cytosolic Asp-Phe hydrolase activity alongside reductions in other enzymes.
Asp-Phe hydrolase activity in diseased human intestinal mucosa → Human intestinal microvillar aspartame hydrolysis source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human mucosal enzyme comparison.
limitations
No demonstrated aspartame-sensitivity syndrome or successful enzyme repletion was established.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
General mucosal disease can change digestive capacity.
primary_references
Intestinal hydrolysis of aspartylphenylalanine--the metabolic product of aspartame. · 1986 · https://pubmed.ncbi.nlm.nih.gov/3743970/ · DOI 10.1016/0016-5085(86)90697-9
trigger_kind
machinery_impairment Imported condition classification; unverified.
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 34–40
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human mucosal enzyme comparison. · source_derived_draft · unverified_draft
## aspartame-mucosal-loss General mucosal disease can change digestive capacity. Diseased intestinal mucosa showed reduced brush-border and cytosolic Asp-Phe hydrolase activity alongside reductions in other enzymes. Model: Human mucosal enzyme comparison. Limitations: No demonstrated aspartame-sensitivity syndrome or successful enzyme repletion was established. Evidence access: Primary abstract Intestinal hydrolysis of aspartylphenylalanine--the metabolic product of aspartame. · 1986 · https://pubmed.ncbi.nlm.nih.gov/3743970/ · DOI 10.1016/0016-5085(86)90697-9
Complete structured claim and evidence
Human duodenal, jejunal and ileal microvillar preparations hydrolyzed aspartame.
Human intestinal microvillar aspartame hydrolysis → Aspartame source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human membranes; parallel pig preparations.
limitations
Does not quantify whole-body absorption or intact circulating parent.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Digestion is supported across sampled intestinal regions.
primary_references
Metabolism of aspartame by human and pig intestinal microvillar peptidases. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8141778/ · DOI 10.1042/bj2980635
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 42–48
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human membranes; parallel pig preparations. · source_derived_draft · unverified_draft
## aspartame-microvillar-cleavage Digestion is supported across sampled intestinal regions. Human duodenal, jejunal and ileal microvillar preparations hydrolyzed aspartame. Model: Human membranes; parallel pig preparations. Limitations: Does not quantify whole-body absorption or intact circulating parent. Evidence access: Primary abstract Metabolism of aspartame by human and pig intestinal microvillar peptidases. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8141778/ · DOI 10.1042/bj2980635
Complete structured claim and evidence
CaCl2 increased aspartame hydrolysis 2.9–4.5-fold in the tested human and pig membrane preparations.
Calcium ion → Human intestinal microvillar aspartame hydrolysis source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Ex vivo microvillar assays.
limitations
Not evidence that calcium supplements improve tolerance.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Calcium availability affected measured enzyme activity.
primary_references
Metabolism of aspartame by human and pig intestinal microvillar peptidases. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8141778/ · DOI 10.1042/bj2980635
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 50–56
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Ex vivo microvillar assays. · source_derived_draft · unverified_draft
## aspartame-calcium-activation Calcium availability affected measured enzyme activity. CaCl2 increased aspartame hydrolysis 2.9–4.5-fold in the tested human and pig membrane preparations. Model: Ex vivo microvillar assays. Limitations: Not evidence that calcium supplements improve tolerance. Evidence access: Primary abstract Metabolism of aspartame by human and pig intestinal microvillar peptidases. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8141778/ · DOI 10.1042/bj2980635
Complete structured claim and evidence
1,10-Phenanthroline or amastatin inhibited membrane aspartame metabolism by more than 78%.
1,10-Phenanthroline → Human intestinal microvillar aspartame hydrolysis source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human and pig membrane inhibitor assays.
limitations
Inhibitor patterns support aminopeptidase A involvement, not an exclusive gene assignment.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Metal-sensitive peptidase activity is a digestive gate.
primary_references
Metabolism of aspartame by human and pig intestinal microvillar peptidases. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8141778/ · DOI 10.1042/bj2980635
trigger_kind
machinery_impairment Imported condition classification; unverified.
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 58–64
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human and pig membrane inhibitor assays. · source_derived_draft · unverified_draft
## aspartame-metal-sensitive-hydrolysis Metal-sensitive peptidase activity is a digestive gate. 1,10-Phenanthroline or amastatin inhibited membrane aspartame metabolism by more than 78%. Model: Human and pig membrane inhibitor assays. Limitations: Inhibitor patterns support aminopeptidase A involvement, not an exclusive gene assignment. Evidence access: Primary abstract Metabolism of aspartame by human and pig intestinal microvillar peptidases. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8141778/ · DOI 10.1042/bj2980635
Complete structured claim and evidence
Purified aminopeptidase N did not hydrolyze aspartame despite partial inhibition of membrane metabolism by actinonin.
Purified aminopeptidase N in the 1994 study, species unresolved → Aspartame source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Purified preparation versus membrane assays.
limitations
Species of purified preparation unresolved in accessed abstract.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
An inhibitor result alone can misidentify the enzyme.
primary_references
Metabolism of aspartame by human and pig intestinal microvillar peptidases. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8141778/ · DOI 10.1042/bj2980635
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 66–72
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified preparation versus membrane assays. · source_derived_draft · unverified_draft
## aspartame-anpep-specificity An inhibitor result alone can misidentify the enzyme. Purified aminopeptidase N did not hydrolyze aspartame despite partial inhibition of membrane metabolism by actinonin. Model: Purified preparation versus membrane assays. Limitations: Species of purified preparation unresolved in accessed abstract. Evidence access: Primary abstract Metabolism of aspartame by human and pig intestinal microvillar peptidases. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8141778/ · DOI 10.1042/bj2980635
Complete structured claim and evidence
Cyclo-Asp-Phe and beta-Asp-Phe methyl ester resisted the tested microvillar and purified A/W peptidase preparations.
Human intestinal microvillar aspartame hydrolysis → Aspartame diketopiperazine / cyclo-Asp-Phe source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human/pig membranes and purified peptidases.
limitations
Enzyme resistance does not establish toxicity or systemic persistence.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Changed molecular geometry changes processing.
primary_references
Metabolism of aspartame by human and pig intestinal microvillar peptidases. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8141778/ · DOI 10.1042/bj2980635
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 74–80
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human/pig membranes and purified peptidases. · source_derived_draft · unverified_draft
## aspartame-degradation-product-resistance Changed molecular geometry changes processing. Cyclo-Asp-Phe and beta-Asp-Phe methyl ester resisted the tested microvillar and purified A/W peptidase preparations. Model: Human/pig membranes and purified peptidases. Limitations: Enzyme resistance does not establish toxicity or systemic persistence. Evidence access: Primary abstract Metabolism of aspartame by human and pig intestinal microvillar peptidases. · 1994 · https://pubmed.ncbi.nlm.nih.gov/8141778/ · DOI 10.1042/bj2980635
Complete structured claim and evidence
In ten adults given 3 g, solution produced an earlier, higher phenylalanine peak than capsules: 191 versus 117 micromol/L at 32 versus 123 minutes.
Aspartame → Human plasma phenylalanine concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Balanced Latin-square comparison.
limitations
Acute high-dose kinetics, not brain or safety equivalence.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
The same dose need not give the same exposure.
primary_references
Plasma amino acid concentrations in normal adults administered aspartame in capsules or solution: lack of bioequivalence. · 1987 · https://pubmed.ncbi.nlm.nih.gov/3574137/ · DOI 10.1016/0026-0495(87)90052-7
trigger_kind
biomarker_context Imported condition classification; unverified.
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 82–88
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Balanced Latin-square comparison. · source_derived_draft · unverified_draft
## aspartame-formulation-phe The same dose need not give the same exposure. In ten adults given 3 g, solution produced an earlier, higher phenylalanine peak than capsules: 191 versus 117 micromol/L at 32 versus 123 minutes. Model: Balanced Latin-square comparison. Limitations: Acute high-dose kinetics, not brain or safety equivalence. Evidence access: Primary abstract Plasma amino acid concentrations in normal adults administered aspartame in capsules or solution: lack of bioequivalence. · 1987 · https://pubmed.ncbi.nlm.nih.gov/3574137/ · DOI 10.1016/0026-0495(87)90052-7
Complete structured claim and evidence
Solution versus capsules produced a higher plasma phenylalanine-to-other-LNAA ratio, 0.36 versus 0.23.
Aspartame → Human plasma phenylalanine/large-neutral-amino-acid ratio source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Same ten-person 3 g comparison.
limitations
The ratio is not a measured change in brain serotonin or dopamine.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Transport competition depends partly on the mixture reaching blood.
primary_references
Plasma amino acid concentrations in normal adults administered aspartame in capsules or solution: lack of bioequivalence. · 1987 · https://pubmed.ncbi.nlm.nih.gov/3574137/ · DOI 10.1016/0026-0495(87)90052-7
trigger_kind
biomarker_context Imported condition classification; unverified.
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 90–96
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same ten-person 3 g comparison. · source_derived_draft · unverified_draft
## aspartame-formulation-ratio Transport competition depends partly on the mixture reaching blood. Solution versus capsules produced a higher plasma phenylalanine-to-other-LNAA ratio, 0.36 versus 0.23. Model: Same ten-person 3 g comparison. Limitations: The ratio is not a measured change in brain serotonin or dopamine. Evidence access: Primary abstract Plasma amino acid concentrations in normal adults administered aspartame in capsules or solution: lack of bioequivalence. · 1987 · https://pubmed.ncbi.nlm.nih.gov/3574137/ · DOI 10.1016/0026-0495(87)90052-7
Complete structured claim and evidence
Peak plasma aspartate was higher and earlier with 3 g solution than capsules: 26.2 versus 10.4 micromol/L.
Aspartame → Plasma aspartate concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Same human comparison.
limitations
Plasma is not synaptic aspartate.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
The other amino-acid product also shows formulation effects.
primary_references
Plasma amino acid concentrations in normal adults administered aspartame in capsules or solution: lack of bioequivalence. · 1987 · https://pubmed.ncbi.nlm.nih.gov/3574137/ · DOI 10.1016/0026-0495(87)90052-7
trigger_kind
biomarker_context Imported condition classification; unverified.
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 98–104
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same human comparison. · source_derived_draft · unverified_draft
## aspartame-formulation-aspartate The other amino-acid product also shows formulation effects. Peak plasma aspartate was higher and earlier with 3 g solution than capsules: 26.2 versus 10.4 micromol/L. Model: Same human comparison. Limitations: Plasma is not synaptic aspartate. Evidence access: Primary abstract Plasma amino acid concentrations in normal adults administered aspartame in capsules or solution: lack of bioequivalence. · 1987 · https://pubmed.ncbi.nlm.nih.gov/3574137/ · DOI 10.1016/0026-0495(87)90052-7
Complete structured claim and evidence
Six adults consumed eight hourly 600 mg servings; phenylalanine rose modestly and plateaued after four to five servings within the reported normal postprandial range.
Aspartame → Human plasma phenylalanine concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human beverage crossover; 4.8 g total over eight servings.
limitations
Small healthy-adult study; not a PKU population or a long-term trial.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Repeated exposure did not produce unlimited accumulation in this protocol.
primary_references
Effect of repeated ingestion of aspartame-sweetened beverage on plasma amino acid, blood methanol, and blood formate concentrations in normal adults. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2566887/ · DOI 10.1016/0026-0495(89)90125-x
trigger_kind
biomarker_context Imported condition classification; unverified.
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 106–112
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human beverage crossover; 4.8 g total over eight servings. · source_derived_draft · unverified_draft
## aspartame-repeated-phenylalanine Repeated exposure did not produce unlimited accumulation in this protocol. Six adults consumed eight hourly 600 mg servings; phenylalanine rose modestly and plateaued after four to five servings within the reported normal postprandial range. Model: Human beverage crossover; 4.8 g total over eight servings. Limitations: Small healthy-adult study; not a PKU population or a long-term trial. Evidence access: Primary abstract Effect of repeated ingestion of aspartame-sweetened beverage on plasma amino acid, blood methanol, and blood formate concentrations in normal adults. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2566887/ · DOI 10.1016/0026-0495(89)90125-x
Complete structured claim and evidence
Methanol and formate remained within reported normal limits; plasma aspartate did not significantly rise in the eight-serving experiment.
Aspartame → Human blood methanol/formate during repeated aspartame ingestion source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Six healthy young adults.
limitations
Normal range is protocol- and assay-dependent, not proof that no metabolism occurred.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Products can be generated without a sustained high blood pool.
primary_references
Effect of repeated ingestion of aspartame-sweetened beverage on plasma amino acid, blood methanol, and blood formate concentrations in normal adults. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2566887/ · DOI 10.1016/0026-0495(89)90125-x
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 114–120
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Six healthy young adults. · source_derived_draft · unverified_draft
## aspartame-repeated-metabolites Products can be generated without a sustained high blood pool. Methanol and formate remained within reported normal limits; plasma aspartate did not significantly rise in the eight-serving experiment. Model: Six healthy young adults. Limitations: Normal range is protocol- and assay-dependent, not proof that no metabolism occurred. Evidence access: Primary abstract Effect of repeated ingestion of aspartame-sweetened beverage on plasma amino acid, blood methanol, and blood formate concentrations in normal adults. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2566887/ · DOI 10.1016/0026-0495(89)90125-x
Complete structured claim and evidence
Blood methanol was below the 0.4 mg/dL detection limit at 34 mg/kg; 100–200 mg/kg doses produced dose-related peaks of 1.27–2.58 mg/dL.
Aspartame → Human blood methanol after aspartame loading source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Thirty adults across dose cohorts.
limitations
These bolus doses and old detection limits do not define a universal toxicity threshold.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
A non-detect depends on the assay; large doses gave measurable exposure.
primary_references
Blood methanol concentrations in normal adult subjects administered abuse doses of aspartame. · 1981 · https://pubmed.ncbi.nlm.nih.gov/7230276/ · DOI 10.1080/15287398109529979
trigger_kind
biomarker_context Imported condition classification; unverified.
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 122–128
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Thirty adults across dose cohorts. · source_derived_draft · unverified_draft
## aspartame-methanol-dose A non-detect depends on the assay; large doses gave measurable exposure. Blood methanol was below the 0.4 mg/dL detection limit at 34 mg/kg; 100–200 mg/kg doses produced dose-related peaks of 1.27–2.58 mg/dL. Model: Thirty adults across dose cohorts. Limitations: These bolus doses and old detection limits do not define a universal toxicity threshold. Evidence access: Primary abstract Blood methanol concentrations in normal adult subjects administered abuse doses of aspartame. · 1981 · https://pubmed.ncbi.nlm.nih.gov/7230276/ · DOI 10.1080/15287398109529979
Complete structured claim and evidence
Six adults receiving 200 mg/kg showed no significant increase in blood formate over baseline.
Aspartame → Human blood formate after aspartame loading source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Highest-dose subset of the loading study.
limitations
Limited sample, duration and assay; no inference about all metabolic disorders.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Methanol appearance did not imply measured formate accumulation.
primary_references
Blood methanol concentrations in normal adult subjects administered abuse doses of aspartame. · 1981 · https://pubmed.ncbi.nlm.nih.gov/7230276/ · DOI 10.1080/15287398109529979
trigger_kind
biomarker_context Imported condition classification; unverified.
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 130–136
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Highest-dose subset of the loading study. · source_derived_draft · unverified_draft
## aspartame-formate-loading Methanol appearance did not imply measured formate accumulation. Six adults receiving 200 mg/kg showed no significant increase in blood formate over baseline. Model: Highest-dose subset of the loading study. Limitations: Limited sample, duration and assay; no inference about all metabolic disorders. Evidence access: Primary abstract Blood methanol concentrations in normal adult subjects administered abuse doses of aspartame. · 1981 · https://pubmed.ncbi.nlm.nih.gov/7230276/ · DOI 10.1080/15287398109529979
Complete structured claim and evidence
In 18 fasted adults across 100, 150 and 200 mg/kg cohorts, mean plasma phenylalanine peaks were 20.3, 35.1 and 48.7 micromol/dL.
Aspartame → Human plasma phenylalanine concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Six people per dose; aspartame in orange juice.
limitations
Healthy subjects, not PKU; no direct neurotransmitter assay.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Large loads produce larger amino-acid excursions.
primary_references
Plasma and erythrocyte concentrations of free amino acids in adult humans administered abuse doses of aspartame. · 1981 · https://pubmed.ncbi.nlm.nih.gov/7230277/ · DOI 10.1080/15287398109529980
trigger_kind
biomarker_context Imported condition classification; unverified.
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 138–144
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Six people per dose; aspartame in orange juice. · source_derived_draft · unverified_draft
## aspartame-high-dose-phe Large loads produce larger amino-acid excursions. In 18 fasted adults across 100, 150 and 200 mg/kg cohorts, mean plasma phenylalanine peaks were 20.3, 35.1 and 48.7 micromol/dL. Model: Six people per dose; aspartame in orange juice. Limitations: Healthy subjects, not PKU; no direct neurotransmitter assay. Evidence access: Primary abstract Plasma and erythrocyte concentrations of free amino acids in adult humans administered abuse doses of aspartame. · 1981 · https://pubmed.ncbi.nlm.nih.gov/7230277/ · DOI 10.1080/15287398109529980
Complete structured claim and evidence
After 34 mg/kg, twelve female PKU heterozygotes had higher peak phenylalanine than ten noncarrier females, 15.1 versus 8.95 micromol/dL.
Aspartame → Human plasma phenylalanine concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human carrier comparison, also including twelve noncarrier men.
limitations
Heterozygotes do not represent patients with biallelic PAH deficiency; the damaged male-baseline sentence in indexed abstract is not reconstructed.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Reduced metabolic reserve can change the response to a precursor source.
primary_references
Plasma phenylalanine levels in phenylketonuric heterozygous and normal adults administered aspartame at 34 mg/kg body weight. · 1981 · https://pubmed.ncbi.nlm.nih.gov/7268794/ · DOI 10.1016/0300-483x(81)90108-6
trigger_kind
biomarker_context Imported condition classification; unverified.
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 146–152
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human carrier comparison, also including twelve noncarrier men. · source_derived_draft · unverified_draft
## aspartame-pku-carrier-kinetics Reduced metabolic reserve can change the response to a precursor source. After 34 mg/kg, twelve female PKU heterozygotes had higher peak phenylalanine than ten noncarrier females, 15.1 versus 8.95 micromol/dL. Model: Human carrier comparison, also including twelve noncarrier men. Limitations: Heterozygotes do not represent patients with biallelic PAH deficiency; the damaged male-baseline sentence in indexed abstract is not reconstructed. Evidence access: Primary abstract Plasma phenylalanine levels in phenylketonuric heterozygous and normal adults administered aspartame at 34 mg/kg body weight. · 1981 · https://pubmed.ncbi.nlm.nih.gov/7268794/ · DOI 10.1016/0300-483x(81)90108-6
Complete structured claim and evidence
Four cynomolgus monkeys had higher labeled blood formate after 900 ppm methanol inhalation when folate-deficient than before depletion, while tracer-derived concentrations remained below endogenous formate.
Folate (vitamin B9) → Formate source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Two-hour lung-only labeled-methanol exposure; repeated after diet-induced folate deficiency.
limitations
This was not aspartame feeding, and does not show aspartame causes folate depletion.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Downstream handling depends on nutrient state and exposure route.
primary_references
Pharmacokinetics of inhaled [14C]methanol and methanol-derived [14C]formate in normal and folate-deficient cynomolgus monkeys. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7940538/ · DOI 10.1006/taap.1994.1202
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 154–160
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Two-hour lung-only labeled-methanol exposure; repeated after diet-induced folate deficiency. · source_derived_draft · unverified_draft
## aspartame-folate-methanol-context Downstream handling depends on nutrient state and exposure route. Four cynomolgus monkeys had higher labeled blood formate after 900 ppm methanol inhalation when folate-deficient than before depletion, while tracer-derived concentrations remained below endogenous formate. Model: Two-hour lung-only labeled-methanol exposure; repeated after diet-induced folate deficiency. Limitations: This was not aspartame feeding, and does not show aspartame causes folate depletion. Evidence access: Primary abstract Pharmacokinetics of inhaled [14C]methanol and methanol-derived [14C]formate in normal and folate-deficient cynomolgus monkeys. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7940538/ · DOI 10.1006/taap.1994.1202
Complete structured claim and evidence
Human T1R2/T1R3 responded to aspartame in heterologous receptor assays.
Aspartame → Human sweet taste receptor TAS1R2/TAS1R3 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary article response panel and abstract
experimental_model
Human receptor coexpression, aspartame response panel.
limitations
Receptor activation is not a quantified human insulin response.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
The intact sweetener has a receptor action before its metabolites are considered.
primary_references
Human receptors for sweet and umami taste. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11917125/ · DOI 10.1073/pnas.072090199
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 162–168
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human receptor coexpression, aspartame response panel. · source_derived_draft · unverified_draft
## aspartame-human-sweet-receptor The intact sweetener has a receptor action before its metabolites are considered. Human T1R2/T1R3 responded to aspartame in heterologous receptor assays. Model: Human receptor coexpression, aspartame response panel. Limitations: Receptor activation is not a quantified human insulin response. Evidence access: Primary article response panel and abstract Human receptors for sweet and umami taste. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11917125/ · DOI 10.1073/pnas.072090199
Complete structured claim and evidence
Mutagenesis identified eleven T1R2 residues important for aspartame responses: S40, Y103, D142, S144, S165, S168, Y215, D278, E302, D307 and R383.
Human taste receptor TAS1R2 → Aspartame source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human receptor mutants and homology models.
limitations
Loss of response can affect binding, folding or activation; not every residue is necessarily a direct contact.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Small changes in the sensor can alter recognition.
primary_references
Characterization of the Binding Site of Aspartame in the Human Sweet Taste Receptor. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26377607/ · DOI 10.1093/chemse/bjv045
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 170–176
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human receptor mutants and homology models. · source_derived_draft · unverified_draft
## aspartame-binding-residues Small changes in the sensor can alter recognition. Mutagenesis identified eleven T1R2 residues important for aspartame responses: S40, Y103, D142, S144, S165, S168, Y215, D278, E302, D307 and R383. Model: Human receptor mutants and homology models. Limitations: Loss of response can affect binding, folding or activation; not every residue is necessarily a direct contact. Evidence access: Primary abstract Characterization of the Binding Site of Aspartame in the Human Sweet Taste Receptor. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26377607/ · DOI 10.1093/chemse/bjv045
Complete structured claim and evidence
The model proposed two pocket waters bridging aspartame carbonyls to D142 and L279.
Aspartame → Human taste receptor TAS1R2 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Docking refined with functional mutagenesis.
limitations
Proposed molecular model, not a directly resolved bound-water structure.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Water-mediated contacts are a testable structural explanation.
primary_references
Characterization of the Binding Site of Aspartame in the Human Sweet Taste Receptor. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26377607/ · DOI 10.1093/chemse/bjv045
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 178–184
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Docking refined with functional mutagenesis. · source_derived_draft · unverified_draft
## aspartame-binding-water-model Water-mediated contacts are a testable structural explanation. The model proposed two pocket waters bridging aspartame carbonyls to D142 and L279. Model: Docking refined with functional mutagenesis. Limitations: Proposed molecular model, not a directly resolved bound-water structure. Evidence access: Primary abstract Characterization of the Binding Site of Aspartame in the Human Sweet Taste Receptor. · 2015 · https://pubmed.ncbi.nlm.nih.gov/26377607/ · DOI 10.1093/chemse/bjv045
Complete structured claim and evidence
Human T1R2 amino-terminal-domain mutants showed ligand-specific and shared requirements across chemically different sweeteners.
Human taste receptor TAS1R2 → Aspartame source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Site-directed mutagenesis and docking.
limitations
A shared receptor is not proof that all sweeteners have interchangeable systemic effects.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Aspartame and other sweeteners need not perturb every receptor contact equally.
primary_references
Characterization of the modes of binding between human sweet taste receptor and low-molecular-weight sweet compounds. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22536376/ · DOI 10.1371/journal.pone.0035380
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 186–192
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Site-directed mutagenesis and docking. · source_derived_draft · unverified_draft
## aspartame-ligand-specific-sites Aspartame and other sweeteners need not perturb every receptor contact equally. Human T1R2 amino-terminal-domain mutants showed ligand-specific and shared requirements across chemically different sweeteners. Model: Site-directed mutagenesis and docking. Limitations: A shared receptor is not proof that all sweeteners have interchangeable systemic effects. Evidence access: Primary abstract Characterization of the modes of binding between human sweet taste receptor and low-molecular-weight sweet compounds. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22536376/ · DOI 10.1371/journal.pone.0035380
Complete structured claim and evidence
Aspartame at 0.1 mM for 24 hours increased Caco-2 monolayer permeability.
Aspartame → Human Caco-2 permeability during aspartame exposure source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text; methods and results
experimental_model
Human colon-cancer-derived cell line; dextran flux and electrical resistance assays.
limitations
Not a living human gut exposure or clinical disease endpoint.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Intact sweetener altered a cultured epithelial barrier.
primary_references
Artificial Sweeteners Disrupt Tight Junctions and Barrier Function in the Intestinal Epithelium through Activation of the Sweet Taste Receptor, T1R3. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32580504/ · DOI 10.3390/nu12061862
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 194–200
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human colon-cancer-derived cell line; dextran flux and electrical resistance assays. · source_derived_draft · unverified_draft
## aspartame-barrier-permeability Intact sweetener altered a cultured epithelial barrier. Aspartame at 0.1 mM for 24 hours increased Caco-2 monolayer permeability. Model: Human colon-cancer-derived cell line; dextran flux and electrical resistance assays. Limitations: Not a living human gut exposure or clinical disease endpoint. Evidence access: Primary full text; methods and results Artificial Sweeteners Disrupt Tight Junctions and Barrier Function in the Intestinal Epithelium through Activation of the Sweet Taste Receptor, T1R3. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32580504/ · DOI 10.3390/nu12061862
Complete structured claim and evidence
The Caco-2 study found reduced cell-surface claudin 3 after 0.1 mM aspartame exposure.
Aspartame → Human claudin 3 / CLDN3 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text; Figure 4
experimental_model
24-hour exposure and surface ELISA.
limitations
Does not establish direct aspartame–claudin binding.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Junction location matters as well as protein presence.
primary_references
Artificial Sweeteners Disrupt Tight Junctions and Barrier Function in the Intestinal Epithelium through Activation of the Sweet Taste Receptor, T1R3. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32580504/ · DOI 10.3390/nu12061862
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 202–208
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 24-hour exposure and surface ELISA. · source_derived_draft · unverified_draft
## aspartame-claudin-surface Junction location matters as well as protein presence. The Caco-2 study found reduced cell-surface claudin 3 after 0.1 mM aspartame exposure. Model: 24-hour exposure and surface ELISA. Limitations: Does not establish direct aspartame–claudin binding. Evidence access: Primary full text; Figure 4 Artificial Sweeteners Disrupt Tight Junctions and Barrier Function in the Intestinal Epithelium through Activation of the Sweet Taste Receptor, T1R3. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32580504/ · DOI 10.3390/nu12061862
Complete structured claim and evidence
T1R3 siRNA attenuated aspartame-associated barrier and claudin-3 changes in Caco-2 cells.
Human taste receptor TAS1R3 → Human Caco-2 permeability during aspartame exposure source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Human cell-line siRNA perturbation.
limitations
Supports functional involvement, not proof of direct binding to T1R3 alone.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Removing a signaling component reduced the response.
primary_references
Artificial Sweeteners Disrupt Tight Junctions and Barrier Function in the Intestinal Epithelium through Activation of the Sweet Taste Receptor, T1R3. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32580504/ · DOI 10.3390/nu12061862
trigger_kind
machinery_impairment Imported condition classification; unverified.
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 210–216
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cell-line siRNA perturbation. · source_derived_draft · unverified_draft
## aspartame-t1r3-knockdown Removing a signaling component reduced the response. T1R3 siRNA attenuated aspartame-associated barrier and claudin-3 changes in Caco-2 cells. Model: Human cell-line siRNA perturbation. Limitations: Supports functional involvement, not proof of direct binding to T1R3 alone. Evidence access: Primary full text Artificial Sweeteners Disrupt Tight Junctions and Barrier Function in the Intestinal Epithelium through Activation of the Sweet Taste Receptor, T1R3. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32580504/ · DOI 10.3390/nu12061862
Complete structured claim and evidence
Aspartame increased the ROS-sensitive fluorescence signal in exposed Caco-2 cells.
Aspartame → Human Caco-2 ROS signal during aspartame exposure source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text; Figure 5
experimental_model
0.1 mM, 24 hours; DCFDA assay.
limitations
Probe fluorescence does not identify a single radical species.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Oxidative signaling is an experimentally measured intermediate.
primary_references
Artificial Sweeteners Disrupt Tight Junctions and Barrier Function in the Intestinal Epithelium through Activation of the Sweet Taste Receptor, T1R3. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32580504/ · DOI 10.3390/nu12061862
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 218–224
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 0.1 mM, 24 hours; DCFDA assay. · source_derived_draft · unverified_draft
## aspartame-ros-induction Oxidative signaling is an experimentally measured intermediate. Aspartame increased the ROS-sensitive fluorescence signal in exposed Caco-2 cells. Model: 0.1 mM, 24 hours; DCFDA assay. Limitations: Probe fluorescence does not identify a single radical species. Evidence access: Primary full text; Figure 5 Artificial Sweeteners Disrupt Tight Junctions and Barrier Function in the Intestinal Epithelium through Activation of the Sweet Taste Receptor, T1R3. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32580504/ · DOI 10.3390/nu12061862
Complete structured claim and evidence
N-acetylcysteine at 1 mM attenuated aspartame-associated oxidative and barrier changes.
N-Acetyl-L-cysteine → Human Caco-2 permeability during aspartame exposure source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text; Figure 5
experimental_model
Caco-2 co-exposure experiments.
limitations
Not evidence that NAC supplements prevent effects of dietary aspartame.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
An antioxidant-related perturbation changed the pathway response.
primary_references
Artificial Sweeteners Disrupt Tight Junctions and Barrier Function in the Intestinal Epithelium through Activation of the Sweet Taste Receptor, T1R3. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32580504/ · DOI 10.3390/nu12061862
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 226–232
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Caco-2 co-exposure experiments. · source_derived_draft · unverified_draft
## aspartame-nac-rescue An antioxidant-related perturbation changed the pathway response. N-acetylcysteine at 1 mM attenuated aspartame-associated oxidative and barrier changes. Model: Caco-2 co-exposure experiments. Limitations: Not evidence that NAC supplements prevent effects of dietary aspartame. Evidence access: Primary full text; Figure 5 Artificial Sweeteners Disrupt Tight Junctions and Barrier Function in the Intestinal Epithelium through Activation of the Sweet Taste Receptor, T1R3. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32580504/ · DOI 10.3390/nu12061862
Complete structured claim and evidence
Claudin-3 overexpression attenuated aspartame-associated permeability and ROS changes in Caco-2 cells.
Human claudin 3 / CLDN3 → Human Caco-2 permeability during aspartame exposure source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human cell-line expression rescue.
limitations
Does not establish that the same rescue is clinically achievable.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Restoring a barrier component altered downstream readouts.
primary_references
Artificial Sweeteners Disrupt Tight Junctions and Barrier Function in the Intestinal Epithelium through Activation of the Sweet Taste Receptor, T1R3. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32580504/ · DOI 10.3390/nu12061862
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 234–240
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cell-line expression rescue. · source_derived_draft · unverified_draft
## aspartame-claudin-rescue Restoring a barrier component altered downstream readouts. Claudin-3 overexpression attenuated aspartame-associated permeability and ROS changes in Caco-2 cells. Model: Human cell-line expression rescue. Limitations: Does not establish that the same rescue is clinically achievable. Evidence access: Primary full text Artificial Sweeteners Disrupt Tight Junctions and Barrier Function in the Intestinal Epithelium through Activation of the Sweet Taste Receptor, T1R3. · 2020 · https://pubmed.ncbi.nlm.nih.gov/32580504/ · DOI 10.3390/nu12061862
Complete structured claim and evidence
The study reported increased insulin secretion with 0.15% aspartame in mice and monkeys.
Aspartame → Mouse insulin response to aspartame source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Animal feeding experiments.
limitations
Exact duration and systemic dose not supplied by accessed abstract; do not infer ordinary human intake.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
A neural or hormonal route can differ from metabolite toxicity.
primary_references
Sweetener aspartame aggravates atherosclerosis through insulin-triggered inflammation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39978336/ · DOI 10.1016/j.cmet.2025.01.006
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 242–248
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Animal feeding experiments. · source_derived_draft · unverified_draft
## aspartame-animal-insulin A neural or hormonal route can differ from metabolite toxicity. The study reported increased insulin secretion with 0.15% aspartame in mice and monkeys. Model: Animal feeding experiments. Limitations: Exact duration and systemic dose not supplied by accessed abstract; do not infer ordinary human intake. Evidence access: Primary abstract Sweetener aspartame aggravates atherosclerosis through insulin-triggered inflammation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39978336/ · DOI 10.1016/j.cmet.2025.01.006
Complete structured claim and evidence
Subdiaphragmatic vagotomy abolished the aspartame-associated insulin rise in the reported experiment.
Mouse bilateral subdiaphragmatic vagotomy → Mouse insulin response to aspartame source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Animal surgical perturbation in the feeding study.
limitations
Does not uniquely identify the initial sweet receptor.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Interrupting the nerve route interrupted the hormone response.
primary_references
Sweetener aspartame aggravates atherosclerosis through insulin-triggered inflammation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39978336/ · DOI 10.1016/j.cmet.2025.01.006
trigger_kind
machinery_impairment Imported condition classification; unverified.
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 250–256
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Animal surgical perturbation in the feeding study. · source_derived_draft · unverified_draft
## aspartame-vagotomy-gate Interrupting the nerve route interrupted the hormone response. Subdiaphragmatic vagotomy abolished the aspartame-associated insulin rise in the reported experiment. Model: Animal surgical perturbation in the feeding study. Limitations: Does not uniquely identify the initial sweet receptor. Evidence access: Primary abstract Sweetener aspartame aggravates atherosclerosis through insulin-triggered inflammation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39978336/ · DOI 10.1016/j.cmet.2025.01.006
Complete structured claim and evidence
Sustained aspartame feeding aggravated plaque formation in ApoE-null mice.
Aspartame → ApoE-null mouse atherosclerosis during aspartame exposure source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
ApoE-deficient mouse feeding study.
limitations
Not a human cardiovascular risk estimate.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
A susceptible vascular model produced a disease endpoint.
primary_references
Sweetener aspartame aggravates atherosclerosis through insulin-triggered inflammation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39978336/ · DOI 10.1016/j.cmet.2025.01.006
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 258–264
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · ApoE-deficient mouse feeding study. · source_derived_draft · unverified_draft
## aspartame-plaque-feeding A susceptible vascular model produced a disease endpoint. Sustained aspartame feeding aggravated plaque formation in ApoE-null mice. Model: ApoE-deficient mouse feeding study. Limitations: Not a human cardiovascular risk estimate. Evidence access: Primary abstract Sweetener aspartame aggravates atherosclerosis through insulin-triggered inflammation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39978336/ · DOI 10.1016/j.cmet.2025.01.006
Complete structured claim and evidence
Slow-release insulin pumps worsened atherosclerosis in ApoE-null mice.
Insulin → ApoE-null mouse atherosclerosis during aspartame exposure source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse insulin-pump experiment.
limitations
Does not prove every aspartame effect is insulin-mediated.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
A mediator intervention supported the proposed chain.
primary_references
Sweetener aspartame aggravates atherosclerosis through insulin-triggered inflammation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39978336/ · DOI 10.1016/j.cmet.2025.01.006
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 266–272
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse insulin-pump experiment. · source_derived_draft · unverified_draft
## aspartame-insulin-pump A mediator intervention supported the proposed chain. Slow-release insulin pumps worsened atherosclerosis in ApoE-null mice. Model: Mouse insulin-pump experiment. Limitations: Does not prove every aspartame effect is insulin-mediated. Evidence access: Primary abstract Sweetener aspartame aggravates atherosclerosis through insulin-triggered inflammation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39978336/ · DOI 10.1016/j.cmet.2025.01.006
Complete structured claim and evidence
Insulin-stimulated arterial endothelial cells upregulated CX3CL1.
Insulin → Arterial-cell CX3CL1 in the 2025 aspartame study, species unresolved source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Arterial endothelial-cell expression profiling.
limitations
Cell species unresolved in accessed abstract; direct aspartame exposure is not asserted.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
A hormone can change an immune-cell recruitment signal.
primary_references
Sweetener aspartame aggravates atherosclerosis through insulin-triggered inflammation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39978336/ · DOI 10.1016/j.cmet.2025.01.006
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 274–280
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Arterial endothelial-cell expression profiling. · source_derived_draft · unverified_draft
## aspartame-endothelial-chemokine A hormone can change an immune-cell recruitment signal. Insulin-stimulated arterial endothelial cells upregulated CX3CL1. Model: Arterial endothelial-cell expression profiling. Limitations: Cell species unresolved in accessed abstract; direct aspartame exposure is not asserted. Evidence access: Primary abstract Sweetener aspartame aggravates atherosclerosis through insulin-triggered inflammation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39978336/ · DOI 10.1016/j.cmet.2025.01.006
Complete structured claim and evidence
Monocyte/macrophage Cx3cr1 deletion abolished aspartame-exacerbated atherosclerosis in the model.
Mouse fractalkine receptor / Cx3cr1 → ApoE-null mouse atherosclerosis during aspartame exposure source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Conditional mouse genetic perturbation.
limitations
One preclinical study, not independently replicated clinical causality.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
A separate immune receptor was required for the added plaque effect.
primary_references
Sweetener aspartame aggravates atherosclerosis through insulin-triggered inflammation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39978336/ · DOI 10.1016/j.cmet.2025.01.006
trigger_kind
machinery_impairment Imported condition classification; unverified.
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 282–288
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Conditional mouse genetic perturbation. · source_derived_draft · unverified_draft
## aspartame-cx3cr1-loss A separate immune receptor was required for the added plaque effect. Monocyte/macrophage Cx3cr1 deletion abolished aspartame-exacerbated atherosclerosis in the model. Model: Conditional mouse genetic perturbation. Limitations: One preclinical study, not independently replicated clinical causality. Evidence access: Primary abstract Sweetener aspartame aggravates atherosclerosis through insulin-triggered inflammation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39978336/ · DOI 10.1016/j.cmet.2025.01.006
Complete structured claim and evidence
The 120-person six-arm sweetener trial reported distinct microbiome and metabolome changes across the sweetener groups, including aspartame, over two weeks.
Aspartame → Human microbiome/metabolome response to aspartame source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Randomized human trial; aspartame arm compared with glucose-vehicle and no-supplement controls.
limitations
Total sample is not the aspartame-arm sample; no specific causal aspartame microbial metabolite is identified here.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
A biological change need not equal a harmful clinical outcome.
primary_references
Personalized microbiome-driven effects of non-nutritive sweeteners on human glucose tolerance. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35987213/ · DOI 10.1016/j.cell.2022.07.016
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 290–296
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Randomized human trial; aspartame arm compared with glucose-vehicle and no-supplement controls. · source_derived_draft · unverified_draft
## aspartame-microbiome-trial A biological change need not equal a harmful clinical outcome. The 120-person six-arm sweetener trial reported distinct microbiome and metabolome changes across the sweetener groups, including aspartame, over two weeks. Model: Randomized human trial; aspartame arm compared with glucose-vehicle and no-supplement controls. Limitations: Total sample is not the aspartame-arm sample; no specific causal aspartame microbial metabolite is identified here. Evidence access: Primary abstract Personalized microbiome-driven effects of non-nutritive sweeteners on human glucose tolerance. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35987213/ · DOI 10.1016/j.cell.2022.07.016
Complete structured claim and evidence
Significant group-level glycemic impairment was reported for saccharin and sucralose, not aspartame, in the two-week trial.
Aspartame → Human glycemic response in the two-week aspartame trial source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Same randomized human trial.
limitations
Short duration and person-specific variation limit inference; not proof of no possible long-term effect.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
The result for one sweetener cannot be assigned to all of them.
primary_references
Personalized microbiome-driven effects of non-nutritive sweeteners on human glucose tolerance. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35987213/ · DOI 10.1016/j.cell.2022.07.016
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 298–304
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same randomized human trial. · source_derived_draft · unverified_draft
## aspartame-glycemia-trial-limit The result for one sweetener cannot be assigned to all of them. Significant group-level glycemic impairment was reported for saccharin and sucralose, not aspartame, in the two-week trial. Model: Same randomized human trial. Limitations: Short duration and person-specific variation limit inference; not proof of no possible long-term effect. Evidence access: Primary abstract Personalized microbiome-driven effects of non-nutritive sweeteners on human glucose tolerance. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35987213/ · DOI 10.1016/j.cell.2022.07.016
Complete structured claim and evidence
A repeated crossover trial reported headaches on 33% of aspartame days versus 24% of placebo days, P=0.04; 18 of 32 randomized participants completed all periods.
Aspartame → Human headache frequency during aspartame challenges source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
About 30 mg/kg/day, seven-day periods; self-identified headache-sensitive volunteers.
limitations
No significant difference in headache duration or intensity; attrition and multiple analyses limit certainty.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
A positive symptom finding comes with substantial missing follow-up.
primary_references
Aspartame ingestion and headaches: a randomized crossover trial. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7936222/ · DOI 10.1212/wnl.44.10.1787
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 306–312
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · About 30 mg/kg/day, seven-day periods; self-identified headache-sensitive volunteers. · source_derived_draft · unverified_draft
## aspartame-headache-positive A positive symptom finding comes with substantial missing follow-up. A repeated crossover trial reported headaches on 33% of aspartame days versus 24% of placebo days, P=0.04; 18 of 32 randomized participants completed all periods. Model: About 30 mg/kg/day, seven-day periods; self-identified headache-sensitive volunteers. Limitations: No significant difference in headache duration or intensity; attrition and multiple analyses limit certainty. Evidence access: Primary abstract Aspartame ingestion and headaches: a randomized crossover trial. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7936222/ · DOI 10.1212/wnl.44.10.1787
Complete structured claim and evidence
An acute crossover challenge in 40 self-reported headache-sensitive adults found headaches in 35% after 30 mg/kg aspartame versus 45% after placebo.
Aspartame → Human headache frequency during aspartame challenges source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Acute human challenge.
limitations
Different exposure duration from the repeated trial; no molecular mechanism identified.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Another blinded study did not reproduce increased headache frequency.
primary_references
Aspartame and susceptibility to headache. · 1987 · https://pubmed.ncbi.nlm.nih.gov/3657889/ · DOI 10.1056/NEJM198711053171903
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 314–320
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Acute human challenge. · source_derived_draft · unverified_draft
## aspartame-headache-null Another blinded study did not reproduce increased headache frequency. An acute crossover challenge in 40 self-reported headache-sensitive adults found headaches in 35% after 30 mg/kg aspartame versus 45% after placebo. Model: Acute human challenge. Limitations: Different exposure duration from the repeated trial; no molecular mechanism identified. Evidence access: Primary abstract Aspartame and susceptibility to headache. · 1987 · https://pubmed.ncbi.nlm.nih.gov/3657889/ · DOI 10.1056/NEJM198711053171903
Complete structured claim and evidence
In 48 self-described sensitive and 48 matched nonsensitive participants, rated symptoms did not differ between 100 mg aspartame and control bars.
Aspartame → Human symptoms after 100 mg aspartame snack-bar challenge source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text and author-list correction
experimental_model
Blinded randomized crossover; sessions at least seven days apart.
limitations
Not a test of all doses, repeated exposure or every vulnerable subgroup. Correction record: Publisher correction concerns author order, affiliations and citation; no experimental-result correction is stated. Correction PMID 25951455 inspected in full text. https://doi.org/10.1371/journal.pone.0126039
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
A low-dose acute controlled challenge did not reproduce reported sensitivity.
primary_references
Aspartame sensitivity? A double blind randomised crossover study. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25786106/ · DOI 10.1371/journal.pone.0116212
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 322–328
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Blinded randomized crossover; sessions at least seven days apart. · source_derived_draft · unverified_draft
## aspartame-acute-sensitivity-null A low-dose acute controlled challenge did not reproduce reported sensitivity. In 48 self-described sensitive and 48 matched nonsensitive participants, rated symptoms did not differ between 100 mg aspartame and control bars. Model: Blinded randomized crossover; sessions at least seven days apart. Limitations: Not a test of all doses, repeated exposure or every vulnerable subgroup. Correction record: Publisher correction concerns author order, affiliations and citation; no experimental-result correction is stated. Correction PMID 25951455 inspected in full text. https://doi.org/10.1371/journal.pone.0126039 Evidence access: Primary full text and author-list correction Aspartame sensitivity? A double blind randomised crossover study. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25786106/ · DOI 10.1371/journal.pone.0116212
Complete structured claim and evidence
GLP-1, GIP, tyrosine and phenylalanine responses were similar with aspartame and control snack bars.
Aspartame → Human GLP-1/GIP response in aspartame snack-bar study source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text and author-list correction
experimental_model
Same human crossover.
limitations
Not comparable to isolated cells or susceptible-mouse feeding by dose or endpoint. Correction record: Publisher correction concerns author order, affiliations and citation; no experimental-result correction is stated. Correction PMID 25951455 inspected in full text. https://doi.org/10.1371/journal.pone.0126039
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
Receptor activity did not translate into a distinct measured response in this meal.
primary_references
Aspartame sensitivity? A double blind randomised crossover study. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25786106/ · DOI 10.1371/journal.pone.0116212
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 330–336
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same human crossover. · source_derived_draft · unverified_draft
## aspartame-snackbar-hormones Receptor activity did not translate into a distinct measured response in this meal. GLP-1, GIP, tyrosine and phenylalanine responses were similar with aspartame and control snack bars. Model: Same human crossover. Limitations: Not comparable to isolated cells or susceptible-mouse feeding by dose or endpoint. Correction record: Publisher correction concerns author order, affiliations and citation; no experimental-result correction is stated. Correction PMID 25951455 inspected in full text. https://doi.org/10.1371/journal.pone.0126039 Evidence access: Primary full text and author-list correction Aspartame sensitivity? A double blind randomised crossover study. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25786106/ · DOI 10.1371/journal.pone.0116212
Complete structured claim and evidence
A seven-day 30 mg/kg/day crossover reported more severe symptoms in participants with depression; the study stopped after 13 people completed because of reactions.
Aspartame → Human mood-disorder symptoms in halted aspartame study source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Small human psychiatric-history comparison.
limitations
Early stopping, small sample and subgroup analysis; no measured neurotransmitter mechanism.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
An early-stopped study signals a question but cannot define a reliable population effect.
primary_references
Adverse reactions to aspartame: double-blind challenge in patients from a vulnerable population. · 1993 · https://pubmed.ncbi.nlm.nih.gov/8373935/ · DOI 10.1016/0006-3223(93)90251-8
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 338–344
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Small human psychiatric-history comparison. · source_derived_draft · unverified_draft
## aspartame-mood-disorder-trial An early-stopped study signals a question but cannot define a reliable population effect. A seven-day 30 mg/kg/day crossover reported more severe symptoms in participants with depression; the study stopped after 13 people completed because of reactions. Model: Small human psychiatric-history comparison. Limitations: Early stopping, small sample and subgroup analysis; no measured neurotransmitter mechanism. Evidence access: Primary abstract Adverse reactions to aspartame: double-blind challenge in patients from a vulnerable population. · 1993 · https://pubmed.ncbi.nlm.nih.gov/8373935/ · DOI 10.1016/0006-3223(93)90251-8
Complete structured claim and evidence
In 102,865 adults followed a median 7.8 years, higher aspartame consumers had an adjusted overall-cancer hazard ratio of 1.15 versus nonconsumers, 95% CI 1.03–1.28.
Aspartame → Human aspartame/cancer association in NutriNet-Sante source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Prospective dietary-record cohort.
limitations
Residual confounding, selection and reverse causality remain possible; no molecular mediator was established.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
An observational association is a discovery lead rather than a proven causal chain.
primary_references
Artificial sweeteners and cancer risk: Results from the NutriNet-Santé population-based cohort study. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35324894/ · DOI 10.1371/journal.pmed.1003950
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 346–352
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Prospective dietary-record cohort. · source_derived_draft · unverified_draft
## aspartame-cancer-cohort An observational association is a discovery lead rather than a proven causal chain. In 102,865 adults followed a median 7.8 years, higher aspartame consumers had an adjusted overall-cancer hazard ratio of 1.15 versus nonconsumers, 95% CI 1.03–1.28. Model: Prospective dietary-record cohort. Limitations: Residual confounding, selection and reverse causality remain possible; no molecular mediator was established. Evidence access: Primary abstract Artificial sweeteners and cancer risk: Results from the NutriNet-Santé population-based cohort study. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35324894/ · DOI 10.1371/journal.pmed.1003950
Complete structured claim and evidence
Labeled methanol inhalation produced labeled blood formate in cynomolgus monkeys.
Methanol → Formate source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Four female monkeys; lung-only exposure for two hours at 10–900 ppm.
limitations
Not an aspartame feeding study; the route and systemic dose differ from digestion of a food sweetener.
nutrient_topic
Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame
plain_language
A traced precursor-product link connects two separate metabolite nodes.
primary_references
Pharmacokinetics of inhaled [14C]methanol and methanol-derived [14C]formate in normal and folate-deficient cynomolgus monkeys. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7940538/ · DOI 10.1006/taap.1994.1202
Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 354–360
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Four female monkeys; lung-only exposure for two hours at 10–900 ppm. · source_derived_draft · unverified_draft
## aspartame-methanol-formate-tracer A traced precursor-product link connects two separate metabolite nodes. Labeled methanol inhalation produced labeled blood formate in cynomolgus monkeys. Model: Four female monkeys; lung-only exposure for two hours at 10–900 ppm. Limitations: Not an aspartame feeding study; the route and systemic dose differ from digestion of a food sweetener. Evidence access: Primary abstract Pharmacokinetics of inhaled [14C]methanol and methanol-derived [14C]formate in normal and folate-deficient cynomolgus monkeys. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7940538/ · DOI 10.1006/taap.1994.1202
Complete structured claim and evidence
PAH catalyzes phenylalanine hydroxylation to tyrosine using BH4, molecular oxygen and non-heme ferrous iron.
Human phenylalanine hydroxylase / PAH → L-Tyrosine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text; reaction background distinguished from new structural experiments
experimental_model
Human PAH structural study; established reaction described in the full-text introduction.
limitations
This record describes the established reaction, not a new dietary intervention or a human iron-deficiency threshold.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Making tyrosine requires a working enzyme and its chemical helpers.
primary_references
Structural basis for ligand-dependent dimerization of phenylalanine hydroxylase regulatory domain. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27049649/ · DOI 10.1038/srep23748
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 14–20
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human PAH structural study; established reaction described in the full-text introduction. · source_derived_draft · unverified_draft
## l-phenylalanine-pah-conversion Making tyrosine requires a working enzyme and its chemical helpers. PAH catalyzes phenylalanine hydroxylation to tyrosine using BH4, molecular oxygen and non-heme ferrous iron. Model: Human PAH structural study; established reaction described in the full-text introduction. Limitations: This record describes the established reaction, not a new dietary intervention or a human iron-deficiency threshold. Evidence access: Primary full text; reaction background distinguished from new structural experiments Structural basis for ligand-dependent dimerization of phenylalanine hydroxylase regulatory domain. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27049649/ · DOI 10.1038/srep23748
Complete structured claim and evidence
B0AT1/SLC6A19 transports neutral amino acids including phenylalanine during intestinal absorption and renal reuptake.
Human neutral amino acid transporter B0AT1 / SLC6A19 → L-Phenylalanine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human B0AT1 structural and transport study; established physiological role described in abstract.
limitations
Transporter identity does not specify a universal saturation threshold.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
The gut and kidney transport machinery helps determine phenylalanine availability.
primary_references
Structure-guided development of a potent human B0AT1 inhibitor effective in a mouse model of phenylketonuria. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42350764/ · DOI 10.1038/s42003-026-10535-y
transport_effect
raises Recorded as acting during intestinal absorption and renal reuptake, both of which are inward.
transport_pool
the enterocyte and tubule cell interior Recorded as acting during intestinal absorption and renal reuptake, both of which are inward.
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 166–172
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human B0AT1 structural and transport study; established physiological role described in abstract. · source_derived_draft · unverified_draft
## l-phenylalanine-renal-transporter The gut and kidney transport machinery helps determine phenylalanine availability. B0AT1/SLC6A19 transports neutral amino acids including phenylalanine during intestinal absorption and renal reuptake. Model: Human B0AT1 structural and transport study; established physiological role described in abstract. Limitations: Transporter identity does not specify a universal saturation threshold. Evidence access: Primary abstract Structure-guided development of a potent human B0AT1 inhibitor effective in a mouse model of phenylketonuria. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42350764/ · DOI 10.1038/s42003-026-10535-y
Complete structured claim and evidence
Human TAT1 expressed in Xenopus oocytes transported tryptophan, tyrosine, phenylalanine and L-DOPA independently of sodium.
Human TAT1 / SLC16A10 → L-Tryptophan source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human cloned transporter; expression strongest in kidney and intestine.
limitations
The paper proposes disease relevance; it does not establish TAT1 defects as the cause of blue diaper syndrome.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Tryptophan also has an aromatic-amino-acid transport route.
primary_references
The human T-type amino acid transporter-1: characterization, gene organization, and chromosomal location. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11827462/ · DOI 10.1006/geno.2001.6678
transport_effect
raises An oocyte transport measurement, which reports the cell interior rising. TAT1's role at the basolateral membrane is efflux, which this record does not measure.
transport_pool
the expressing cell An oocyte transport measurement, which reports the cell interior rising. TAT1's role at the basolateral membrane is efflux, which this record does not measure.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 50–56
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human cloned transporter; expression strongest in kidney and intestine. · source_derived_draft · unverified_draft
## tryptophan-tat1-transport Tryptophan also has an aromatic-amino-acid transport route. Human TAT1 expressed in Xenopus oocytes transported tryptophan, tyrosine, phenylalanine and L-DOPA independently of sodium. Model: Human cloned transporter; expression strongest in kidney and intestine. Limitations: The paper proposes disease relevance; it does not establish TAT1 defects as the cause of blue diaper syndrome. Evidence access: Primary abstract The human T-type amino acid transporter-1: characterization, gene organization, and chromosomal location. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11827462/ · DOI 10.1006/geno.2001.6678
Complete structured claim and evidence
Human LAT2/SLC3A2 transported methionine; leucine and phenylalanine stimulated methionine efflux even against an inward methionine gradient.
Human L-type amino acid transporter 2 / LAT2 / SLC7A8 → L-Methionine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human transporter in Xenopus oocytes; tracer influx and efflux.
limitations
Does not show that ordinary mixed meals deplete methionine.
nutrient_topic
L-Methionine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Methionine
plain_language
Transport depends on substrates on both sides of the membrane.
primary_references
Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12117417/ · DOI 10.1042/BJ20020841
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19) · lines 28–34
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human transporter in Xenopus oocytes; tracer influx and efflux. · source_derived_draft · unverified_draft
## methionine-lat2-exchange Transport depends on substrates on both sides of the membrane. Human LAT2/SLC3A2 transported methionine; leucine and phenylalanine stimulated methionine efflux even against an inward methionine gradient. Model: Human transporter in Xenopus oocytes; tracer influx and efflux. Limitations: Does not show that ordinary mixed meals deplete methionine. Evidence access: Primary abstract Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12117417/ · DOI 10.1042/BJ20020841
Complete structured claim and evidence
After 100 mg/kg oral phenylalanine in six healthy men, plasma phenylalanine rose about elevenfold and brain uptake of the artificial large-neutral-amino-acid tracer carbon-11 ACHC fell from 0.036 to 0.019 mL/g/min.
L-Phenylalanine → Human brain influx of carbon-11 ACHC tracer source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human PET loading study in six men.
limitations
ACHC is a transport tracer; each individual natural amino acid was not directly measured. This is not a normal-meal threshold.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
A large phenylalanine load can compete with other molecules for brain entry.
primary_references
Inhibition of neutral amino acid transport across the human blood-brain barrier by phenylalanine. · 1995 · https://pubmed.ncbi.nlm.nih.gov/7861158/ · DOI 10.1046/j.1471-4159.1995.64031252.x
trigger_kind
biomarker_context Imported condition classification; unverified.
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 190–196
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human PET loading study in six men. · source_derived_draft · unverified_draft
## l-phenylalanine-brain-competition A large phenylalanine load can compete with other molecules for brain entry. After 100 mg/kg oral phenylalanine in six healthy men, plasma phenylalanine rose about elevenfold and brain uptake of the artificial large-neutral-amino-acid tracer carbon-11 ACHC fell from 0.036 to 0.019 mL/g/min. Model: Human PET loading study in six men. Limitations: ACHC is a transport tracer; each individual natural amino acid was not directly measured. This is not a normal-meal threshold. Evidence access: Primary abstract Inhibition of neutral amino acid transport across the human blood-brain barrier by phenylalanine. · 1995 · https://pubmed.ncbi.nlm.nih.gov/7861158/ · DOI 10.1046/j.1471-4159.1995.64031252.x
Complete structured claim and evidence
Phenylalanine bound at the interface of two ACT regulatory domains and stabilized the human PAH regulatory-domain dimer.
L-Phenylalanine → Human phenylalanine hydroxylase / PAH source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Isolated human PAH regulatory domain; 1.8-angstrom crystal structure and biophysical assays; crystallization used 10 mM phenylalanine.
limitations
An isolated domain at experimental concentrations does not establish an oral-dose activation threshold.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Phenylalanine helps switch on the machinery that processes it.
primary_references
Structural basis for ligand-dependent dimerization of phenylalanine hydroxylase regulatory domain. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27049649/ · DOI 10.1038/srep23748
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 22–28
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Isolated human PAH regulatory domain; 1.8-angstrom crystal structure and biophysical assays; crystallization used 10 mM phenylalanine. · source_derived_draft · unverified_draft
## l-phenylalanine-pah-allostery Phenylalanine helps switch on the machinery that processes it. Phenylalanine bound at the interface of two ACT regulatory domains and stabilized the human PAH regulatory-domain dimer. Model: Isolated human PAH regulatory domain; 1.8-angstrom crystal structure and biophysical assays; crystallization used 10 mM phenylalanine. Limitations: An isolated domain at experimental concentrations does not establish an oral-dose activation threshold. Evidence access: Primary full text Structural basis for ligand-dependent dimerization of phenylalanine hydroxylase regulatory domain. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27049649/ · DOI 10.1038/srep23748
Complete structured claim and evidence
Biallelic DNAJC12 variants in six patients from four families accompanied hyperphenylalaninemia and neurotransmitter abnormalities; functional studies found reduced PAH activity.
Human chaperone DNAJC12 → Human phenylalanine hydroxylase / PAH source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Human genetic case series and functional experiments.
limitations
Early combined BH4/neurotransmitter-precursor treatment was not a controlled test of phenylalanine supplementation.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Phenylalanine can accumulate because its supporting machinery is defective.
primary_references
Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28132689/ · DOI 10.1016/j.ajhg.2017.01.002
trigger_kind
machinery_impairment Imported condition classification; unverified.
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 110–116
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human genetic case series and functional experiments. · source_derived_draft · unverified_draft
## l-phenylalanine-dnaj-failure Phenylalanine can accumulate because its supporting machinery is defective. Biallelic DNAJC12 variants in six patients from four families accompanied hyperphenylalaninemia and neurotransmitter abnormalities; functional studies found reduced PAH activity. Model: Human genetic case series and functional experiments. Limitations: Early combined BH4/neurotransmitter-precursor treatment was not a controlled test of phenylalanine supplementation. Evidence access: Primary abstract Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28132689/ · DOI 10.1016/j.ajhg.2017.01.002
Complete structured claim and evidence
Recombinant human GFRP enabled phenylalanine-dependent stimulation of recombinant human GCH1.
L-Phenylalanine → GCH1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Recombinant human proteins; primary abstract.
limitations
GCH1 controls an early BH4-biosynthesis step; this is not proof that supplemental phenylalanine raises BH4 in every tissue.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
The substrate can signal for more of the cofactor-making machinery to work.
primary_references
Bacterial lipopolysaccharide down-regulates expression of GTP cyclohydrolase I feedback regulatory protein. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11799107/ · DOI 10.1074/jbc.M107326200
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 38–44
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant human proteins; primary abstract. · source_derived_draft · unverified_draft
## l-phenylalanine-gch1-feedforward The substrate can signal for more of the cofactor-making machinery to work. Recombinant human GFRP enabled phenylalanine-dependent stimulation of recombinant human GCH1. Model: Recombinant human proteins; primary abstract. Limitations: GCH1 controls an early BH4-biosynthesis step; this is not proof that supplemental phenylalanine raises BH4 in every tissue. Evidence access: Primary abstract Bacterial lipopolysaccharide down-regulates expression of GTP cyclohydrolase I feedback regulatory protein. · 2002 · https://pubmed.ncbi.nlm.nih.gov/11799107/ · DOI 10.1074/jbc.M107326200
Complete structured claim and evidence
In an 89-participant six-week PKU trial, sapropterin 10 mg/kg/day lowered mean phenylalanine by 236 micromol/L versus a 3 micromol/L rise with placebo; 44% versus 9% had at least a 30% reduction.
Sapropterin, pharmaceutical tetrahydrobiopterin → Human plasma phenylalanine concentration source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Randomized human PKU study enriched through prior responsiveness assessment.
limitations
Not all PAH defects respond; trial dose is historical evidence, not individualized guidance.
nutrient_topic
L-Phenylalanine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Phenylalanine
plain_language
Providing the pharmaceutical cofactor helped some patients, with substantial response variation.
primary_references
Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17693179/ · DOI 10.1016/S0140-6736(07)61234-3
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19) · lines 222–228
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Randomized human PKU study enriched through prior responsiveness assessment. · source_derived_draft · unverified_draft
## l-phenylalanine-sapropterin-response Providing the pharmaceutical cofactor helped some patients, with substantial response variation. In an 89-participant six-week PKU trial, sapropterin 10 mg/kg/day lowered mean phenylalanine by 236 micromol/L versus a 3 micromol/L rise with placebo; 44% versus 9% had at least a 30% reduction. Model: Randomized human PKU study enriched through prior responsiveness assessment. Limitations: Not all PAH defects respond; trial dose is historical evidence, not individualized guidance. Evidence access: Primary abstract Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study. · 2007 · https://pubmed.ncbi.nlm.nih.gov/17693179/ · DOI 10.1016/S0140-6736(07)61234-3
Complete structured claim and evidence
Human GOT1 catalyzes reversible amino transfer between aspartate and 2-oxoglutarate, producing oxaloacetate and glutamate.
Human cytosolic aspartate aminotransferase / GOT1 → L-Aspartate source_derived_draftungraded
Experimental context and source evidence
experimental_model
Purified human cytosolic GOT1 and GPT; coupled kinetic assays
exposure
Kinetic assays at pH 7.4 and 37 C
limitations
Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds.
nutrient_topic
Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B6
organism
Homo sapiens
plain_language
This B6-dependent enzyme links amino-acid and carbon metabolism.
primary_references
[b6-transaminases-2022] Using Steady-State Kinetics to Quantitate Substrate Selectivity and Specificity: A Case Study with Two Human Transaminases. (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC8875635/ DOI: 10.3390/molecules27041398
tissue_or_cell_type
Purified recombinant protein; no intact tissue
Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 741–751
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human cytosolic GOT1 and GPT; coupled kinetic assays · source_derived_draft · unverified_draft
### b6-met-got1-reaction Human GOT1 catalyzes reversible amino transfer between aspartate and 2-oxoglutarate, producing oxaloacetate and glutamate. Condition category: normal nutrient_topic: Vitamin B6 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This B6-dependent enzyme links amino-acid and carbon metabolism. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein; no intact tissue experimental_model: Purified human cytosolic GOT1 and GPT; coupled kinetic assays limitations: Purified-enzyme evidence does not define dietary requirements or cellular PLP thresholds. exposure: Kinetic assays at pH 7.4 and 37 C [b6-transaminases-2022] Using Steady-State Kinetics to Quantitate Substrate Selectivity and Specificity: A Case Study with Two Human Transaminases. (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC8875635/ DOI: 10.3390/molecules27041398
Complete structured claim and evidence
Human ASNS catalyzes ATP-dependent conversion of aspartate and glutamine to asparagine and glutamate through coupled glutaminase and synthetase chemistry.
Human asparagine synthetase / ASNS → L-Asparagine source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human recombinant ASNS structural and biochemical study; reaction characterized in the study framework.
limitations
A functioning reaction does not guarantee that adding substrate raises the product in every tissue. Correction record: The 2019 author correction added omitted author affiliations and funding acknowledgements; no mechanism or data change was stated. PMID 31799439; DOI 10.1038/s42003-019-0690-1. https://www.nature.com/articles/s42003-019-0690-1
nutrient_topic
L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate
plain_language
Making asparagine needs both aspartate and a nitrogen donor, plus energy.
primary_references
High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31552298/ · DOI 10.1038/s42003-019-0587-z
L-Aspartate: redox transfer, nitrogen partitioning 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 recombinant ASNS structural and biochemical study; reaction characterized in the study framework. · source_derived_draft · unverified_draft
## l-aspartate-asns-reaction Making asparagine needs both aspartate and a nitrogen donor, plus energy. Human ASNS catalyzes ATP-dependent conversion of aspartate and glutamine to asparagine and glutamate through coupled glutaminase and synthetase chemistry. Model: Human recombinant ASNS structural and biochemical study; reaction characterized in the study framework. Limitations: A functioning reaction does not guarantee that adding substrate raises the product in every tissue. Correction record: The 2019 author correction added omitted author affiliations and funding acknowledgements; no mechanism or data change was stated. PMID 31799439; DOI 10.1038/s42003-019-0690-1. https://www.nature.com/articles/s42003-019-0690-1 Evidence access: Primary full text High-resolution crystal structure of human asparagine synthetase enables analysis of inhibitor binding and selectivity. · 2019 · https://pubmed.ncbi.nlm.nih.gov/31552298/ · DOI 10.1038/s42003-019-0587-z
Complete structured claim and evidence
Human cytosolic DARS1 catalyzes attachment of aspartate to its cognate tRNA; its 2.25-angstrom homodimer structure defines the cytosolic enzyme separately from mitochondrial DARS2.
Human cytosolic aspartyl-tRNA synthetase / DARS1 → Human cytosolic aspartate tRNA source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human recombinant cytosolic enzyme structural study.
limitations
Structural suggestions about release from the multisynthetase complex are not treated as demonstrated nutrient signaling.
nutrient_topic
L-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Aspartate
plain_language
Aspartate must be placed on the correct transfer RNA to enter proteins.
primary_references
Crystal structure of human cytosolic aspartyl-tRNA synthetase, a component of multi-tRNA synthetase complex. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23609930/ · DOI 10.1002/prot.24306
L-Aspartate: redox transfer, nitrogen partitioning 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 · Human recombinant cytosolic enzyme structural study. · source_derived_draft · unverified_draft
## l-aspartate-dars1-translation Aspartate must be placed on the correct transfer RNA to enter proteins. Human cytosolic DARS1 catalyzes attachment of aspartate to its cognate tRNA; its 2.25-angstrom homodimer structure defines the cytosolic enzyme separately from mitochondrial DARS2. Model: Human recombinant cytosolic enzyme structural study. Limitations: Structural suggestions about release from the multisynthetase complex are not treated as demonstrated nutrient signaling. Evidence access: Primary full text Crystal structure of human cytosolic aspartyl-tRNA synthetase, a component of multi-tRNA synthetase complex. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23609930/ · DOI 10.1002/prot.24306
Complete structured claim and evidence
Provided carbon-13 formate entered cytosolic 10-formyl-THF and ATP in wild-type HEK293T cells through the MTHFD1 assimilation route.
Human MTHFD1 → Formate source_derived_draftungraded
Experimental context and source evidence
experimental_model
Formate rescue and metabolomics
exposure
Carbon-13 formate tracer in wild-type cells; Figure 2d.
limitations
Tracing supports pathway use but is not an isolated enzyme assay or dietary recommendation.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Homo sapiens
plain_language
Cells incorporate formate carbon into purine nucleotides.
primary_references
[ducker-2016] Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway (2016). https://pubmed.ncbi.nlm.nih.gov/27211901/ DOI: 10.1016/j.cmet.2016.04.016
tissue_or_cell_type
HEK293T cells
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 911–921
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Formate rescue and metabolomics · source_derived_draft · unverified_draft
### formate-mthfd1-assimilation Provided carbon-13 formate entered cytosolic 10-formyl-THF and ATP in wild-type HEK293T cells through the MTHFD1 assimilation route. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cells incorporate formate carbon into purine nucleotides. organism: Homo sapiens tissue_or_cell_type: HEK293T cells experimental_model: Formate rescue and metabolomics limitations: Tracing supports pathway use but is not an isolated enzyme assay or dietary recommendation. exposure: Carbon-13 formate tracer in wild-type cells; Figure 2d. [ducker-2016] Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway (2016). https://pubmed.ncbi.nlm.nih.gov/27211901/ DOI: 10.1016/j.cmet.2016.04.016
Complete structured claim and evidence
Nuclear MTHFD1 supplies formate-derived one-carbon units for thymidylate synthesis through its folate-interconversion activities.
Human MTHFD1 → 5,10-Methylenetetrahydrofolate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
ATP and NADPH support folate-mediated carbon use.
experimental_model
Localization and folate-pathway experiments
exposure
Assay conditions described in the linked primary study.
limitations
Compartmental flux varies with cell cycle.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Homo sapiens
plain_language
Formate can feed DNA-base production inside the nucleus.
primary_references
[field-2014] Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency (2014). https://pubmed.ncbi.nlm.nih.gov/25213861/ DOI: 10.1074/jbc.m114.599589
tissue_or_cell_type
HeLa and MCF7 cells
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 936–947
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Localization and folate-pathway experiments · source_derived_draft · unverified_draft
### mthfd1-formate-nuclear-carbon Nuclear MTHFD1 supplies formate-derived one-carbon units for thymidylate synthesis through its folate-interconversion activities. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Formate can feed DNA-base production inside the nucleus. organism: Homo sapiens tissue_or_cell_type: HeLa and MCF7 cells experimental_model: Localization and folate-pathway experiments limitations: Compartmental flux varies with cell cycle. exposure: Assay conditions described in the linked primary study. cross_nutrient: ATP and NADPH support folate-mediated carbon use. [field-2014] Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency (2014). https://pubmed.ncbi.nlm.nih.gov/25213861/ DOI: 10.1074/jbc.m114.599589
Complete structured claim and evidence
Human phosphopantetheinyl transferase transfers a CoA-derived prosthetic group to ALDH1L2 Ser375.
Human 4-phosphopantetheinyl transferase / AASDHPPT → Human ALDH1L2 source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
B5-derived CoA supplies phosphopantetheine; direct CoA handoff tested, dietary B5 link upstream.
experimental_model
Reconstitution and site-directed mutagenesis
exposure
Assay conditions described in the linked primary study.
limitations
Does not establish dietary B5 deficiency or repletion effects.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Homo sapiens
plain_language
A CoA-derived arm prepares the folate enzyme for catalysis.
primary_references
[strickland-2011] Enzymatic properties of ALDH1L2, a mitochondrial 10-formyltetrahydrofolate dehydrogenase (2011). https://pubmed.ncbi.nlm.nih.gov/21238436/ DOI: 10.1016/j.cbi.2011.01.008
tissue_or_cell_type
Cell-free
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1046–1057
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reconstitution and site-directed mutagenesis · source_derived_draft · unverified_draft
### aldh1l2-coa-arm Human phosphopantetheinyl transferase transfers a CoA-derived prosthetic group to ALDH1L2 Ser375. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A CoA-derived arm prepares the folate enzyme for catalysis. organism: Homo sapiens tissue_or_cell_type: Cell-free experimental_model: Reconstitution and site-directed mutagenesis limitations: Does not establish dietary B5 deficiency or repletion effects. exposure: Assay conditions described in the linked primary study. cross_nutrient: B5-derived CoA supplies phosphopantetheine; direct CoA handoff tested, dietary B5 link upstream. [strickland-2011] Enzymatic properties of ALDH1L2, a mitochondrial 10-formyltetrahydrofolate dehydrogenase (2011). https://pubmed.ncbi.nlm.nih.gov/21238436/ DOI: 10.1016/j.cbi.2011.01.008
Complete structured claim and evidence
Phosphopantetheinylation restored recombinant ALDH1L2 folate dehydrogenase activity with NADPH formation.
Human ALDH1L2 phosphopantetheinylated at Ser375 → 10-Formyltetrahydrofolate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
CoA maturation enables the folate-to-NADPH reaction.
experimental_model
Recombinant enzyme activation assay
exposure
Assay conditions described in the linked primary study.
limitations
Figure 5 used stable dideazafolate analogue rather than physiological folate.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Homo sapiens
plain_language
The installed arm enables oxidation of folate-bound carbon.
primary_references
[strickland-2011] Enzymatic properties of ALDH1L2, a mitochondrial 10-formyltetrahydrofolate dehydrogenase (2011). https://pubmed.ncbi.nlm.nih.gov/21238436/ DOI: 10.1016/j.cbi.2011.01.008
tissue_or_cell_type
Cell-free
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1059–1070
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant enzyme activation assay · source_derived_draft · unverified_draft
### aldh1l2-activation-folate-oxidation Phosphopantetheinylation restored recombinant ALDH1L2 folate dehydrogenase activity with NADPH formation. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The installed arm enables oxidation of folate-bound carbon. organism: Homo sapiens tissue_or_cell_type: Cell-free experimental_model: Recombinant enzyme activation assay limitations: Figure 5 used stable dideazafolate analogue rather than physiological folate. exposure: Assay conditions described in the linked primary study. cross_nutrient: CoA maturation enables the folate-to-NADPH reaction. [strickland-2011] Enzymatic properties of ALDH1L2, a mitochondrial 10-formyltetrahydrofolate dehydrogenase (2011). https://pubmed.ncbi.nlm.nih.gov/21238436/ DOI: 10.1016/j.cbi.2011.01.008
Complete structured claim and evidence
Plcb2 knockout abolished tested sweet, amino-acid and bitter responses while sparing sour and salty responses in the reported mouse experiments.
Mouse phospholipase C beta 2 / Plcb2 → Mouse sweet, bitter and umami taste responses source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse knockout taste behavior and nerve assays.
limitations
Reported assay phenotype; not an MSG deficiency or a universal result at every stimulus concentration.
nutrient_topic
Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate
plain_language
Recognizing the molecule requires downstream signaling machinery.
primary_references
Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12581520/ · DOI 10.1016/s0092-8674(03)00071-0
trigger_kind
machinery_impairment Imported condition classification; unverified.
Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 90–96
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse knockout taste behavior and nerve assays. · source_derived_draft · unverified_draft
## monosodium-glutamate-plcb2-loss Recognizing the molecule requires downstream signaling machinery. Plcb2 knockout abolished tested sweet, amino-acid and bitter responses while sparing sour and salty responses in the reported mouse experiments. Model: Mouse knockout taste behavior and nerve assays. Limitations: Reported assay phenotype; not an MSG deficiency or a universal result at every stimulus concentration. Evidence access: Primary abstract Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12581520/ · DOI 10.1016/s0092-8674(03)00071-0
Complete structured claim and evidence
Trpm5 knockout disrupted the same tested taste modalities in the mouse study.
Mouse calcium-activated monovalent cation channel / Trpm5 → Mouse sweet, bitter and umami taste responses source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse genetic loss-of-function.
limitations
Separate from human TRPM5 and from steviol-glycoside effects in other preparations.
nutrient_topic
Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate
plain_language
An ion channel is another gate after receptor recognition.
primary_references
Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12581520/ · DOI 10.1016/s0092-8674(03)00071-0
trigger_kind
machinery_impairment Imported condition classification; unverified.
Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 98–104
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse genetic loss-of-function. · source_derived_draft · unverified_draft
## monosodium-glutamate-trpm5-loss An ion channel is another gate after receptor recognition. Trpm5 knockout disrupted the same tested taste modalities in the mouse study. Model: Mouse genetic loss-of-function. Limitations: Separate from human TRPM5 and from steviol-glycoside effects in other preparations. Evidence access: Primary abstract Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. · 2003 · https://pubmed.ncbi.nlm.nih.gov/12581520/ · DOI 10.1016/s0092-8674(03)00071-0
Complete structured claim and evidence
Calhm1 knockout reduced taste-evoked ATP release without eliminating taste-cell excitability to the stimuli.
Mouse CALHM1 / Calhm1 → Mouse type II taste-cell ATP release source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse taste-bud knockout physiology.
limitations
The later CALHM3 work refines the channel composition; CALHM1 is not treated as the sole physiological subunit.
nutrient_topic
Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate
plain_language
A cell can detect a stimulus yet fail to transmit its message.
primary_references
CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23467090/ · DOI 10.1038/nature11906
trigger_kind
machinery_impairment Imported condition classification; unverified.
Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 114–120
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse taste-bud knockout physiology. · source_derived_draft · unverified_draft
## monosodium-glutamate-calhm1-release A cell can detect a stimulus yet fail to transmit its message. Calhm1 knockout reduced taste-evoked ATP release without eliminating taste-cell excitability to the stimuli. Model: Mouse taste-bud knockout physiology. Limitations: The later CALHM3 work refines the channel composition; CALHM1 is not treated as the sole physiological subunit. Evidence access: Primary abstract CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23467090/ · DOI 10.1038/nature11906
Complete structured claim and evidence
Calhm3 deletion abolished taste-evoked ATP release and disrupted GPCR-mediated taste perception in mice.
Mouse CALHM3 / Calhm3 → Mouse type II taste-cell ATP release source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse knockout experiments.
limitations
Shares investigators with the CALHM1 study; no human deficiency threshold follows.
nutrient_topic
Monosodium Glutamate (MSG) collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Monosodium L-glutamate
plain_language
Intact upstream sensing cannot compensate for a missing release channel.
primary_references
CALHM3 Is Essential for Rapid Ion Channel-Mediated Purinergic Neurotransmission of GPCR-Mediated Tastes. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29681531/ · DOI 10.1016/j.neuron.2018.03.043
trigger_kind
machinery_impairment Imported condition classification; unverified.
Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20) · lines 130–136
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse knockout experiments. · source_derived_draft · unverified_draft
## monosodium-glutamate-calhm3-loss Intact upstream sensing cannot compensate for a missing release channel. Calhm3 deletion abolished taste-evoked ATP release and disrupted GPCR-mediated taste perception in mice. Model: Mouse knockout experiments. Limitations: Shares investigators with the CALHM1 study; no human deficiency threshold follows. Evidence access: Primary abstract CALHM3 Is Essential for Rapid Ion Channel-Mediated Purinergic Neurotransmission of GPCR-Mediated Tastes. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29681531/ · DOI 10.1016/j.neuron.2018.03.043
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.

Present substrate with impaired digestive processing

Condition: machinery_impairment · Diseased mucosa or experimental enzyme inhibitors.

Normal role: Digestive enzymes process parent and dipeptide.

Recorded consequence: Reduced measured hydrolysis.

Scope: Human/pig preparations.

Formulation and metabolic reserve change blood exposure

Condition: biomarker_context · Different dosing, formulation and carrier status.

Normal role: Absorption and metabolism determine circulating pools.

Recorded consequence: Different amino-acid and methanol kinetics.

Scope: Human short-term studies.

Silencing a sensor attenuates a cell-culture effect

Condition: machinery_impairment · T1R3 siRNA.

Normal role: T1R3 participates in the tested epithelial response.

Recorded consequence: Reduced barrier response.

Scope: Human Caco-2 cells.

Interrupting the nerve route blocks an animal hormone response

Condition: machinery_impairment · Surgical vagotomy.

Normal role: Parasympathetic signaling can regulate insulin release.

Recorded consequence: Loss of the reported aspartame-associated insulin rise.

Scope: Animal experiments.

Immune-cell receptor loss prevents the added plaque effect

Condition: machinery_impairment · Monocyte/macrophage Cx3cr1 deletion.

Normal role: Chemokine signaling recruits inflammatory cells.

Recorded consequence: No aspartame-exacerbated plaque effect in the tested model.

Scope: ApoE-deficient mice.

The sources

Every document behind this chapter is preserved word for word. Open one to read it in full with its recorded conflicts marked in place.

Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20)AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · unverified_draftRead preserved source
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source
L-Aspartate: redox transfer, nitrogen partitioning and cross-nutrient mechanisms (2026-09-19)AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · unverified_draftRead preserved source
L-Methionine: transport, methylation, sulfur metabolism and cross-nutrient mechanisms (2026-09-19)AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · unverified_draftRead preserved source
L-Phenylalanine: transport, protein synthesis, cofactor recycling and cross-nutrient mechanisms (2026-09-19)AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · unverified_draftRead preserved source
Monosodium Glutamate (MSG): taste, gut sensing, exposure and cross-nutrient mechanisms (2026-09-20)AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · unverified_draftRead preserved source
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19)AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · unverified_draftRead preserved source
Vitamin B6: mechanisms, deficiency and nutrient interactions (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source

Recorded disagreements

Where two sources say different things, both are kept and the difference is explained. You can discuss a disagreement or propose a mechanism that might account for it.

Aspartame headache challenges: increased frequency versus no increaseTwo blinded studies in self-reported headache-sensitive adults reached differing conclusions. The repeated trial reported more headache days; the acute trial did not find more headaches. Exposure schedule, selection, attrition and endpoint definition differ and may explain the results, but a common mechanism has not been demonstrated.Read the recorded disagreement

Open questions in this collection

Questions the curators could not answer from the sources in front of them, kept here with the reason each one is still open. These are gaps in this collection, not findings or proof that no one has studied them.

Chapters are assembled from supplied drafts and curated literature summaries. Statements remain unverified against the primary studies, and the ledger is not medical advice.

Evidence, AI assistance and curation standards

Aspartame

The mechanisms

The intestinal study describes ester-bond hydrolysis of aspartame to Asp-Phe before further dipeptide digestion.

Brush-border and cytosolic preparations hydrolyzed Asp-Phe; cytosolic fractionation identified one activity peak distinct from seven previously described peptidases.

Diseased intestinal mucosa showed reduced brush-border and cytosolic Asp-Phe hydrolase activity alongside reductions in other enzymes.

Human duodenal, jejunal and ileal microvillar preparations hydrolyzed aspartame.

CaCl2 increased aspartame hydrolysis 2.9–4.5-fold in the tested human and pig membrane preparations.

1,10-Phenanthroline or amastatin inhibited membrane aspartame metabolism by more than 78%.

Purified aminopeptidase N did not hydrolyze aspartame despite partial inhibition of membrane metabolism by actinonin.

Cyclo-Asp-Phe and beta-Asp-Phe methyl ester resisted the tested microvillar and purified A/W peptidase preparations.

In ten adults given 3 g, solution produced an earlier, higher phenylalanine peak than capsules: 191 versus 117 micromol/L at 32 versus 123 minutes.

Solution versus capsules produced a higher plasma phenylalanine-to-other-LNAA ratio, 0.36 versus 0.23.

Peak plasma aspartate was higher and earlier with 3 g solution than capsules: 26.2 versus 10.4 micromol/L.

Six adults consumed eight hourly 600 mg servings; phenylalanine rose modestly and plateaued after four to five servings within the reported normal postprandial range.

Methanol and formate remained within reported normal limits; plasma aspartate did not significantly rise in the eight-serving experiment.

Blood methanol was below the 0.4 mg/dL detection limit at 34 mg/kg; 100–200 mg/kg doses produced dose-related peaks of 1.27–2.58 mg/dL.

Six adults receiving 200 mg/kg showed no significant increase in blood formate over baseline.

In 18 fasted adults across 100, 150 and 200 mg/kg cohorts, mean plasma phenylalanine peaks were 20.3, 35.1 and 48.7 micromol/dL.

After 34 mg/kg, twelve female PKU heterozygotes had higher peak phenylalanine than ten noncarrier females, 15.1 versus 8.95 micromol/dL.

Four cynomolgus monkeys had higher labeled blood formate after 900 ppm methanol inhalation when folate-deficient than before depletion, while tracer-derived concentrations remained below endogenous formate.

Human T1R2/T1R3 responded to aspartame in heterologous receptor assays.

Mutagenesis identified eleven T1R2 residues important for aspartame responses: S40, Y103, D142, S144, S165, S168, Y215, D278, E302, D307 and R383.

The model proposed two pocket waters bridging aspartame carbonyls to D142 and L279.

Human T1R2 amino-terminal-domain mutants showed ligand-specific and shared requirements across chemically different sweeteners.

Aspartame at 0.1 mM for 24 hours increased Caco-2 monolayer permeability.

The Caco-2 study found reduced cell-surface claudin 3 after 0.1 mM aspartame exposure.

T1R3 siRNA attenuated aspartame-associated barrier and claudin-3 changes in Caco-2 cells.

Aspartame increased the ROS-sensitive fluorescence signal in exposed Caco-2 cells.

N-acetylcysteine at 1 mM attenuated aspartame-associated oxidative and barrier changes.

Claudin-3 overexpression attenuated aspartame-associated permeability and ROS changes in Caco-2 cells.

The study reported increased insulin secretion with 0.15% aspartame in mice and monkeys.

Subdiaphragmatic vagotomy abolished the aspartame-associated insulin rise in the reported experiment.

Sustained aspartame feeding aggravated plaque formation in ApoE-null mice.

Slow-release insulin pumps worsened atherosclerosis in ApoE-null mice.

Insulin-stimulated arterial endothelial cells upregulated CX3CL1.

Monocyte/macrophage Cx3cr1 deletion abolished aspartame-exacerbated atherosclerosis in the model.

The 120-person six-arm sweetener trial reported distinct microbiome and metabolome changes across the sweetener groups, including aspartame, over two weeks.

Significant group-level glycemic impairment was reported for saccharin and sucralose, not aspartame, in the two-week trial.

A repeated crossover trial reported headaches on 33% of aspartame days versus 24% of placebo days, P=0.04; 18 of 32 randomized participants completed all periods.

An acute crossover challenge in 40 self-reported headache-sensitive adults found headaches in 35% after 30 mg/kg aspartame versus 45% after placebo.

In 48 self-described sensitive and 48 matched nonsensitive participants, rated symptoms did not differ between 100 mg aspartame and control bars.

GLP-1, GIP, tyrosine and phenylalanine responses were similar with aspartame and control snack bars.

A seven-day 30 mg/kg/day crossover reported more severe symptoms in participants with depression; the study stopped after 13 people completed because of reactions.

In 102,865 adults followed a median 7.8 years, higher aspartame consumers had an adjusted overall-cancer hazard ratio of 1.15 versus nonconsumers, 95% CI 1.03–1.28.

Labeled methanol inhalation produced labeled blood formate in cynomolgus monkeys.

PAH catalyzes phenylalanine hydroxylation to tyrosine using BH4, molecular oxygen and non-heme ferrous iron.

B0AT1/SLC6A19 transports neutral amino acids including phenylalanine during intestinal absorption and renal reuptake.

Human TAT1 expressed in Xenopus oocytes transported tryptophan, tyrosine, phenylalanine and L-DOPA independently of sodium.

Human LAT2/SLC3A2 transported methionine; leucine and phenylalanine stimulated methionine efflux even against an inward methionine gradient.

After 100 mg/kg oral phenylalanine in six healthy men, plasma phenylalanine rose about elevenfold and brain uptake of the artificial large-neutral-amino-acid tracer carbon-11 ACHC fell from 0.036 to 0.019 mL/g/min.

Phenylalanine bound at the interface of two ACT regulatory domains and stabilized the human PAH regulatory-domain dimer.

Biallelic DNAJC12 variants in six patients from four families accompanied hyperphenylalaninemia and neurotransmitter abnormalities; functional studies found reduced PAH activity.

Recombinant human GFRP enabled phenylalanine-dependent stimulation of recombinant human GCH1.

In an 89-participant six-week PKU trial, sapropterin 10 mg/kg/day lowered mean phenylalanine by 236 micromol/L versus a 3 micromol/L rise with placebo; 44% versus 9% had at least a 30% reduction.

Human GOT1 catalyzes reversible amino transfer between aspartate and 2-oxoglutarate, producing oxaloacetate and glutamate.

Human ASNS catalyzes ATP-dependent conversion of aspartate and glutamine to asparagine and glutamate through coupled glutaminase and synthetase chemistry.

Human cytosolic DARS1 catalyzes attachment of aspartate to its cognate tRNA; its 2.25-angstrom homodimer structure defines the cytosolic enzyme separately from mitochondrial DARS2.

Provided carbon-13 formate entered cytosolic 10-formyl-THF and ATP in wild-type HEK293T cells through the MTHFD1 assimilation route.

Nuclear MTHFD1 supplies formate-derived one-carbon units for thymidylate synthesis through its folate-interconversion activities.

Human phosphopantetheinyl transferase transfers a CoA-derived prosthetic group to ALDH1L2 Ser375.

Phosphopantetheinylation restored recombinant ALDH1L2 folate dehydrogenase activity with NADPH formation.

Plcb2 knockout abolished tested sweet, amino-acid and bitter responses while sparing sour and salty responses in the reported mouse experiments.

Trpm5 knockout disrupted the same tested taste modalities in the mouse study.

Calhm1 knockout reduced taste-evoked ATP release without eliminating taste-cell excitability to the stimuli.

Calhm3 deletion abolished taste-evoked ATP release and disrupted GPCR-mediated taste perception in mice.

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