Nutrient chapter

Folate (vitamin B9)

Folate is a family of compounds that carry one-carbon units for nucleotide synthesis and connected methylation reactions. Folic acid, reduced folates and their cellular forms remain independently identified. Nutrient family, distinct from folic acid and individual reduced folate forms.

131 recorded mechanisms · 30 availability situations · 1 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.

Partially purified human jejunal brush-border folate hydrolase progressively removed glutamates, producing predominantly monoglutamate after 120 minutes.
Human glutamate carboxypeptidase II / FOLH1 → Folate polyglutamates source_derived_draftungraded
Experimental context and source evidence
experimental_model
Partially purified human jejunal brush-border enzyme
exposure
Radiolabeled synthetic folate polyglutamates in enzyme incubations
limitations
Ex-vivo digestion, not a meal bioavailability measurement.
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
Food folate tails are shortened before absorption.
primary_references
[reisenauer1981] Human jejunal brush border folate conjugase. Characteristics and inhibition by salicylazosulfapyridine (1981). https://pubmed.ncbi.nlm.nih.gov/6113848/ DOI: 10.1016/0005-2744(81)90271-0
tissue_or_cell_type
Jejunal brush border
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 82–92
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Partially purified human jejunal brush-border enzyme · source_derived_draft · unverified_draft
### folate-brush-border-deconjugation Partially purified human jejunal brush-border folate hydrolase progressively removed glutamates, producing predominantly monoglutamate after 120 minutes. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Food folate tails are shortened before absorption. organism: Homo sapiens tissue_or_cell_type: Jejunal brush border experimental_model: Partially purified human jejunal brush-border enzyme limitations: Ex-vivo digestion, not a meal bioavailability measurement. exposure: Radiolabeled synthetic folate polyglutamates in enzyme incubations [reisenauer1981] Human jejunal brush border folate conjugase. Characteristics and inhibition by salicylazosulfapyridine (1981). https://pubmed.ncbi.nlm.nih.gov/6113848/ DOI: 10.1016/0005-2744(81)90271-0
Complete structured claim and evidence
Sulfasalazine competitively inhibited human jejunal brush-border folate hydrolase, with reported Ki 0.13 mM.
Sulfasalazine → Human glutamate carboxypeptidase II / FOLH1 source_derived_draftungraded
Experimental context and source evidence
experimental_model
Partially purified human jejunal brush-border enzyme
exposure
In-vitro inhibitor concentration series
limitations
Does not quantify clinical malabsorption or establish every drug mechanism.
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
This drug can inhibit the folate digestion enzyme.
primary_references
[reisenauer1981] Human jejunal brush border folate conjugase. Characteristics and inhibition by salicylazosulfapyridine (1981). https://pubmed.ncbi.nlm.nih.gov/6113848/ DOI: 10.1016/0005-2744(81)90271-0
tissue_or_cell_type
Jejunal brush border
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 94–104
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Partially purified human jejunal brush-border enzyme · source_derived_draft · unverified_draft
### folate-sulfasalazine-conjugase-inhibition Sulfasalazine competitively inhibited human jejunal brush-border folate hydrolase, with reported Ki 0.13 mM. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: This drug can inhibit the folate digestion enzyme. organism: Homo sapiens tissue_or_cell_type: Jejunal brush border experimental_model: Partially purified human jejunal brush-border enzyme limitations: Does not quantify clinical malabsorption or establish every drug mechanism. exposure: In-vitro inhibitor concentration series [reisenauer1981] Human jejunal brush border folate conjugase. Characteristics and inhibition by salicylazosulfapyridine (1981). https://pubmed.ncbi.nlm.nih.gov/6113848/ DOI: 10.1016/0005-2744(81)90271-0
Complete structured claim and evidence
Human GCPII structures and mutagenesis identified an arene-binding site that recognizes the folate portion of polyglutamate substrates.
Human glutamate carboxypeptidase II / FOLH1 → Folate polyglutamates source_derived_draftungraded
Experimental context and source evidence
experimental_model
Recombinant human GCPII structure and enzyme assays
exposure
Substrate complexes and arene-site mutants
limitations
Catalytically inactive structures require the accompanying kinetic experiments for functional interpretation.
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 enzyme recognizes more than the glutamate tail.
primary_references
[navratil2014] Structural and biochemical characterization of the folyl-poly-γ-l-glutamate hydrolyzing activity of human glutamate carboxypeptidase II (2014). https://pubmed.ncbi.nlm.nih.gov/24863754/ DOI: 10.1111/febs.12857
tissue_or_cell_type
Purified recombinant protein
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 106–116
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human GCPII structure and enzyme assays · source_derived_draft · unverified_draft
### folate-gcpii-arene-recognition Human GCPII structures and mutagenesis identified an arene-binding site that recognizes the folate portion of polyglutamate substrates. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The enzyme recognizes more than the glutamate tail. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein experimental_model: Recombinant human GCPII structure and enzyme assays limitations: Catalytically inactive structures require the accompanying kinetic experiments for functional interpretation. exposure: Substrate complexes and arene-site mutants [navratil2014] Structural and biochemical characterization of the folyl-poly-γ-l-glutamate hydrolyzing activity of human glutamate carboxypeptidase II (2014). https://pubmed.ncbi.nlm.nih.gov/24863754/ DOI: 10.1111/febs.12857
Complete structured claim and evidence
Human GCPII crystal structures resolved two zinc ions at the catalytic center, bridged by water or hydroxide and Asp387.
Zinc(II) ion → Human glutamate carboxypeptidase II / FOLH1 source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Zinc-folate: molecular catalytic-site dependency; dietary zinc deficiency was not tested.
experimental_model
Recombinant human GCPII crystallography
exposure
Glutamate, phosphate and inhibitor-bound structures
limitations
Structural cofactor evidence does not establish zinc intake thresholds.
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 folate-processing enzyme contains a two-zinc catalytic site.
primary_references
[mesters2006] Structure of glutamate carboxypeptidase II, a drug target in neuronal damage and prostate cancer (2006). https://pubmed.ncbi.nlm.nih.gov/16467855/ DOI: 10.1038/sj.emboj.7600969
tissue_or_cell_type
Purified recombinant protein
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 118–129
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human GCPII crystallography · source_derived_draft · unverified_draft
### folate-gcpii-zinc-catalytic-center Human GCPII crystal structures resolved two zinc ions at the catalytic center, bridged by water or hydroxide and Asp387. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The folate-processing enzyme contains a two-zinc catalytic site. organism: Homo sapiens tissue_or_cell_type: Purified recombinant protein experimental_model: Recombinant human GCPII crystallography limitations: Structural cofactor evidence does not establish zinc intake thresholds. exposure: Glutamate, phosphate and inhibitor-bound structures cross_nutrient: Zinc-folate: molecular catalytic-site dependency; dietary zinc deficiency was not tested. [mesters2006] Structure of glutamate carboxypeptidase II, a drug target in neuronal damage and prostate cancer (2006). https://pubmed.ncbi.nlm.nih.gov/16467855/ DOI: 10.1038/sj.emboj.7600969
Complete structured claim and evidence
Expression of human PCFT produced high-affinity, proton-coupled folate uptake with enhanced activity at acidic pH.
Human proton-coupled folate transporter / SLC46A1 → Folate monoglutamates source_derived_draftungraded
Experimental context and source evidence
experimental_model
Human transporter expression, electrophysiology and affected family
exposure
Folate substrates across pH conditions
limitations
Expression-system kinetics are not whole-intestine absorption fractions.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Human transporter in cellular/oocyte expression systems
plain_language
PCFT uses acidic conditions to help folate enter cells.
primary_references
[qiu2006] Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption (2006). https://pubmed.ncbi.nlm.nih.gov/17129779/ DOI: 10.1016/j.cell.2006.09.041
tissue_or_cell_type
Membrane transport models
transport_effect
raises Recorded as high-affinity proton-coupled folate uptake.
transport_pool
the expressing cell Recorded as high-affinity proton-coupled folate uptake.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 131–141
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human transporter expression, electrophysiology and affected family · source_derived_draft · unverified_draft
### folate-pcft-proton-coupled-entry Expression of human PCFT produced high-affinity, proton-coupled folate uptake with enhanced activity at acidic pH. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: PCFT uses acidic conditions to help folate enter cells. organism: Human transporter in cellular/oocyte expression systems tissue_or_cell_type: Membrane transport models experimental_model: Human transporter expression, electrophysiology and affected family limitations: Expression-system kinetics are not whole-intestine absorption fractions. exposure: Folate substrates across pH conditions [qiu2006] Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption (2006). https://pubmed.ncbi.nlm.nih.gov/17129779/ DOI: 10.1016/j.cell.2006.09.041
Complete structured claim and evidence
A PCFT loss-of-function mutation in the studied family established a genetic cause of hereditary folate malabsorption.
SLC46A1 loss-of-function genotype in Qiu 2006 family → Intestinal folate uptake source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Human transporter expression, electrophysiology and affected family
exposure
Inherited mutation
limitations
Rare familial disorder; not dietary withdrawal.
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
An inherited transport defect can reduce folate absorption.
primary_references
[qiu2006] Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption (2006). https://pubmed.ncbi.nlm.nih.gov/17129779/ DOI: 10.1016/j.cell.2006.09.041
tissue_or_cell_type
Intestinal absorption and family genetics
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 143–153
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human transporter expression, electrophysiology and affected family · source_derived_draft · unverified_draft
### folate-pcft-inherited-malabsorption A PCFT loss-of-function mutation in the studied family established a genetic cause of hereditary folate malabsorption. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: An inherited transport defect can reduce folate absorption. organism: Homo sapiens tissue_or_cell_type: Intestinal absorption and family genetics experimental_model: Human transporter expression, electrophysiology and affected family limitations: Rare familial disorder; not dietary withdrawal. exposure: Inherited mutation [qiu2006] Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption (2006). https://pubmed.ncbi.nlm.nih.gov/17129779/ DOI: 10.1016/j.cell.2006.09.041
Complete structured claim and evidence
Cryo-EM resolved 5-methyltetrahydrofolate in the central substrate pocket of human SLC19A1.
Human reduced folate carrier / SLC19A1 → 5-Methyltetrahydrofolate source_derived_draftungraded
Experimental context and source evidence
experimental_model
Human SLC19A1 structures and HEK293F uptake assays
exposure
5-MTHF-bound cryo-EM complex
limitations
Static inward-facing structure does not itself measure a complete transport 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
RFC directly recognizes methylfolate.
primary_references
[dang2022] Molecular mechanism of substrate recognition by folate transporter SLC19A1 (2022). https://pubmed.ncbi.nlm.nih.gov/36575193/ DOI: 10.1038/s41421-022-00508-w
tissue_or_cell_type
Purified transporter and HEK293F cells
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 155–165
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human SLC19A1 structures and HEK293F uptake assays · source_derived_draft · unverified_draft
### folate-rfc-methylfolate-binding Cryo-EM resolved 5-methyltetrahydrofolate in the central substrate pocket of human SLC19A1. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: RFC directly recognizes methylfolate. organism: Homo sapiens tissue_or_cell_type: Purified transporter and HEK293F cells experimental_model: Human SLC19A1 structures and HEK293F uptake assays limitations: Static inward-facing structure does not itself measure a complete transport cycle. exposure: 5-MTHF-bound cryo-EM complex [dang2022] Molecular mechanism of substrate recognition by folate transporter SLC19A1 (2022). https://pubmed.ncbi.nlm.nih.gov/36575193/ DOI: 10.1038/s41421-022-00508-w
Complete structured claim and evidence
Human SLC19A1 bound thiamine diphosphate in the same pocket as 5-MTHF; thiamine diphosphate inhibited methotrexate uptake with IC50 about 19 micromolar.
Thiamine diphosphate → Human reduced folate carrier / SLC19A1 source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
B1-folate: phosphorylated thiamine and folates share RFC recognition; exclusive physiological counter-substrate status remains unproven.
experimental_model
Human SLC19A1 structures and HEK293F uptake assays
exposure
Binding assays and extracellular competition
limitations
Supports shared recognition; does not prove dietary B1 deficiency blocks folate delivery.
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 vitamin B1 cofactor can occupy the folate carrier.
primary_references
[dang2022] Molecular mechanism of substrate recognition by folate transporter SLC19A1 (2022). https://pubmed.ncbi.nlm.nih.gov/36575193/ DOI: 10.1038/s41421-022-00508-w
tissue_or_cell_type
Purified transporter and HEK293F cells
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 167–178
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human SLC19A1 structures and HEK293F uptake assays · source_derived_draft · unverified_draft
### folate-rfc-thdp-shared-pocket Human SLC19A1 bound thiamine diphosphate in the same pocket as 5-MTHF; thiamine diphosphate inhibited methotrexate uptake with IC50 about 19 micromolar. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A vitamin B1 cofactor can occupy the folate carrier. organism: Homo sapiens tissue_or_cell_type: Purified transporter and HEK293F cells experimental_model: Human SLC19A1 structures and HEK293F uptake assays limitations: Supports shared recognition; does not prove dietary B1 deficiency blocks folate delivery. exposure: Binding assays and extracellular competition cross_nutrient: B1-folate: phosphorylated thiamine and folates share RFC recognition; exclusive physiological counter-substrate status remains unproven. [dang2022] Molecular mechanism of substrate recognition by folate transporter SLC19A1 (2022). https://pubmed.ncbi.nlm.nih.gov/36575193/ DOI: 10.1038/s41421-022-00508-w
Complete structured claim and evidence
RFC overexpression increased thiamine-monophosphate influx approximately fivefold in mouse R16 leukemia cells relative to the parent line.
Mouse reduced folate carrier / Slc19a1 → Thiamine monophosphate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
B1-folate: shared carrier for folate and TMP; free thiamine is a different substrate.
experimental_model
Mouse L1210/R16 leukemia transport experiments
exposure
Short radiolabeled TMP uptake assays
limitations
Extracellular TMP hydrolysis and transformed cells constrain extrapolation.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Mus musculus
plain_language
A folate carrier also transported a phosphorylated B1 form.
primary_references
[zhao2002] Reduced folate carrier transports thiamine monophosphate: an alternative route for thiamine delivery into mammalian cells (2002). https://pubmed.ncbi.nlm.nih.gov/11997266/ DOI: 10.1152/ajpcell.00547.2001
tissue_or_cell_type
L1210/R16 leukemia cells
transport_effect
raises Overexpression increased thiamine-monophosphate influx about fivefold.
transport_pool
the expressing cell Overexpression increased thiamine-monophosphate influx about fivefold.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 180–191
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse L1210/R16 leukemia transport experiments · source_derived_draft · unverified_draft
### folate-mouse-rfc-tmp-entry RFC overexpression increased thiamine-monophosphate influx approximately fivefold in mouse R16 leukemia cells relative to the parent line. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A folate carrier also transported a phosphorylated B1 form. organism: Mus musculus tissue_or_cell_type: L1210/R16 leukemia cells experimental_model: Mouse L1210/R16 leukemia transport experiments limitations: Extracellular TMP hydrolysis and transformed cells constrain extrapolation. exposure: Short radiolabeled TMP uptake assays cross_nutrient: B1-folate: shared carrier for folate and TMP; free thiamine is a different substrate. [zhao2002] Reduced folate carrier transports thiamine monophosphate: an alternative route for thiamine delivery into mammalian cells (2002). https://pubmed.ncbi.nlm.nih.gov/11997266/ DOI: 10.1152/ajpcell.00547.2001
Complete structured claim and evidence
Methotrexate inhibited the RFC-mediated component of thiamine-monophosphate influx in mouse L1210 cells.
Methotrexate → Thiamine monophosphate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
B1-antifolate: competition at RFC under the tested drug exposure.
experimental_model
Mouse L1210/R16 leukemia transport experiments
exposure
50 nM TMP with 100 micromolar methotrexate
limitations
Pharmacological cell experiment, not a clinical thiamine-deficiency outcome.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Mus musculus
plain_language
An antifolate competed with phosphorylated B1 entry.
primary_references
[zhao2002] Reduced folate carrier transports thiamine monophosphate: an alternative route for thiamine delivery into mammalian cells (2002). https://pubmed.ncbi.nlm.nih.gov/11997266/ DOI: 10.1152/ajpcell.00547.2001
tissue_or_cell_type
L1210 leukemia cells
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 193–204
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mouse L1210/R16 leukemia transport experiments · source_derived_draft · unverified_draft
### folate-mtx-tmp-transport-competition Methotrexate inhibited the RFC-mediated component of thiamine-monophosphate influx in mouse L1210 cells. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: An antifolate competed with phosphorylated B1 entry. organism: Mus musculus tissue_or_cell_type: L1210 leukemia cells experimental_model: Mouse L1210/R16 leukemia transport experiments limitations: Pharmacological cell experiment, not a clinical thiamine-deficiency outcome. exposure: 50 nM TMP with 100 micromolar methotrexate cross_nutrient: B1-antifolate: competition at RFC under the tested drug exposure. [zhao2002] Reduced folate carrier transports thiamine monophosphate: an alternative route for thiamine delivery into mammalian cells (2002). https://pubmed.ncbi.nlm.nih.gov/11997266/ DOI: 10.1152/ajpcell.00547.2001
Complete structured claim and evidence
Human FOLR1 and FITC-conjugated folic acid moved together from basolateral to apical sides of polarized rat choroid-plexus cells.
Human folate receptor alpha / FOLR1 → Choroid plexus folate transcytosis source_derived_draftungraded
Experimental context and source evidence
evidence_location
Figure 2: polarized FITC-folic-acid cotransport
experimental_model
Human FOLR1 in rat choroid-plexus cells, human CSF, mouse injections
exposure
Human FOLR1 transfection and FITC-folic-acid imaging
limitations
Engineered cellular barrier and fluorescent conjugate; not direct native-5-MTHF or whole-human transport measurement.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Human protein in rat cells
plain_language
The receptor helped folate cross a modeled brain-fluid barrier.
primary_references
[grapp2013] Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma (2013). https://pubmed.ncbi.nlm.nih.gov/23828504/ DOI: 10.1038/ncomms3123
tissue_or_cell_type
Polarized choroid-plexus cells
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 206–217
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human FOLR1 in rat choroid-plexus cells, human CSF, mouse injections · source_derived_draft · unverified_draft
### folate-fralpha-polarized-transfer Human FOLR1 and FITC-conjugated folic acid moved together from basolateral to apical sides of polarized rat choroid-plexus cells. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The receptor helped folate cross a modeled brain-fluid barrier. organism: Human protein in rat cells tissue_or_cell_type: Polarized choroid-plexus cells experimental_model: Human FOLR1 in rat choroid-plexus cells, human CSF, mouse injections limitations: Engineered cellular barrier and fluorescent conjugate; not direct native-5-MTHF or whole-human transport measurement. exposure: Human FOLR1 transfection and FITC-folic-acid imaging evidence_location: Figure 2: polarized FITC-folic-acid cotransport [grapp2013] Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma (2013). https://pubmed.ncbi.nlm.nih.gov/23828504/ DOI: 10.1038/ncomms3123
Complete structured claim and evidence
Intraventricular injection experiments showed greater brain-parenchymal delivery of FOLR1-positive than FOLR1-negative exosomes in mice.
FOLR1-positive exosomes → Brain parenchymal exosome delivery source_derived_draftungraded
Experimental context and source evidence
experimental_model
Human FOLR1 in rat choroid-plexus cells, human CSF, mouse injections
exposure
Intraventricular exosome administration
limitations
Injection bypasses entry from blood; does not prove all brain folate follows this route.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Mus musculus receiving human-FOLR1-associated exosomes
plain_language
Receptor-bearing vesicles reached brain tissue in this experiment.
primary_references
[grapp2013] Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma (2013). https://pubmed.ncbi.nlm.nih.gov/23828504/ DOI: 10.1038/ncomms3123
tissue_or_cell_type
Brain parenchyma
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 219–229
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human FOLR1 in rat choroid-plexus cells, human CSF, mouse injections · source_derived_draft · unverified_draft
### folate-fralpha-exosome-brain-entry Intraventricular injection experiments showed greater brain-parenchymal delivery of FOLR1-positive than FOLR1-negative exosomes in mice. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Receptor-bearing vesicles reached brain tissue in this experiment. organism: Mus musculus receiving human-FOLR1-associated exosomes tissue_or_cell_type: Brain parenchyma experimental_model: Human FOLR1 in rat choroid-plexus cells, human CSF, mouse injections limitations: Injection bypasses entry from blood; does not prove all brain folate follows this route. exposure: Intraventricular exosome administration [grapp2013] Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma (2013). https://pubmed.ncbi.nlm.nih.gov/23828504/ DOI: 10.1038/ncomms3123
Complete structured claim and evidence
Two siblings with FOLR1 Q118X/C175X variants had severe CSF folate depletion despite unremarkable plasma and erythrocyte folate.
Human compound-heterozygous FOLR1 Q118X/C175X genotype → CSF 5-methyltetrahydrofolate concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Children with FOLR1 variants and patient fibroblasts
exposure
Inherited compound-heterozygous genotype
limitations
Observations in two siblings; does not generalize to common folate variation.
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
Normal blood folate did not exclude impaired brain delivery.
primary_references
[steinfeld2009] Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism (2009). https://pubmed.ncbi.nlm.nih.gov/19732866/ DOI: 10.1016/j.ajhg.2009.08.005
tissue_or_cell_type
CSF, plasma and erythrocytes
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 231–241
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Children with FOLR1 variants and patient fibroblasts · source_derived_draft · unverified_draft
### folate-folr1-csf-peripheral-dissociation Two siblings with FOLR1 Q118X/C175X variants had severe CSF folate depletion despite unremarkable plasma and erythrocyte folate. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Normal blood folate did not exclude impaired brain delivery. organism: Homo sapiens tissue_or_cell_type: CSF, plasma and erythrocytes experimental_model: Children with FOLR1 variants and patient fibroblasts limitations: Observations in two siblings; does not generalize to common folate variation. exposure: Inherited compound-heterozygous genotype [steinfeld2009] Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism (2009). https://pubmed.ncbi.nlm.nih.gov/19732866/ DOI: 10.1016/j.ajhg.2009.08.005
Complete structured claim and evidence
Introducing wild-type human FOLR1 restored specific surface folate binding in fibroblasts from the nonsense-variant patient.
Human folate receptor alpha / FOLR1 → Folate receptor surface binding source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Children with FOLR1 variants and patient fibroblasts
exposure
Retroviral wild-type FOLR1 expression; 5 nM radioligand
limitations
Receptor binding assay, not transcytosis.
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
Replacing the missing receptor restored cellular binding.
primary_references
[steinfeld2009] Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism (2009). https://pubmed.ncbi.nlm.nih.gov/19732866/ DOI: 10.1016/j.ajhg.2009.08.005
tissue_or_cell_type
Patient fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 243–253
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Children with FOLR1 variants and patient fibroblasts · source_derived_draft · unverified_draft
### folate-folr1-fibroblast-binding-rescue Introducing wild-type human FOLR1 restored specific surface folate binding in fibroblasts from the nonsense-variant patient. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Replacing the missing receptor restored cellular binding. organism: Homo sapiens tissue_or_cell_type: Patient fibroblasts experimental_model: Children with FOLR1 variants and patient fibroblasts limitations: Receptor binding assay, not transcytosis. exposure: Retroviral wild-type FOLR1 expression; 5 nM radioligand [steinfeld2009] Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism (2009). https://pubmed.ncbi.nlm.nih.gov/19732866/ DOI: 10.1016/j.ajhg.2009.08.005
Complete structured claim and evidence
Purified human cytosolic FPGS used tetrahydrofolate as an effective substrate for polyglutamate synthesis.
Human cytosolic FPGS isoform → Tetrahydrofolate source_derived_draftungraded
Experimental context and source evidence
experimental_model
Purified human cytosolic FPGS expressed in bacteria
exposure
Comparative substrate enzyme assays
limitations
Purified substrate preference does not quantify intact-cell flux.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Homo sapiens protein expressed in Escherichia coli
plain_language
FPGS adds tails that help retain usable folate.
primary_references
[chen1996] Purification and properties of human cytosolic folylpoly-gamma-glutamate synthetase and organization, localization, and differential splicing of its gene (1996). https://pubmed.ncbi.nlm.nih.gov/8662720/ DOI: 10.1074/jbc.271.22.13077
tissue_or_cell_type
Purified enzyme
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 255–265
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human cytosolic FPGS expressed in bacteria · source_derived_draft · unverified_draft
### folate-fpgs-thf-substrate Purified human cytosolic FPGS used tetrahydrofolate as an effective substrate for polyglutamate synthesis. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: FPGS adds tails that help retain usable folate. organism: Homo sapiens protein expressed in Escherichia coli tissue_or_cell_type: Purified enzyme experimental_model: Purified human cytosolic FPGS expressed in bacteria limitations: Purified substrate preference does not quantify intact-cell flux. exposure: Comparative substrate enzyme assays [chen1996] Purification and properties of human cytosolic folylpoly-gamma-glutamate synthetase and organization, localization, and differential splicing of its gene (1996). https://pubmed.ncbi.nlm.nih.gov/8662720/ DOI: 10.1074/jbc.271.22.13077
Complete structured claim and evidence
Dihydrofolate was also an effective substrate for purified human cytosolic FPGS.
Human cytosolic FPGS isoform → 7,8-Dihydrofolate source_derived_draftungraded
Experimental context and source evidence
experimental_model
Purified human cytosolic FPGS expressed in bacteria
exposure
Comparative substrate enzyme assays
limitations
Does not establish net DHF pool size in human tissues.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Homo sapiens protein expressed in Escherichia coli
plain_language
Polyglutamate tails can be attached before DHF is reduced.
primary_references
[chen1996] Purification and properties of human cytosolic folylpoly-gamma-glutamate synthetase and organization, localization, and differential splicing of its gene (1996). https://pubmed.ncbi.nlm.nih.gov/8662720/ DOI: 10.1074/jbc.271.22.13077
tissue_or_cell_type
Purified enzyme
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 267–277
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human cytosolic FPGS expressed in bacteria · source_derived_draft · unverified_draft
### folate-fpgs-dhf-substrate Dihydrofolate was also an effective substrate for purified human cytosolic FPGS. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Polyglutamate tails can be attached before DHF is reduced. organism: Homo sapiens protein expressed in Escherichia coli tissue_or_cell_type: Purified enzyme experimental_model: Purified human cytosolic FPGS expressed in bacteria limitations: Does not establish net DHF pool size in human tissues. exposure: Comparative substrate enzyme assays [chen1996] Purification and properties of human cytosolic folylpoly-gamma-glutamate synthetase and organization, localization, and differential splicing of its gene (1996). https://pubmed.ncbi.nlm.nih.gov/8662720/ DOI: 10.1074/jbc.271.22.13077
Complete structured claim and evidence
Human cytosolic FPGS reconstitution supported persistent folate pools in AUXB1 cells; labeled folate loss was not measurable over three cell generations.
Human cytosolic FPGS isoform → Cellular folate retention source_derived_draftungraded
Experimental context and source evidence
experimental_model
Human FPGS isoforms in Chinese hamster AUXB1 cells
exposure
Doxycycline-induced cytosolic FPGS and tracer chase
limitations
Non-detection applies to the tested cell model and observation window.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Human enzyme in Cricetulus griseus cells
plain_language
Cytosolic tail-building helped keep folate inside cells.
primary_references
[lawrence2014] Mammalian mitochondrial and cytosolic folylpolyglutamate synthetase maintain the subcellular compartmentalization of folates (2014). https://pubmed.ncbi.nlm.nih.gov/25164808/ DOI: 10.1074/jbc.m114.593244
tissue_or_cell_type
AUXB1 cells
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 279–289
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human FPGS isoforms in Chinese hamster AUXB1 cells · source_derived_draft · unverified_draft
### folate-fpgs-cytosolic-trapping Human cytosolic FPGS reconstitution supported persistent folate pools in AUXB1 cells; labeled folate loss was not measurable over three cell generations. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cytosolic tail-building helped keep folate inside cells. organism: Human enzyme in Cricetulus griseus cells tissue_or_cell_type: AUXB1 cells experimental_model: Human FPGS isoforms in Chinese hamster AUXB1 cells limitations: Non-detection applies to the tested cell model and observation window. exposure: Doxycycline-induced cytosolic FPGS and tracer chase [lawrence2014] Mammalian mitochondrial and cytosolic folylpolyglutamate synthetase maintain the subcellular compartmentalization of folates (2014). https://pubmed.ncbi.nlm.nih.gov/25164808/ DOI: 10.1074/jbc.m114.593244
Complete structured claim and evidence
Mitochondrial human FPGS maintained a separately retained mitochondrial folate-polyglutamate pool in reconstituted AUXB1 cells.
Human mitochondrial FPGS isoform → Mitochondrial folate accumulation source_derived_draftungraded
Experimental context and source evidence
experimental_model
Human FPGS isoforms in Chinese hamster AUXB1 cells
exposure
Induced mitochondrial FPGS and fractionation
limitations
Compartment separation is specific to the validated fractionation experiment.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Human enzyme in Cricetulus griseus cells
plain_language
Mitochondria make and keep their own folate tails.
primary_references
[lawrence2014] Mammalian mitochondrial and cytosolic folylpolyglutamate synthetase maintain the subcellular compartmentalization of folates (2014). https://pubmed.ncbi.nlm.nih.gov/25164808/ DOI: 10.1074/jbc.m114.593244
tissue_or_cell_type
AUXB1 mitochondria
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 291–301
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human FPGS isoforms in Chinese hamster AUXB1 cells · source_derived_draft · unverified_draft
### folate-fpgs-mitochondrial-trapping Mitochondrial human FPGS maintained a separately retained mitochondrial folate-polyglutamate pool in reconstituted AUXB1 cells. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Mitochondria make and keep their own folate tails. organism: Human enzyme in Cricetulus griseus cells tissue_or_cell_type: AUXB1 mitochondria experimental_model: Human FPGS isoforms in Chinese hamster AUXB1 cells limitations: Compartment separation is specific to the validated fractionation experiment. exposure: Induced mitochondrial FPGS and fractionation [lawrence2014] Mammalian mitochondrial and cytosolic folylpolyglutamate synthetase maintain the subcellular compartmentalization of folates (2014). https://pubmed.ncbi.nlm.nih.gov/25164808/ DOI: 10.1074/jbc.m114.593244
Complete structured claim and evidence
Tracer experiments detected no intact folate-polyglutamate transfer from mitochondria to cytosol in the tested human-FPGS-reconstituted hamster cells.
Folate polyglutamates → Mitochondrial folate polyglutamate export source_derived_draftungraded
Experimental context and source evidence
experimental_model
Human FPGS isoforms in Chinese hamster AUXB1 cells
exposure
Compartment-specific FPGS induction and tracer chase
limitations
Detection-limited result, not proof of universal impermeability.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Human enzyme in Cricetulus griseus cells
plain_language
Stored mitochondrial folates did not measurably replenish the cytosol.
primary_references
[lawrence2014] Mammalian mitochondrial and cytosolic folylpolyglutamate synthetase maintain the subcellular compartmentalization of folates (2014). https://pubmed.ncbi.nlm.nih.gov/25164808/ DOI: 10.1074/jbc.m114.593244
tissue_or_cell_type
AUXB1 mitochondrial and cytosolic fractions
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 303–313
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human FPGS isoforms in Chinese hamster AUXB1 cells · source_derived_draft · unverified_draft
### folate-polyglutamate-no-mito-export Tracer experiments detected no intact folate-polyglutamate transfer from mitochondria to cytosol in the tested human-FPGS-reconstituted hamster cells. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Stored mitochondrial folates did not measurably replenish the cytosol. organism: Human enzyme in Cricetulus griseus cells tissue_or_cell_type: AUXB1 mitochondrial and cytosolic fractions experimental_model: Human FPGS isoforms in Chinese hamster AUXB1 cells limitations: Detection-limited result, not proof of universal impermeability. exposure: Compartment-specific FPGS induction and tracer chase [lawrence2014] Mammalian mitochondrial and cytosolic folylpolyglutamate synthetase maintain the subcellular compartmentalization of folates (2014). https://pubmed.ncbi.nlm.nih.gov/25164808/ DOI: 10.1074/jbc.m114.593244
Complete structured claim and evidence
Mitochondrial-only FPGS expression relieved the glycine supplementation requirement of AUXB1 cells.
Human mitochondrial FPGS isoform → Glycine biosynthesis source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Human FPGS isoforms in Chinese hamster AUXB1 cells
exposure
Mitochondrial FPGS reconstitution with nutrient complementation
limitations
Growth complementation is indirect evidence of glycine synthetic capacity.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Human enzyme in Cricetulus griseus cells
plain_language
Restoring mitochondrial folate retention restored glycine independence.
primary_references
[lawrence2014] Mammalian mitochondrial and cytosolic folylpolyglutamate synthetase maintain the subcellular compartmentalization of folates (2014). https://pubmed.ncbi.nlm.nih.gov/25164808/ DOI: 10.1074/jbc.m114.593244
tissue_or_cell_type
AUXB1 cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 315–325
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human FPGS isoforms in Chinese hamster AUXB1 cells · source_derived_draft · unverified_draft
### folate-fpgs-mito-glycine-complementation Mitochondrial-only FPGS expression relieved the glycine supplementation requirement of AUXB1 cells. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Restoring mitochondrial folate retention restored glycine independence. organism: Human enzyme in Cricetulus griseus cells tissue_or_cell_type: AUXB1 cells experimental_model: Human FPGS isoforms in Chinese hamster AUXB1 cells limitations: Growth complementation is indirect evidence of glycine synthetic capacity. exposure: Mitochondrial FPGS reconstitution with nutrient complementation [lawrence2014] Mammalian mitochondrial and cytosolic folylpolyglutamate synthetase maintain the subcellular compartmentalization of folates (2014). https://pubmed.ncbi.nlm.nih.gov/25164808/ DOI: 10.1074/jbc.m114.593244
Complete structured claim and evidence
GGH overexpression lowered long-chain folate-polyglutamate content in HCT116 cells.
GGH overexpression in HCT116 → Folate polyglutamates source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
GGH-modulated human HCT116 cancer cells
exposure
Sense-GGH vector versus control
limitations
Long-chain content was estimated using conjugase-treated versus untreated assay differences.
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
More tail trimming reduced retained long-chain folates.
primary_references
[kim2013] γ-Glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate (2013). https://pubmed.ncbi.nlm.nih.gov/24045662/ DOI: 10.1038/bjc.2013.579
tissue_or_cell_type
HCT116 cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 327–337
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · GGH-modulated human HCT116 cancer cells · source_derived_draft · unverified_draft
### folate-ggh-overexpression-tail-loss GGH overexpression lowered long-chain folate-polyglutamate content in HCT116 cells. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: More tail trimming reduced retained long-chain folates. organism: Homo sapiens tissue_or_cell_type: HCT116 cells experimental_model: GGH-modulated human HCT116 cancer cells limitations: Long-chain content was estimated using conjugase-treated versus untreated assay differences. exposure: Sense-GGH vector versus control [kim2013] γ-Glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate (2013). https://pubmed.ncbi.nlm.nih.gov/24045662/ DOI: 10.1038/bjc.2013.579
Complete structured claim and evidence
GGH-targeted siRNA increased long-chain folate-polyglutamate content in HCT116 cells.
GGH silencing in HCT116 → Folate polyglutamates source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
GGH-modulated human HCT116 cancer cells
exposure
Targeted siRNA versus control
limitations
Does not imply universal drug sensitization across folate conditions.
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
Less tail trimming increased the retained folate pool.
primary_references
[kim2013] γ-Glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate (2013). https://pubmed.ncbi.nlm.nih.gov/24045662/ DOI: 10.1038/bjc.2013.579
tissue_or_cell_type
HCT116 cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 339–349
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · GGH-modulated human HCT116 cancer cells · source_derived_draft · unverified_draft
### folate-ggh-silencing-tail-retention GGH-targeted siRNA increased long-chain folate-polyglutamate content in HCT116 cells. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Less tail trimming increased the retained folate pool. organism: Homo sapiens tissue_or_cell_type: HCT116 cells experimental_model: GGH-modulated human HCT116 cancer cells limitations: Does not imply universal drug sensitization across folate conditions. exposure: Targeted siRNA versus control [kim2013] γ-Glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate (2013). https://pubmed.ncbi.nlm.nih.gov/24045662/ DOI: 10.1038/bjc.2013.579
Complete structured claim and evidence
DHFR reduces folic acid to dihydrofolate before further reduction to tetrahydrofolate.
Human dihydrofolate reductase / DHFR → Folic acid source_derived_draftungraded
Experimental context and source evidence
experimental_model
Fresh human liver extracts from six donors and rat comparison
exposure
Folic acid substrate with NADPH
limitations
Reaction identity; liver rates cannot define a universal intake ceiling.
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
Folic acid needs a reduction step before it becomes usable folate.
primary_references
[bailey2009] The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake (2009). https://pubmed.ncbi.nlm.nih.gov/19706381/ DOI: 10.1073/pnas.0902072106
tissue_or_cell_type
Liver enzyme preparations
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 351–361
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Fresh human liver extracts from six donors and rat comparison · source_derived_draft · unverified_draft
### folate-dhfr-folic-acid-first-reduction DHFR reduces folic acid to dihydrofolate before further reduction to tetrahydrofolate. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Folic acid needs a reduction step before it becomes usable folate. organism: Homo sapiens tissue_or_cell_type: Liver enzyme preparations experimental_model: Fresh human liver extracts from six donors and rat comparison limitations: Reaction identity; liver rates cannot define a universal intake ceiling. exposure: Folic acid substrate with NADPH [bailey2009] The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake (2009). https://pubmed.ncbi.nlm.nih.gov/19706381/ DOI: 10.1073/pnas.0902072106
Complete structured claim and evidence
Human liver DHFR converted 7,8-dihydrofolate to tetrahydrofolate in NADPH-containing assays.
Human dihydrofolate reductase / DHFR → 7,8-Dihydrofolate source_derived_draftungraded
Experimental context and source evidence
experimental_model
Fresh human liver extracts from six donors and rat comparison
exposure
DHF substrate; THF quantified by HPLC
limitations
Assay chemistry, not an outcome study.
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
DHFR regenerates reduced folate from DHF.
primary_references
[bailey2009] The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake (2009). https://pubmed.ncbi.nlm.nih.gov/19706381/ DOI: 10.1073/pnas.0902072106
tissue_or_cell_type
Liver extracts
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 363–373
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Fresh human liver extracts from six donors and rat comparison · source_derived_draft · unverified_draft
### folate-dhfr-dhf-recycling Human liver DHFR converted 7,8-dihydrofolate to tetrahydrofolate in NADPH-containing assays. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: DHFR regenerates reduced folate from DHF. organism: Homo sapiens tissue_or_cell_type: Liver extracts experimental_model: Fresh human liver extracts from six donors and rat comparison limitations: Assay chemistry, not an outcome study. exposure: DHF substrate; THF quantified by HPLC [bailey2009] The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake (2009). https://pubmed.ncbi.nlm.nih.gov/19706381/ DOI: 10.1073/pnas.0902072106
Complete structured claim and evidence
Folic-acid reduction per gram of six human livers averaged less than 2% of rat liver activity at physiological pH, with nearly fivefold human variation.
Human dihydrofolate reductase / DHFR → Folic acid source_derived_draftungraded
Experimental context and source evidence
experimental_model
Fresh human liver extracts from six donors and rat comparison
exposure
Matched ex-vivo activity assay
limitations
Small tissue series; neither whole-body clearance nor harm was measured.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Homo sapiens and Rattus norvegicus comparison
plain_language
Human liver processing was slow and varied between samples.
primary_references
[bailey2009] The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake (2009). https://pubmed.ncbi.nlm.nih.gov/19706381/ DOI: 10.1073/pnas.0902072106
tissue_or_cell_type
Fresh liver extracts
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 375–385
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Fresh human liver extracts from six donors and rat comparison · source_derived_draft · unverified_draft
### folate-human-liver-folic-acid-slow-processing Folic-acid reduction per gram of six human livers averaged less than 2% of rat liver activity at physiological pH, with nearly fivefold human variation. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Human liver processing was slow and varied between samples. organism: Homo sapiens and Rattus norvegicus comparison tissue_or_cell_type: Fresh liver extracts experimental_model: Fresh human liver extracts from six donors and rat comparison limitations: Small tissue series; neither whole-body clearance nor harm was measured. exposure: Matched ex-vivo activity assay [bailey2009] The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake (2009). https://pubmed.ncbi.nlm.nih.gov/19706381/ DOI: 10.1073/pnas.0902072106
Complete structured claim and evidence
Fifteen minutes after oral labeled folic acid, 80 ± 12% of portal dose-derived folate remained unchanged in five evaluable TIPSS subjects among six dosed.
Folic acid → Portal venous unmetabolized folic acid fraction source_derived_draftungraded
Experimental context and source evidence
experimental_model
Portal/peripheral isotope crossover in six TIPSS patients
exposure
500 nmol oral isotope-labeled folic acid, about 220 micrograms
limitations
The sixth subject had no detectable labeled portal folate at 15 minutes; small liver-disease cohort and shunt-altered peripheral kinetics.
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
Much folic acid reached the liver unchanged.
primary_references
[patanwala2014] Folic acid handling by the human gut: implications for food fortification and supplementation (2014). https://pubmed.ncbi.nlm.nih.gov/24944062/ DOI: 10.3945/ajcn.113.080507
tissue_or_cell_type
Hepatic portal blood
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 387–397
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Portal/peripheral isotope crossover in six TIPSS patients · source_derived_draft · unverified_draft
### folate-portal-folic-acid-unmodified Fifteen minutes after oral labeled folic acid, 80 ± 12% of portal dose-derived folate remained unchanged in five evaluable TIPSS subjects among six dosed. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Much folic acid reached the liver unchanged. organism: Homo sapiens tissue_or_cell_type: Hepatic portal blood experimental_model: Portal/peripheral isotope crossover in six TIPSS patients limitations: The sixth subject had no detectable labeled portal folate at 15 minutes; small liver-disease cohort and shunt-altered peripheral kinetics. exposure: 500 nmol oral isotope-labeled folic acid, about 220 micrograms [patanwala2014] Folic acid handling by the human gut: implications for food fortification and supplementation (2014). https://pubmed.ncbi.nlm.nih.gov/24944062/ DOI: 10.3945/ajcn.113.080507
Complete structured claim and evidence
After oral labeled 6S-5-formylTHF, portal folate was predominantly labeled 5-MTHF at 15 minutes; unchanged formylTHF was 4 ± 18%.
5-Formyltetrahydrofolate → 5-Methyltetrahydrofolate source_derived_draftungraded
Experimental context and source evidence
experimental_model
Portal/peripheral isotope crossover in six TIPSS patients
exposure
500 nmol labeled 6S-5-formylTHF; four comparator participants
limitations
Does not show superiority for clinical outcomes.
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 gut readily processed the reduced folate in this comparison.
primary_references
[patanwala2014] Folic acid handling by the human gut: implications for food fortification and supplementation (2014). https://pubmed.ncbi.nlm.nih.gov/24944062/ DOI: 10.3945/ajcn.113.080507
tissue_or_cell_type
Hepatic portal blood
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 399–409
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Portal/peripheral isotope crossover in six TIPSS patients · source_derived_draft · unverified_draft
### folate-portal-formyl-to-methyl-conversion After oral labeled 6S-5-formylTHF, portal folate was predominantly labeled 5-MTHF at 15 minutes; unchanged formylTHF was 4 ± 18%. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The gut readily processed the reduced folate in this comparison. organism: Homo sapiens tissue_or_cell_type: Hepatic portal blood experimental_model: Portal/peripheral isotope crossover in six TIPSS patients limitations: Does not show superiority for clinical outcomes. exposure: 500 nmol labeled 6S-5-formylTHF; four comparator participants [patanwala2014] Folic acid handling by the human gut: implications for food fortification and supplementation (2014). https://pubmed.ncbi.nlm.nih.gov/24944062/ DOI: 10.3945/ajcn.113.080507
Complete structured claim and evidence
During the tested five-day fortified cereal/bread regimen, unchanged folic acid appeared in serum at 266 micrograms per meal.
Folic acid → Serum unmetabolized folic acid concentration source_derived_draftungraded
Experimental context and source evidence
experimental_model
Acute fortified-food/supplement exposure in volunteers
exposure
Acute fortified-food dosing schedules
limitations
Study-specific detectability; not a universal threshold or evidence of toxicity.
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
Some ingested folic acid circulated unchanged.
primary_references
[kelly1997] Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements (1997). https://pubmed.ncbi.nlm.nih.gov/9174474/ DOI: 10.1093/ajcn/65.6.1790
tissue_or_cell_type
Serum in young and older volunteers
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 411–421
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Acute fortified-food/supplement exposure in volunteers · source_derived_draft · unverified_draft
### folate-kelly-postprandial-umfa During the tested five-day fortified cereal/bread regimen, unchanged folic acid appeared in serum at 266 micrograms per meal. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Some ingested folic acid circulated unchanged. organism: Homo sapiens tissue_or_cell_type: Serum in young and older volunteers experimental_model: Acute fortified-food/supplement exposure in volunteers limitations: Study-specific detectability; not a universal threshold or evidence of toxicity. exposure: Acute fortified-food dosing schedules [kelly1997] Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements (1997). https://pubmed.ncbi.nlm.nih.gov/9174474/ DOI: 10.1093/ajcn/65.6.1790
Complete structured claim and evidence
UMFA above the 0.3 nmol/L detection limit occurred in over 95% of NHANES supplement users and nonusers; fasting status influenced concentrations.
Folic acid → Serum unmetabolized folic acid concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
experimental_model
Cross-sectional NHANES 2007-2008 serum vitamer measurements
exposure
Cross-sectional fortified-population sampling
limitations
Detection depends on assay sensitivity and sampling; no adverse outcome tested.
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 detectable blood marker is not by itself a harm threshold.
primary_references
[pfeiffer2015] Unmetabolized folic acid is detected in nearly all serum samples from US children, adolescents, and adults (2015). https://pubmed.ncbi.nlm.nih.gov/25733468/ DOI: 10.3945/jn.114.201210
tissue_or_cell_type
Serum; NHANES 2007-2008
trigger_kind
biomarker_context Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 423–433
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cross-sectional NHANES 2007-2008 serum vitamer measurements · source_derived_draft · unverified_draft
### folate-nhanes-umfa-detection UMFA above the 0.3 nmol/L detection limit occurred in over 95% of NHANES supplement users and nonusers; fasting status influenced concentrations. Condition category: biomarker_context nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A detectable blood marker is not by itself a harm threshold. organism: Homo sapiens tissue_or_cell_type: Serum; NHANES 2007-2008 experimental_model: Cross-sectional NHANES 2007-2008 serum vitamer measurements limitations: Detection depends on assay sensitivity and sampling; no adverse outcome tested. exposure: Cross-sectional fortified-population sampling [pfeiffer2015] Unmetabolized folic acid is detected in nearly all serum samples from US children, adolescents, and adults (2015). https://pubmed.ncbi.nlm.nih.gov/25733468/ DOI: 10.3945/jn.114.201210
Complete structured claim and evidence
Purified full-length human MTHFR had apparent Km values of 35.5 micromolar for NADPH and 3760 micromolar for NADH.
Methylenetetrahydrofolate reductase / MTHFR → NADPH source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Folate reduction uses nicotinamide reducing equivalents.
experimental_model
Recombinant human MTHFR; kinetics and structures.
limitations
Affinity does not quantify cellular flux.
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
MTHFR strongly preferred NADPH in this assay.
primary_references
[froese-2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2
tissue_or_cell_type
Purified protein
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 435–445
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MTHFR; kinetics and structures. · source_derived_draft · unverified_draft
### folate-methyl-nadph-preference Purified full-length human MTHFR had apparent Km values of 35.5 micromolar for NADPH and 3760 micromolar for NADH. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: MTHFR strongly preferred NADPH in this assay. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Recombinant human MTHFR; kinetics and structures. limitations: Affinity does not quantify cellular flux. cross_nutrient: Folate reduction uses nicotinamide reducing equivalents. [froese-2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2
Complete structured claim and evidence
FAD supplied before a 46 C, five-minute incubation preserved more MTHFR activity than FAD added after heating.
FAD → Methylenetetrahydrofolate reductase / MTHFR source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
B2-derived FAD affects folate-enzyme stability.
experimental_model
Recombinant human MTHFR; kinetics and structures.
exposure
FAD before versus after heating
limitations
Heat challenge is not physiological riboflavin deficiency.
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
Flavin protected the enzyme during heat stress.
primary_references
[froese-2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2
tissue_or_cell_type
Purified protein
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 447–458
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MTHFR; kinetics and structures. · source_derived_draft · unverified_draft
### folate-methyl-fad-heat-protection FAD supplied before a 46 C, five-minute incubation preserved more MTHFR activity than FAD added after heating. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Flavin protected the enzyme during heat stress. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Recombinant human MTHFR; kinetics and structures. limitations: Heat challenge is not physiological riboflavin deficiency. exposure: FAD before versus after heating cross_nutrient: B2-derived FAD affects folate-enzyme stability. [froese-2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2
Complete structured claim and evidence
Dual SAM binding rearranged the human MTHFR linker and inserted a loop that blocked catalytic substrate access.
S-Adenosyl-L-methionine → Methylenetetrahydrofolate reductase / MTHFR source_derived_draftungraded
Experimental context and source evidence
experimental_model
Recombinant human MTHFR; cryo-EM and biochemistry.
limitations
Not a whole-body SAM threshold.
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
SAM switches MTHFR into a closed shape.
primary_references
[mthfr-allostery-2024] Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase (2024). https://pubmed.ncbi.nlm.nih.gov/38622112/ DOI: 10.1038/s41467-024-47174-y
tissue_or_cell_type
Purified protein
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 460–469
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MTHFR; cryo-EM and biochemistry. · source_derived_draft · unverified_draft
### folate-methyl-sam-dual-binding Dual SAM binding rearranged the human MTHFR linker and inserted a loop that blocked catalytic substrate access. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: SAM switches MTHFR into a closed shape. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Recombinant human MTHFR; cryo-EM and biochemistry. limitations: Not a whole-body SAM threshold. [mthfr-allostery-2024] Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase (2024). https://pubmed.ncbi.nlm.nih.gov/38622112/ DOI: 10.1038/s41467-024-47174-y
Complete structured claim and evidence
Single SAH occupancy accompanied a flexible catalytic domain with an exposed active site in human MTHFR structures.
S-Adenosyl-L-homocysteine → Methylenetetrahydrofolate reductase / MTHFR source_derived_draftungraded
Experimental context and source evidence
experimental_model
Recombinant human MTHFR; cryo-EM and biochemistry.
limitations
Does not imply SAH promotes all methyltransferases.
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 SAH-bound structure leaves the catalytic site accessible.
primary_references
[mthfr-allostery-2024] Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase (2024). https://pubmed.ncbi.nlm.nih.gov/38622112/ DOI: 10.1038/s41467-024-47174-y
tissue_or_cell_type
Purified protein
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 471–480
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MTHFR; cryo-EM and biochemistry. · source_derived_draft · unverified_draft
### folate-methyl-sah-active-state Single SAH occupancy accompanied a flexible catalytic domain with an exposed active site in human MTHFR structures. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The SAH-bound structure leaves the catalytic site accessible. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Recombinant human MTHFR; cryo-EM and biochemistry. limitations: Does not imply SAH promotes all methyltransferases. [mthfr-allostery-2024] Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase (2024). https://pubmed.ncbi.nlm.nih.gov/38622112/ DOI: 10.1038/s41467-024-47174-y
Complete structured claim and evidence
Reconstituted human MTR transfers methylfolate-derived methyl groups through cobalamin to homocysteine, producing methionine and THF.
Cobalamin-dependent methionine synthase / MTR → L-Methionine source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Folate methyl transfer requires B12.
experimental_model
Human MTR/MTRR expressed in insect cells; purified enzymes and extracts.
limitations
Chemistry, not dietary response.
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
B12-dependent MTR recycles both homocysteine and folate.
primary_references
[yamada-2006] Human methionine synthase reductase is a molecular chaperone for human methionine synthase (2006). https://pubmed.ncbi.nlm.nih.gov/16769880/ DOI: 10.1073/pnas.0603694103
tissue_or_cell_type
Purified protein
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 482–492
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human MTR/MTRR expressed in insect cells; purified enzymes and extracts. · source_derived_draft · unverified_draft
### folate-methyl-mtr-methyl-transfer Reconstituted human MTR transfers methylfolate-derived methyl groups through cobalamin to homocysteine, producing methionine and THF. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: B12-dependent MTR recycles both homocysteine and folate. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Human MTR/MTRR expressed in insect cells; purified enzymes and extracts. limitations: Chemistry, not dietary response. cross_nutrient: Folate methyl transfer requires B12. [yamada-2006] Human methionine synthase reductase is a molecular chaperone for human methionine synthase (2006). https://pubmed.ncbi.nlm.nih.gov/16769880/ DOI: 10.1073/pnas.0603694103
Complete structured claim and evidence
Human MTRR stabilized apo-MTR and enhanced holoenzyme formation from methylcobalamin in the presence of NADPH.
Methionine synthase reductase / MTRR → Cobalamin-dependent methionine synthase / MTR source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Flavin-dependent MTRR supports B12-enzyme assembly.
experimental_model
Human MTR/MTRR expressed in insect cells; purified enzymes and extracts.
limitations
In-vitro assembly.
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
MTRR also helps MTR acquire its cofactor.
primary_references
[yamada-2006] Human methionine synthase reductase is a molecular chaperone for human methionine synthase (2006). https://pubmed.ncbi.nlm.nih.gov/16769880/ DOI: 10.1073/pnas.0603694103
tissue_or_cell_type
Human proteins expressed in insect cells
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 494–504
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human MTR/MTRR expressed in insect cells; purified enzymes and extracts. · source_derived_draft · unverified_draft
### folate-methyl-mtrr-apoenzyme Human MTRR stabilized apo-MTR and enhanced holoenzyme formation from methylcobalamin in the presence of NADPH. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: MTRR also helps MTR acquire its cofactor. organism: Homo sapiens tissue_or_cell_type: Human proteins expressed in insect cells experimental_model: Human MTR/MTRR expressed in insect cells; purified enzymes and extracts. limitations: In-vitro assembly. cross_nutrient: Flavin-dependent MTRR supports B12-enzyme assembly. [yamada-2006] Human methionine synthase reductase is a molecular chaperone for human methionine synthase (2006). https://pubmed.ncbi.nlm.nih.gov/16769880/ DOI: 10.1073/pnas.0603694103
Complete structured claim and evidence
Human MTRR sustained human MTR, whereas bacterial flavodoxin/flavodoxin reductase did not significantly support the human enzyme.
Methionine synthase reductase / MTRR → Cobalamin-dependent methionine synthase / MTR source_derived_draftungraded
Experimental context and source evidence
experimental_model
Human MTR/MTRR expressed in insect cells; purified enzymes and extracts.
limitations
Bacterial proteins are assay comparators.
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 electron-donor partners were species selective.
primary_references
[yamada-2006] Human methionine synthase reductase is a molecular chaperone for human methionine synthase (2006). https://pubmed.ncbi.nlm.nih.gov/16769880/ DOI: 10.1073/pnas.0603694103
tissue_or_cell_type
Purified proteins
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 506–515
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human MTR/MTRR expressed in insect cells; purified enzymes and extracts. · source_derived_draft · unverified_draft
### folate-methyl-mtrr-species-recognition Human MTRR sustained human MTR, whereas bacterial flavodoxin/flavodoxin reductase did not significantly support the human enzyme. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The electron-donor partners were species selective. organism: Homo sapiens tissue_or_cell_type: Purified proteins experimental_model: Human MTR/MTRR expressed in insect cells; purified enzymes and extracts. limitations: Bacterial proteins are assay comparators. [yamada-2006] Human methionine synthase reductase is a molecular chaperone for human methionine synthase (2006). https://pubmed.ncbi.nlm.nih.gov/16769880/ DOI: 10.1073/pnas.0603694103
Complete structured claim and evidence
MTR knockout in tumour cells using physiological extracellular folates caused trapping and limited assimilation into other folate forms.
MTR gene (Homo sapiens) → 5-Methyltetrahydrofolate source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
Methylfolate does not remove the B12-dependent MTR requirement.
evidence_location
Ghergurovich 2021 Fig. 3A; physiological folate experiments Fig. 2 and Extended Data Fig. 2.
experimental_model
Isotope tracing in tumour cells, mouse tissues and xenografts.
exposure
CRISPR MTR deletion; folic acid or 5-methyl-THF medium; physiological folate-mixture experiments
limitations
Nutrient environment matters.
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
Methylfolate still needs MTR for reuse.
primary_references
[ghergurovich-2021] Methionine synthase supports tumour tetrahydrofolate pools (2021). https://pubmed.ncbi.nlm.nih.gov/34799699/ DOI: 10.1038/s42255-021-00465-w
tissue_or_cell_type
HCT116 human colorectal cancer cells (folate profiling)
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 517–529
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isotope tracing in tumour cells, mouse tissues and xenografts. · source_derived_draft · unverified_draft
### folate-methyl-mtr-ko-trap MTR knockout in tumour cells using physiological extracellular folates caused trapping and limited assimilation into other folate forms. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Methylfolate still needs MTR for reuse. organism: Homo sapiens tissue_or_cell_type: HCT116 human colorectal cancer cells (folate profiling) experimental_model: Isotope tracing in tumour cells, mouse tissues and xenografts. limitations: Nutrient environment matters. cross_nutrient: Methylfolate does not remove the B12-dependent MTR requirement. exposure: CRISPR MTR deletion; folic acid or 5-methyl-THF medium; physiological folate-mixture experiments evidence_location: Ghergurovich 2021 Fig. 3A; physiological folate experiments Fig. 2 and Extended Data Fig. 2. [ghergurovich-2021] Methionine synthase supports tumour tetrahydrofolate pools (2021). https://pubmed.ncbi.nlm.nih.gov/34799699/ DOI: 10.1038/s42255-021-00465-w
Complete structured claim and evidence
Isotope tracing found MTR-derived synthesis contributed only a minor fraction of methionine in the tested human cancer-cell cultures.
Cobalamin-dependent methionine synthase / MTR → L-Methionine source_derived_draftungraded
Experimental context and source evidence
evidence_location
Ghergurovich 2021 Fig. 1C-D: four-hour [U-13C]methionine tracing.
experimental_model
Isotope tracing in tumour cells, mouse tissues and xenografts.
limitations
Restricted here to human cells; not every tissue or nutrient environment.
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
Folate recycling mattered despite small net methionine production.
primary_references
[ghergurovich-2021] Methionine synthase supports tumour tetrahydrofolate pools (2021). https://pubmed.ncbi.nlm.nih.gov/34799699/ DOI: 10.1038/s42255-021-00465-w
tissue_or_cell_type
Human cancer-cell cultures
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 531–541
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isotope tracing in tumour cells, mouse tissues and xenografts. · source_derived_draft · unverified_draft
### folate-methyl-mtr-minor-methionine Isotope tracing found MTR-derived synthesis contributed only a minor fraction of methionine in the tested human cancer-cell cultures. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Folate recycling mattered despite small net methionine production. organism: Homo sapiens tissue_or_cell_type: Human cancer-cell cultures experimental_model: Isotope tracing in tumour cells, mouse tissues and xenografts. limitations: Restricted here to human cells; not every tissue or nutrient environment. evidence_location: Ghergurovich 2021 Fig. 1C-D: four-hour [U-13C]methionine tracing. [ghergurovich-2021] Methionine synthase supports tumour tetrahydrofolate pools (2021). https://pubmed.ncbi.nlm.nih.gov/34799699/ DOI: 10.1038/s42255-021-00465-w
Complete structured claim and evidence
In B12-impaired HeLa nuclei, the fraction of measured nuclear folate present as 5-methyl-THF increased over fourfold, while the THF fraction fell approximately 50%, versus replete controls.
Nitrous oxide → 5-Methyltetrahydrofolate source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
B12 function controls usable folate.
experimental_model
N2O-treated HeLa cells and cblG patient fibroblasts.
limitations
Fig. 2 reports percentages of measured folate species, not absolute concentrations; chemical/culture impairment is not a dietary threshold.
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 nuclear folate mixture shifted toward methylfolate.
primary_references
[palmer-2017] Folate rescues vitamin B12 depletion-induced inhibition of nuclear thymidylate biosynthesis and genome instability (2017). https://pubmed.ncbi.nlm.nih.gov/28461497/ DOI: 10.1073/pnas.1619582114
tissue_or_cell_type
HeLa nuclear fractions
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 543–553
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · N2O-treated HeLa cells and cblG patient fibroblasts. · source_derived_draft · unverified_draft
### folate-methyl-nuclear-methyl-trap In B12-impaired HeLa nuclei, the fraction of measured nuclear folate present as 5-methyl-THF increased over fourfold, while the THF fraction fell approximately 50%, versus replete controls. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The nuclear folate mixture shifted toward methylfolate. organism: Homo sapiens tissue_or_cell_type: HeLa nuclear fractions experimental_model: N2O-treated HeLa cells and cblG patient fibroblasts. limitations: Fig. 2 reports percentages of measured folate species, not absolute concentrations; chemical/culture impairment is not a dietary threshold. cross_nutrient: B12 function controls usable folate. [palmer-2017] Folate rescues vitamin B12 depletion-induced inhibition of nuclear thymidylate biosynthesis and genome instability (2017). https://pubmed.ncbi.nlm.nih.gov/28461497/ DOI: 10.1073/pnas.1619582114
Complete structured claim and evidence
The fraction of measured intracellular folate present as 5-methyl-THF was 2.5-fold higher in cblG WG4215 fibroblasts than in control MCH058 fibroblasts.
MTR gene (Homo sapiens) → 5-Methyltetrahydrofolate source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
N2O-treated HeLa cells and cblG patient fibroblasts.
limitations
Fig. 2A reports folate-species percentages, not absolute amounts; one disease/control cell-line comparison.
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
Genetic MTR loss shifted the measured folate mixture toward methylfolate.
primary_references
[palmer-2017] Folate rescues vitamin B12 depletion-induced inhibition of nuclear thymidylate biosynthesis and genome instability (2017). https://pubmed.ncbi.nlm.nih.gov/28461497/ DOI: 10.1073/pnas.1619582114
tissue_or_cell_type
Patient fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 555–564
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · N2O-treated HeLa cells and cblG patient fibroblasts. · source_derived_draft · unverified_draft
### folate-methyl-cblg-methyl-trap The fraction of measured intracellular folate present as 5-methyl-THF was 2.5-fold higher in cblG WG4215 fibroblasts than in control MCH058 fibroblasts. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Genetic MTR loss shifted the measured folate mixture toward methylfolate. organism: Homo sapiens tissue_or_cell_type: Patient fibroblasts experimental_model: N2O-treated HeLa cells and cblG patient fibroblasts. limitations: Fig. 2A reports folate-species percentages, not absolute amounts; one disease/control cell-line comparison. [palmer-2017] Folate rescues vitamin B12 depletion-induced inhibition of nuclear thymidylate biosynthesis and genome instability (2017). https://pubmed.ncbi.nlm.nih.gov/28461497/ DOI: 10.1073/pnas.1619582114
Complete structured claim and evidence
Hypomorphic Mtrr gt/gt mice had higher plasma homocysteine than controls.
Mtrr gene (Mus musculus) → Homocysteine source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Mtrr gene-trap hypomorphic mice and controls.
limitations
Not all human MTRR variants.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Mus musculus
plain_language
Partial reactivation failure impaired homocysteine handling.
primary_references
[elmore-2007] Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase (2007). https://pubmed.ncbi.nlm.nih.gov/17369066/ DOI: 10.1016/j.ymgme.2007.02.001
tissue_or_cell_type
Plasma
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 566–575
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mtrr gene-trap hypomorphic mice and controls. · source_derived_draft · unverified_draft
### folate-methyl-mtrr-mouse-hcy Hypomorphic Mtrr gt/gt mice had higher plasma homocysteine than controls. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Partial reactivation failure impaired homocysteine handling. organism: Mus musculus tissue_or_cell_type: Plasma experimental_model: Mtrr gene-trap hypomorphic mice and controls. limitations: Not all human MTRR variants. [elmore-2007] Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase (2007). https://pubmed.ncbi.nlm.nih.gov/17369066/ DOI: 10.1016/j.ymgme.2007.02.001
Complete structured claim and evidence
Mtrr gt/gt mice had lower plasma methionine than controls.
Mtrr gene (Mus musculus) → L-Methionine source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Mtrr gene-trap hypomorphic mice and controls.
limitations
Not a direct tissue methylation assay.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Mus musculus
plain_language
The same defect reduced circulating methionine.
primary_references
[elmore-2007] Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase (2007). https://pubmed.ncbi.nlm.nih.gov/17369066/ DOI: 10.1016/j.ymgme.2007.02.001
tissue_or_cell_type
Plasma
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 577–586
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mtrr gene-trap hypomorphic mice and controls. · source_derived_draft · unverified_draft
### folate-methyl-mtrr-mouse-met Mtrr gt/gt mice had lower plasma methionine than controls. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same defect reduced circulating methionine. organism: Mus musculus tissue_or_cell_type: Plasma experimental_model: Mtrr gene-trap hypomorphic mice and controls. limitations: Not a direct tissue methylation assay. [elmore-2007] Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase (2007). https://pubmed.ncbi.nlm.nih.gov/17369066/ DOI: 10.1016/j.ymgme.2007.02.001
Complete structured claim and evidence
Mtrr gene-trap mice did not show decreased SAM:SAH ratios in most tissues despite disturbed remethylation.
Mtrr gene (Mus musculus) → SAM:SAH concentration ratio source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Mtrr gene-trap hypomorphic mice and controls.
limitations
Ratio is not DNA methylation.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Mus musculus
plain_language
The ratio did not fall uniformly.
primary_references
[elmore-2007] Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase (2007). https://pubmed.ncbi.nlm.nih.gov/17369066/ DOI: 10.1016/j.ymgme.2007.02.001
tissue_or_cell_type
Assayed tissue panel
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 588–597
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mtrr gene-trap hypomorphic mice and controls. · source_derived_draft · unverified_draft
### folate-methyl-mtrr-mouse-ratio Mtrr gene-trap mice did not show decreased SAM:SAH ratios in most tissues despite disturbed remethylation. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The ratio did not fall uniformly. organism: Mus musculus tissue_or_cell_type: Assayed tissue panel experimental_model: Mtrr gene-trap hypomorphic mice and controls. limitations: Ratio is not DNA methylation. [elmore-2007] Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase (2007). https://pubmed.ncbi.nlm.nih.gov/17369066/ DOI: 10.1016/j.ymgme.2007.02.001
Complete structured claim and evidence
Mtrr gt/gt mice showed increased tissue methyltetrahydrofolate.
Mtrr gene (Mus musculus) → 5-Methyltetrahydrofolate source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Mtrr gene-trap hypomorphic mice and controls.
limitations
Abstract-level tissue aggregate; no universal fold change.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Mus musculus
plain_language
Reduced reductase function altered folate distribution.
primary_references
[elmore-2007] Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase (2007). https://pubmed.ncbi.nlm.nih.gov/17369066/ DOI: 10.1016/j.ymgme.2007.02.001
tissue_or_cell_type
Tissue extracts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 599–608
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Mtrr gene-trap hypomorphic mice and controls. · source_derived_draft · unverified_draft
### folate-methyl-mtrr-mouse-methylfolate Mtrr gt/gt mice showed increased tissue methyltetrahydrofolate. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Reduced reductase function altered folate distribution. organism: Mus musculus tissue_or_cell_type: Tissue extracts experimental_model: Mtrr gene-trap hypomorphic mice and controls. limitations: Abstract-level tissue aggregate; no universal fold change. [elmore-2007] Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase (2007). https://pubmed.ncbi.nlm.nih.gov/17369066/ DOI: 10.1016/j.ymgme.2007.02.001
Complete structured claim and evidence
Purified human BHMT uses betaine and homocysteine in the alternative methionine-forming reaction.
Betaine-homocysteine S-methyltransferase / BHMT → L-Methionine source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Betaine/choline and folate routes meet at homocysteine.
experimental_model
Recombinant human BHMT and human liver-derived BHMT.
limitations
Does not establish complete folate substitution in vivo.
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
Betaine supplies another recycling route.
primary_references
[millian-1998] Human betaine-homocysteine methyltransferase is a zinc metalloenzyme (1998). https://pubmed.ncbi.nlm.nih.gov/9681996/ DOI: 10.1006/abbi.1998.0757
tissue_or_cell_type
Recombinant and liver-derived enzyme
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 610–620
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human BHMT and human liver-derived BHMT. · source_derived_draft · unverified_draft
### folate-methyl-bhmt-reaction Purified human BHMT uses betaine and homocysteine in the alternative methionine-forming reaction. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Betaine supplies another recycling route. organism: Homo sapiens tissue_or_cell_type: Recombinant and liver-derived enzyme experimental_model: Recombinant human BHMT and human liver-derived BHMT. limitations: Does not establish complete folate substitution in vivo. cross_nutrient: Betaine/choline and folate routes meet at homocysteine. [millian-1998] Human betaine-homocysteine methyltransferase is a zinc metalloenzyme (1998). https://pubmed.ncbi.nlm.nih.gov/9681996/ DOI: 10.1006/abbi.1998.0757
Complete structured claim and evidence
Chemical zinc removal inactivated human BHMT; zinc reconstitution restored its activity and metal content.
Zinc(II) ion → Betaine-homocysteine S-methyltransferase / BHMT source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Zinc supports parallel remethylation.
experimental_model
Recombinant human BHMT and human liver-derived BHMT.
limitations
Demetallation is not dietary zinc deficiency.
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 betaine route requires a zinc-containing enzyme.
primary_references
[millian-1998] Human betaine-homocysteine methyltransferase is a zinc metalloenzyme (1998). https://pubmed.ncbi.nlm.nih.gov/9681996/ DOI: 10.1006/abbi.1998.0757
tissue_or_cell_type
Purified protein
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 622–632
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human BHMT and human liver-derived BHMT. · source_derived_draft · unverified_draft
### folate-methyl-bhmt-zinc Chemical zinc removal inactivated human BHMT; zinc reconstitution restored its activity and metal content. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The betaine route requires a zinc-containing enzyme. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Recombinant human BHMT and human liver-derived BHMT. limitations: Demetallation is not dietary zinc deficiency. cross_nutrient: Zinc supports parallel remethylation. [millian-1998] Human betaine-homocysteine methyltransferase is a zinc metalloenzyme (1998). https://pubmed.ncbi.nlm.nih.gov/9681996/ DOI: 10.1006/abbi.1998.0757
Complete structured claim and evidence
Bhmt deletion raised hepatic total homocysteine sixfold and plasma total homocysteine eightfold in mice.
Bhmt gene (Mus musculus) → Homocysteine source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
Loss of betaine recycling burdens shared homocysteine handling.
experimental_model
Bhmt-null mice and wild-type controls.
limitations
Complete knockout, not common human polymorphisms.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Mus musculus
plain_language
Other pathways did not fully compensate.
primary_references
[teng-2011] Deletion of betaine-homocysteine S-methyltransferase in mice perturbs choline and 1-carbon metabolism, resulting in fatty liver and hepatocellular carcinomas (2011). https://pubmed.ncbi.nlm.nih.gov/21878621/ DOI: 10.1074/jbc.m111.265348
tissue_or_cell_type
Liver and plasma
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 634–644
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bhmt-null mice and wild-type controls. · source_derived_draft · unverified_draft
### folate-methyl-bhmt-ko-hcy Bhmt deletion raised hepatic total homocysteine sixfold and plasma total homocysteine eightfold in mice. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Other pathways did not fully compensate. organism: Mus musculus tissue_or_cell_type: Liver and plasma experimental_model: Bhmt-null mice and wild-type controls. limitations: Complete knockout, not common human polymorphisms. cross_nutrient: Loss of betaine recycling burdens shared homocysteine handling. [teng-2011] Deletion of betaine-homocysteine S-methyltransferase in mice perturbs choline and 1-carbon metabolism, resulting in fatty liver and hepatocellular carcinomas (2011). https://pubmed.ncbi.nlm.nih.gov/21878621/ DOI: 10.1074/jbc.m111.265348
Complete structured claim and evidence
Bhmt-null mouse liver contained 43% less SAM than wild type.
Bhmt gene (Mus musculus) → S-Adenosyl-L-methionine source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Bhmt-null mice and wild-type controls.
limitations
Concentration is not methylation flux.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Mus musculus
plain_language
The hepatic methyl-donor pool fell.
primary_references
[teng-2011] Deletion of betaine-homocysteine S-methyltransferase in mice perturbs choline and 1-carbon metabolism, resulting in fatty liver and hepatocellular carcinomas (2011). https://pubmed.ncbi.nlm.nih.gov/21878621/ DOI: 10.1074/jbc.m111.265348
tissue_or_cell_type
Liver
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 646–655
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bhmt-null mice and wild-type controls. · source_derived_draft · unverified_draft
### folate-methyl-bhmt-ko-sam Bhmt-null mouse liver contained 43% less SAM than wild type. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The hepatic methyl-donor pool fell. organism: Mus musculus tissue_or_cell_type: Liver experimental_model: Bhmt-null mice and wild-type controls. limitations: Concentration is not methylation flux. [teng-2011] Deletion of betaine-homocysteine S-methyltransferase in mice perturbs choline and 1-carbon metabolism, resulting in fatty liver and hepatocellular carcinomas (2011). https://pubmed.ncbi.nlm.nih.gov/21878621/ DOI: 10.1074/jbc.m111.265348
Complete structured claim and evidence
Bhmt-null mouse liver contained about threefold more SAH than wild type.
Bhmt gene (Mus musculus) → S-Adenosyl-L-homocysteine source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Bhmt-null mice and wild-type controls.
limitations
No direct epigenetic inference.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Mus musculus
plain_language
The spent methyl-donor pool increased.
primary_references
[teng-2011] Deletion of betaine-homocysteine S-methyltransferase in mice perturbs choline and 1-carbon metabolism, resulting in fatty liver and hepatocellular carcinomas (2011). https://pubmed.ncbi.nlm.nih.gov/21878621/ DOI: 10.1074/jbc.m111.265348
tissue_or_cell_type
Liver
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 657–666
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bhmt-null mice and wild-type controls. · source_derived_draft · unverified_draft
### folate-methyl-bhmt-ko-sah Bhmt-null mouse liver contained about threefold more SAH than wild type. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The spent methyl-donor pool increased. organism: Mus musculus tissue_or_cell_type: Liver experimental_model: Bhmt-null mice and wild-type controls. limitations: No direct epigenetic inference. [teng-2011] Deletion of betaine-homocysteine S-methyltransferase in mice perturbs choline and 1-carbon metabolism, resulting in fatty liver and hepatocellular carcinomas (2011). https://pubmed.ncbi.nlm.nih.gov/21878621/ DOI: 10.1074/jbc.m111.265348
Complete structured claim and evidence
Feeding 20 mg folate/kg diet did not ameliorate elevated plasma homocysteine in Bhmt-null mice.
Folic acid → Homocysteine source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
Folate/betaine compensation has limits.
experimental_model
Bhmt-null and wild-type mice; four-week folate feeding.
exposure
0, 2 or 20 mg folate/kg diet
limitations
Mouse four-week experiment, not a human treatment rule.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Mus musculus
plain_language
Extra folate did not restore this missing route.
primary_references
[teng-2012] Homocysteinemia in mice with genetic betaine homocysteine S-methyltransferase deficiency is independent of dietary folate intake (2012). https://pubmed.ncbi.nlm.nih.gov/23014492/ DOI: 10.3945/jn.112.166835
tissue_or_cell_type
Plasma
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 668–679
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bhmt-null and wild-type mice; four-week folate feeding. · source_derived_draft · unverified_draft
### folate-methyl-folate-no-hcy-rescue-bhmt Feeding 20 mg folate/kg diet did not ameliorate elevated plasma homocysteine in Bhmt-null mice. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Extra folate did not restore this missing route. organism: Mus musculus tissue_or_cell_type: Plasma experimental_model: Bhmt-null and wild-type mice; four-week folate feeding. limitations: Mouse four-week experiment, not a human treatment rule. exposure: 0, 2 or 20 mg folate/kg diet cross_nutrient: Folate/betaine compensation has limits. [teng-2012] Homocysteinemia in mice with genetic betaine homocysteine S-methyltransferase deficiency is independent of dietary folate intake (2012). https://pubmed.ncbi.nlm.nih.gov/23014492/ DOI: 10.3945/jn.112.166835
Complete structured claim and evidence
The 20 mg folate/kg diet increased hepatic SAM in Bhmt-null mice versus 0 and 2 mg/kg diets.
Folic acid → S-Adenosyl-L-methionine source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Bhmt-null and wild-type mice; four-week folate feeding.
exposure
Four-week feeding
limitations
No proof of restored DNA methylation.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Mus musculus
plain_language
SAM improved despite persistent high homocysteine.
primary_references
[teng-2012] Homocysteinemia in mice with genetic betaine homocysteine S-methyltransferase deficiency is independent of dietary folate intake (2012). https://pubmed.ncbi.nlm.nih.gov/23014492/ DOI: 10.3945/jn.112.166835
tissue_or_cell_type
Liver
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 681–691
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bhmt-null and wild-type mice; four-week folate feeding. · source_derived_draft · unverified_draft
### folate-methyl-folate-sam-bhmt The 20 mg folate/kg diet increased hepatic SAM in Bhmt-null mice versus 0 and 2 mg/kg diets. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: SAM improved despite persistent high homocysteine. organism: Mus musculus tissue_or_cell_type: Liver experimental_model: Bhmt-null and wild-type mice; four-week folate feeding. limitations: No proof of restored DNA methylation. exposure: Four-week feeding [teng-2012] Homocysteinemia in mice with genetic betaine homocysteine S-methyltransferase deficiency is independent of dietary folate intake (2012). https://pubmed.ncbi.nlm.nih.gov/23014492/ DOI: 10.3945/jn.112.166835
Complete structured claim and evidence
Combined low-folate/low-choline feeding lowered plasma choline by 28% in men and 25% in women.
Folate (vitamin B9) → Choline source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Folate and choline status are coupled.
experimental_model
Metabolic-unit depletion/repletion: 11 men, 10 women.
exposure
Men: 25 micrograms folate/238 mg choline daily; women: 56 micrograms/147 mg
limitations
No functional choline deficiency by measured transaminase/lipid endpoints.
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
Folate restriction strained choline markers during low choline intake.
primary_references
[jacob-1999] Folate nutriture alters choline status of women and men fed low choline diets (1999). https://pubmed.ncbi.nlm.nih.gov/10082779/ DOI: 10.1093/jn/129.3.712
tissue_or_cell_type
Plasma
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 693–704
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metabolic-unit depletion/repletion: 11 men, 10 women. · source_derived_draft · unverified_draft
### folate-methyl-low-folate-choline Combined low-folate/low-choline feeding lowered plasma choline by 28% in men and 25% in women. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Folate restriction strained choline markers during low choline intake. organism: Homo sapiens tissue_or_cell_type: Plasma experimental_model: Metabolic-unit depletion/repletion: 11 men, 10 women. limitations: No functional choline deficiency by measured transaminase/lipid endpoints. exposure: Men: 25 micrograms folate/238 mg choline daily; women: 56 micrograms/147 mg cross_nutrient: Folate and choline status are coupled. [jacob-1999] Folate nutriture alters choline status of women and men fed low choline diets (1999). https://pubmed.ncbi.nlm.nih.gov/10082779/ DOI: 10.1093/jn/129.3.712
Complete structured claim and evidence
Men on the combined low-folate/low-choline diet showed 26% lower plasma phosphatidylcholine.
Folate (vitamin B9) → Phosphatidylcholine source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Folate/choline restriction affects circulating phospholipid.
experimental_model
Metabolic-unit depletion/repletion: 11 men, 10 women.
limitations
Male cohort; concentration does not identify biosynthetic flux.
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 choline-containing lipid also declined.
primary_references
[jacob-1999] Folate nutriture alters choline status of women and men fed low choline diets (1999). https://pubmed.ncbi.nlm.nih.gov/10082779/ DOI: 10.1093/jn/129.3.712
tissue_or_cell_type
Plasma
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 706–716
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metabolic-unit depletion/repletion: 11 men, 10 women. · source_derived_draft · unverified_draft
### folate-methyl-low-folate-pc Men on the combined low-folate/low-choline diet showed 26% lower plasma phosphatidylcholine. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A choline-containing lipid also declined. organism: Homo sapiens tissue_or_cell_type: Plasma experimental_model: Metabolic-unit depletion/repletion: 11 men, 10 women. limitations: Male cohort; concentration does not identify biosynthetic flux. cross_nutrient: Folate/choline restriction affects circulating phospholipid. [jacob-1999] Folate nutriture alters choline status of women and men fed low choline diets (1999). https://pubmed.ncbi.nlm.nih.gov/10082779/ DOI: 10.1093/jn/129.3.712
Complete structured claim and evidence
Folate repletion returned depressed plasma choline-status measures to baseline or above in the low-choline feeding studies.
Folic acid → Choline source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Folate repletion modifies choline status.
experimental_model
Metabolic-unit depletion/repletion: 11 men, 10 women.
exposure
2-6 weeks folic-acid repletion
limitations
Not evidence folate replaces dietary choline.
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
Restoring folate improved the choline markers.
primary_references
[jacob-1999] Folate nutriture alters choline status of women and men fed low choline diets (1999). https://pubmed.ncbi.nlm.nih.gov/10082779/ DOI: 10.1093/jn/129.3.712
tissue_or_cell_type
Plasma
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 718–729
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metabolic-unit depletion/repletion: 11 men, 10 women. · source_derived_draft · unverified_draft
### folate-methyl-folate-choline-repletion Folate repletion returned depressed plasma choline-status measures to baseline or above in the low-choline feeding studies. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Restoring folate improved the choline markers. organism: Homo sapiens tissue_or_cell_type: Plasma experimental_model: Metabolic-unit depletion/repletion: 11 men, 10 women. limitations: Not evidence folate replaces dietary choline. exposure: 2-6 weeks folic-acid repletion cross_nutrient: Folate repletion modifies choline status. [jacob-1999] Folate nutriture alters choline status of women and men fed low choline diets (1999). https://pubmed.ncbi.nlm.nih.gov/10082779/ DOI: 10.1093/jn/129.3.712
Complete structured claim and evidence
Nonpregnant MTHFR rs1801133 carriers had lower labeled betaine:phosphatidylcholine enrichment ratios than noncarriers (0.8 versus 0.9).
MTHFR Ala222Val protein → Choline partitioning between betaine and phosphatidylcholine source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
Folate-pathway genotype relates to choline allocation.
experimental_model
Choline feeding and isotope tracing in women across reproductive states.
limitations
Genotypes not randomized; ratio is a pathway proxy.
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
Relative choline allocation shifted toward phosphatidylcholine.
primary_references
[ganz-2016] Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis (2016). https://pubmed.ncbi.nlm.nih.gov/27342765/ DOI: 10.1096/fj.201500138rr
tissue_or_cell_type
Plasma tracer metabolites
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 731–741
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Choline feeding and isotope tracing in women across reproductive states. · source_derived_draft · unverified_draft
### folate-methyl-variant-choline-allocation Nonpregnant MTHFR rs1801133 carriers had lower labeled betaine:phosphatidylcholine enrichment ratios than noncarriers (0.8 versus 0.9). Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Relative choline allocation shifted toward phosphatidylcholine. organism: Homo sapiens tissue_or_cell_type: Plasma tracer metabolites experimental_model: Choline feeding and isotope tracing in women across reproductive states. limitations: Genotypes not randomized; ratio is a pathway proxy. cross_nutrient: Folate-pathway genotype relates to choline allocation. [ganz-2016] Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis (2016). https://pubmed.ncbi.nlm.nih.gov/27342765/ DOI: 10.1096/fj.201500138rr
Complete structured claim and evidence
In nonpregnant MTHFR rs1801133 carriers receiving 930 mg choline/day, the betaine-d9:PC-d9 enrichment ratio was 0.87, matching noncarriers receiving 480 mg/day (0.87); noncarriers receiving 930 mg/day had a ratio of 1.0.
Choline → Choline partitioning between betaine and phosphatidylcholine source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
Choline modifies a folate-genotype-associated phenotype.
experimental_model
Choline feeding and isotope tracing in women across reproductive states.
exposure
480 versus 930 mg/day; recommended folate intake
limitations
The matched reference is noncarriers at 480 mg/day, not noncarriers at the same 930 mg/day; subgroup result, not universal restoration or dosing advice.
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
Higher intake brought carriers to the lower-intake noncarrier reference value.
primary_references
[ganz-2016] Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis (2016). https://pubmed.ncbi.nlm.nih.gov/27342765/ DOI: 10.1096/fj.201500138rr
tissue_or_cell_type
Plasma tracer metabolites
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 743–754
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Choline feeding and isotope tracing in women across reproductive states. · source_derived_draft · unverified_draft
### folate-methyl-choline-intake-variant In nonpregnant MTHFR rs1801133 carriers receiving 930 mg choline/day, the betaine-d9:PC-d9 enrichment ratio was 0.87, matching noncarriers receiving 480 mg/day (0.87); noncarriers receiving 930 mg/day had a ratio of 1.0. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Higher intake brought carriers to the lower-intake noncarrier reference value. organism: Homo sapiens tissue_or_cell_type: Plasma tracer metabolites experimental_model: Choline feeding and isotope tracing in women across reproductive states. limitations: The matched reference is noncarriers at 480 mg/day, not noncarriers at the same 930 mg/day; subgroup result, not universal restoration or dosing advice. exposure: 480 versus 930 mg/day; recommended folate intake cross_nutrient: Choline modifies a folate-genotype-associated phenotype. [ganz-2016] Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis (2016). https://pubmed.ncbi.nlm.nih.gov/27342765/ DOI: 10.1096/fj.201500138rr
Complete structured claim and evidence
Rat GNMT activity assays measured SAM-dependent glycine methylation to sarcosine.
Glycine N-methyltransferase (Rattus norvegicus) → Sarcosine source_derived_draftungraded
Experimental context and source evidence
experimental_model
Native rat liver and bacterially expressed rat GNMT.
limitations
Does not quantify whole-body methyl demand.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Rattus norvegicus
plain_language
GNMT spends a SAM methyl group on glycine.
primary_references
[luka-2008] Acetylation of N-terminal valine of glycine N-methyltransferase affects enzyme inhibition by folate (2008). https://pubmed.ncbi.nlm.nih.gov/18501206/ DOI: 10.1016/j.bbapap.2008.04.016
tissue_or_cell_type
Native/recombinant rat enzyme
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 756–765
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Native rat liver and bacterially expressed rat GNMT. · source_derived_draft · unverified_draft
### folate-methyl-gnmt-methyl-use Rat GNMT activity assays measured SAM-dependent glycine methylation to sarcosine. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: GNMT spends a SAM methyl group on glycine. organism: Rattus norvegicus tissue_or_cell_type: Native/recombinant rat enzyme experimental_model: Native rat liver and bacterially expressed rat GNMT. limitations: Does not quantify whole-body methyl demand. [luka-2008] Acetylation of N-terminal valine of glycine N-methyltransferase affects enzyme inhibition by folate (2008). https://pubmed.ncbi.nlm.nih.gov/18501206/ DOI: 10.1016/j.bbapap.2008.04.016
Complete structured claim and evidence
Folate pentaglutamate produced 50% inhibition of native rat GNMT at 1.3 micromolar.
5-Methyltetrahydrofolate pentaglutamate → Glycine N-methyltransferase (Rattus norvegicus) source_derived_draftungraded
Experimental context and source evidence
experimental_model
Native rat liver and bacterially expressed rat GNMT.
limitations
Not a human circulating threshold.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Rattus norvegicus
plain_language
A folate form restrains SAM use by GNMT.
primary_references
[luka-2008] Acetylation of N-terminal valine of glycine N-methyltransferase affects enzyme inhibition by folate (2008). https://pubmed.ncbi.nlm.nih.gov/18501206/ DOI: 10.1016/j.bbapap.2008.04.016
tissue_or_cell_type
Purified liver enzyme
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 767–776
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Native rat liver and bacterially expressed rat GNMT. · source_derived_draft · unverified_draft
### folate-methyl-gnmt-folate-inhibition Folate pentaglutamate produced 50% inhibition of native rat GNMT at 1.3 micromolar. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A folate form restrains SAM use by GNMT. organism: Rattus norvegicus tissue_or_cell_type: Purified liver enzyme experimental_model: Native rat liver and bacterially expressed rat GNMT. limitations: Not a human circulating threshold. [luka-2008] Acetylation of N-terminal valine of glycine N-methyltransferase affects enzyme inhibition by folate (2008). https://pubmed.ncbi.nlm.nih.gov/18501206/ DOI: 10.1016/j.bbapap.2008.04.016
Complete structured claim and evidence
Non-acetylated recombinant GNMT required 590 micromolar folate pentaglutamate for 50% inhibition, versus 1.3 micromolar for native acetylated GNMT.
5-Methyltetrahydrofolate pentaglutamate → Glycine N-methyltransferase (Rattus norvegicus) source_derived_draftungraded
Experimental context and source evidence
experimental_model
Native rat liver and bacterially expressed rat GNMT.
limitations
Recombinant potency cannot be directly transferred to liver.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Rattus norvegicus
plain_language
Protein modification changed inhibitory sensitivity.
primary_references
[luka-2008] Acetylation of N-terminal valine of glycine N-methyltransferase affects enzyme inhibition by folate (2008). https://pubmed.ncbi.nlm.nih.gov/18501206/ DOI: 10.1016/j.bbapap.2008.04.016
tissue_or_cell_type
Native versus recombinant rat enzyme
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 778–787
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Native rat liver and bacterially expressed rat GNMT. · source_derived_draft · unverified_draft
### folate-methyl-gnmt-acetylation Non-acetylated recombinant GNMT required 590 micromolar folate pentaglutamate for 50% inhibition, versus 1.3 micromolar for native acetylated GNMT. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Protein modification changed inhibitory sensitivity. organism: Rattus norvegicus tissue_or_cell_type: Native versus recombinant rat enzyme experimental_model: Native rat liver and bacterially expressed rat GNMT. limitations: Recombinant potency cannot be directly transferred to liver. [luka-2008] Acetylation of N-terminal valine of glycine N-methyltransferase affects enzyme inhibition by folate (2008). https://pubmed.ncbi.nlm.nih.gov/18501206/ DOI: 10.1016/j.bbapap.2008.04.016
Complete structured claim and evidence
Seven weeks at 115 micrograms DFE/day produced a nonsignificant tendency toward increased DNA methyl acceptance (P=0.08).
Folate (vitamin B9) → Genomic DNA methylation source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Young MTHFR 677CC/TT women; controlled folate feeding.
limitations
Assay-specific trend, not demonstrated global hypomethylation.
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
This result suggested but did not establish a methylation decrease.
primary_references
[shelnutt-2004] Methylenetetrahydrofolate reductase 677C-->T polymorphism affects DNA methylation in response to controlled folate intake in young women (2004). https://pubmed.ncbi.nlm.nih.gov/15350988/ DOI: 10.1016/j.jnutbio.2004.04.003
tissue_or_cell_type
Blood-derived genomic DNA
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 789–798
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Young MTHFR 677CC/TT women; controlled folate feeding. · source_derived_draft · unverified_draft
### folate-methyl-young-dna-trend Seven weeks at 115 micrograms DFE/day produced a nonsignificant tendency toward increased DNA methyl acceptance (P=0.08). Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: This result suggested but did not establish a methylation decrease. organism: Homo sapiens tissue_or_cell_type: Blood-derived genomic DNA experimental_model: Young MTHFR 677CC/TT women; controlled folate feeding. limitations: Assay-specific trend, not demonstrated global hypomethylation. [shelnutt-2004] Methylenetetrahydrofolate reductase 677C-->T polymorphism affects DNA methylation in response to controlled folate intake in young women (2004). https://pubmed.ncbi.nlm.nih.gov/15350988/ DOI: 10.1016/j.jnutbio.2004.04.003
Complete structured claim and evidence
During 400 micrograms DFE/day repletion, DNA methylcytosine:total-cytosine increased significantly only in MTHFR 677TT women.
Folate (vitamin B9) → Genomic DNA methylation source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Young MTHFR 677CC/TT women; controlled folate feeding.
exposure
Seven weeks after depletion
limitations
Within-group significance alone does not establish a genotype interaction.
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 directly measured DNA-base response differed across genotype groups.
primary_references
[shelnutt-2004] Methylenetetrahydrofolate reductase 677C-->T polymorphism affects DNA methylation in response to controlled folate intake in young women (2004). https://pubmed.ncbi.nlm.nih.gov/15350988/ DOI: 10.1016/j.jnutbio.2004.04.003
tissue_or_cell_type
Blood-derived genomic DNA
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 800–810
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Young MTHFR 677CC/TT women; controlled folate feeding. · source_derived_draft · unverified_draft
### folate-methyl-young-tt-repletion During 400 micrograms DFE/day repletion, DNA methylcytosine:total-cytosine increased significantly only in MTHFR 677TT women. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The directly measured DNA-base response differed across genotype groups. organism: Homo sapiens tissue_or_cell_type: Blood-derived genomic DNA experimental_model: Young MTHFR 677CC/TT women; controlled folate feeding. limitations: Within-group significance alone does not establish a genotype interaction. exposure: Seven weeks after depletion [shelnutt-2004] Methylenetetrahydrofolate reductase 677C-->T polymorphism affects DNA methylation in response to controlled folate intake in young women (2004). https://pubmed.ncbi.nlm.nih.gov/15350988/ DOI: 10.1016/j.jnutbio.2004.04.003
Complete structured claim and evidence
Purified human MTHFD2 oxidizes 5,10-methylene-THF using NAD+ to form methenyl-THF and NADH.
Human MTHFD2 → 5,10-Methylenetetrahydrofolate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Nicotinamide cofactors connect folate chemistry to redox metabolism.
experimental_model
Purified recombinant enzyme
exposure
Assay conditions described in the linked primary study.
limitations
Cellular cofactor partition is not quantified.
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
This mitochondrial enzyme extracts electrons from folate-bound carbon.
primary_references
[shin-2017] Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase (2017). https://pubmed.ncbi.nlm.nih.gov/29225823/ DOI: 10.1186/s40170-017-0173-0
tissue_or_cell_type
Cell-free
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 812–823
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant enzyme · source_derived_draft · unverified_draft
### mthfd2-nad-oxidation Purified human MTHFD2 oxidizes 5,10-methylene-THF using NAD+ to form methenyl-THF and NADH. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: This mitochondrial enzyme extracts electrons from folate-bound carbon. organism: Homo sapiens tissue_or_cell_type: Cell-free experimental_model: Purified recombinant enzyme limitations: Cellular cofactor partition is not quantified. exposure: Assay conditions described in the linked primary study. cross_nutrient: Nicotinamide cofactors connect folate chemistry to redox metabolism. [shin-2017] Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase (2017). https://pubmed.ncbi.nlm.nih.gov/29225823/ DOI: 10.1186/s40170-017-0173-0
Complete structured claim and evidence
Human MTHFD2 also uses NADP+ with methylene-THF pentaglutamate; NADP-linked activity increases relative to the monoglutamate assay.
Human MTHFD2 → NADP+ source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Folate polyglutamylation changes nicotinamide-cofactor use.
experimental_model
Purified recombinant enzyme
exposure
Mono- versus pentaglutamate folate substrates; controlled NAD(P)+ assays.
limitations
Kinetics do not establish dominant in vivo NADPH production.
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 folate tail affects which electron carrier the enzyme uses.
primary_references
[shin-2017] Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase (2017). https://pubmed.ncbi.nlm.nih.gov/29225823/ DOI: 10.1186/s40170-017-0173-0
tissue_or_cell_type
Cell-free
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 825–836
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant enzyme · source_derived_draft · unverified_draft
### mthfd2-nadp-polyglutamate Human MTHFD2 also uses NADP+ with methylene-THF pentaglutamate; NADP-linked activity increases relative to the monoglutamate assay. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The folate tail affects which electron carrier the enzyme uses. organism: Homo sapiens tissue_or_cell_type: Cell-free experimental_model: Purified recombinant enzyme limitations: Kinetics do not establish dominant in vivo NADPH production. exposure: Mono- versus pentaglutamate folate substrates; controlled NAD(P)+ assays. cross_nutrient: Folate polyglutamylation changes nicotinamide-cofactor use. [shin-2017] Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase (2017). https://pubmed.ncbi.nlm.nih.gov/29225823/ DOI: 10.1186/s40170-017-0173-0
Complete structured claim and evidence
Rat MTHFD2L catalyzes methylene-THF oxidation with either NAD+ or NADP+.
Rat mitochondrial MTHFD2L → 5,10-Methylenetetrahydrofolate source_derived_draftungraded
Experimental context and source evidence
experimental_model
Purified recombinant rat protein
exposure
Assay conditions described in the linked primary study.
limitations
Human ortholog flux was not measured.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Rattus norvegicus
plain_language
A second mitochondrial enzyme can use either electron carrier.
primary_references
[shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573
tissue_or_cell_type
Cell-free
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 838–848
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant rat protein · source_derived_draft · unverified_draft
### rat-mthfd2l-oxidation Rat MTHFD2L catalyzes methylene-THF oxidation with either NAD+ or NADP+. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A second mitochondrial enzyme can use either electron carrier. organism: Rattus norvegicus tissue_or_cell_type: Cell-free experimental_model: Purified recombinant rat protein limitations: Human ortholog flux was not measured. exposure: Assay conditions described in the linked primary study. [shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573
Complete structured claim and evidence
Rat MTHFD2L also has methenyl-THF cyclohydrolase activity, linking methenyl-THF to 10-formyl-THF.
Rat mitochondrial MTHFD2L → 10-Formyltetrahydrofolate source_derived_draftungraded
Experimental context and source evidence
experimental_model
Purified recombinant rat protein
exposure
Assay conditions described in the linked primary study.
limitations
Reaction direction depends on chemical conditions.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Rattus norvegicus
plain_language
The same protein performs the next folate conversion.
primary_references
[shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573
tissue_or_cell_type
Cell-free
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 850–860
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified recombinant rat protein · source_derived_draft · unverified_draft
### rat-mthfd2l-cyclohydrolase Rat MTHFD2L also has methenyl-THF cyclohydrolase activity, linking methenyl-THF to 10-formyl-THF. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same protein performs the next folate conversion. organism: Rattus norvegicus tissue_or_cell_type: Cell-free experimental_model: Purified recombinant rat protein limitations: Reaction direction depends on chemical conditions. exposure: Assay conditions described in the linked primary study. [shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573
Complete structured claim and evidence
The NAD+-dependent rat MTHFD2L dehydrogenase assay requires magnesium in the presence of phosphate.
Mg2+ → Rat mitochondrial MTHFD2L source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Direct magnesium/phosphate requirement in folate oxidation.
experimental_model
Cofactor omission/addition assays
exposure
Assay conditions described in the linked primary study.
limitations
No dietary magnesium threshold follows from these assays.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Rattus norvegicus
plain_language
Magnesium supports this NAD-linked folate reaction.
primary_references
[shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573
tissue_or_cell_type
Cell-free
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 862–873
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cofactor omission/addition assays · source_derived_draft · unverified_draft
### rat-mthfd2l-magnesium-phosphate The NAD+-dependent rat MTHFD2L dehydrogenase assay requires magnesium in the presence of phosphate. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Magnesium supports this NAD-linked folate reaction. organism: Rattus norvegicus tissue_or_cell_type: Cell-free experimental_model: Cofactor omission/addition assays limitations: No dietary magnesium threshold follows from these assays. exposure: Assay conditions described in the linked primary study. cross_nutrient: Direct magnesium/phosphate requirement in folate oxidation. [shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573
Complete structured claim and evidence
Human MTHFD1L expressed in CHO cells behaves as a peripheral protein at the matrix face of the inner mitochondrial membrane.
Human MTHFD1L → Inner mitochondrial membrane source_derived_draftungraded
Experimental context and source evidence
experimental_model
Tagged human protein, mitochondrial fractionation
exposure
Assay conditions described in the linked primary study.
limitations
Tagging and heterologous expression may affect localization.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Homo sapiens protein in Cricetulus griseus cells
plain_language
The formate-pathway enzyme sits on the mitochondrial inner surface.
primary_references
[prasannan-2009] Human mitochondrial C1-tetrahydrofolate synthase: submitochondrial localization of the full-length enzyme and characterization of a short isoform (2009). https://pubmed.ncbi.nlm.nih.gov/18996079/ DOI: 10.1016/j.abb.2008.10.028
tissue_or_cell_type
CHO cells
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 875–885
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Tagged human protein, mitochondrial fractionation · source_derived_draft · unverified_draft
### mthfd1l-matrix-face Human MTHFD1L expressed in CHO cells behaves as a peripheral protein at the matrix face of the inner mitochondrial membrane. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The formate-pathway enzyme sits on the mitochondrial inner surface. organism: Homo sapiens protein in Cricetulus griseus cells tissue_or_cell_type: CHO cells experimental_model: Tagged human protein, mitochondrial fractionation limitations: Tagging and heterologous expression may affect localization. exposure: Assay conditions described in the linked primary study. [prasannan-2009] Human mitochondrial C1-tetrahydrofolate synthase: submitochondrial localization of the full-length enzyme and characterization of a short isoform (2009). https://pubmed.ncbi.nlm.nih.gov/18996079/ DOI: 10.1016/j.abb.2008.10.028
Complete structured claim and evidence
The purified short human MTHFD1L isoform lacked detectable methylene-THF dehydrogenase activity.
Human MTHFD1L short isoform → 5,10-Methylenetetrahydrofolate source_derived_draftungraded
Experimental context and source evidence
experimental_model
Purified short isoform
exposure
Assay conditions described in the linked primary study.
limitations
Negative activity result is assay-specific; full-length MTHFD1L has synthetase activity.
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
This short isoform cannot be assumed to replace MTHFD2.
primary_references
[prasannan-2009] Human mitochondrial C1-tetrahydrofolate synthase: submitochondrial localization of the full-length enzyme and characterization of a short isoform (2009). https://pubmed.ncbi.nlm.nih.gov/18996079/ DOI: 10.1016/j.abb.2008.10.028
tissue_or_cell_type
Cell-free
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 887–897
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified short isoform · source_derived_draft · unverified_draft
### mthfd1l-short-no-dehydrogenase The purified short human MTHFD1L isoform lacked detectable methylene-THF dehydrogenase activity. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: This short isoform cannot be assumed to replace MTHFD2. organism: Homo sapiens tissue_or_cell_type: Cell-free experimental_model: Purified short isoform limitations: Negative activity result is assay-specific; full-length MTHFD1L has synthetase activity. exposure: Assay conditions described in the linked primary study. [prasannan-2009] Human mitochondrial C1-tetrahydrofolate synthase: submitochondrial localization of the full-length enzyme and characterization of a short isoform (2009). https://pubmed.ncbi.nlm.nih.gov/18996079/ DOI: 10.1016/j.abb.2008.10.028
Complete structured claim and evidence
MTHFD2 deletion depleted formyl-folate availability and activated cytosolic serine-derived one-carbon production.
Human MTHFD2 gene → Human MTHFD1 source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
CRISPR and isotope tracing
exposure
Assay conditions described in the linked primary study.
limitations
Compensation depends on nutrient availability.
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 can reroute carbon production after losing the mitochondrial pathway.
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
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 899–909
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · CRISPR and isotope tracing · source_derived_draft · unverified_draft
### mitochondrial-loss-cytosolic-reversal MTHFD2 deletion depleted formyl-folate availability and activated cytosolic serine-derived one-carbon production. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cells can reroute carbon production after losing the mitochondrial pathway. organism: Homo sapiens tissue_or_cell_type: HEK293T cells experimental_model: CRISPR and isotope tracing limitations: Compensation depends on nutrient availability. exposure: Assay conditions described in the linked primary study. [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
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
In nutrient-replete HEK293T and HCT116 cells, isotope tracing showed net SHMT1 flux toward serine synthesis.
SHMT1 → L-Serine source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Links existing B6-dependent SHMT chemistry to folate flux direction.
experimental_model
Stable-isotope tracing
exposure
Assay conditions described in the linked primary study.
limitations
Not a universal direction across tissues or nutrition states.
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
SHMT1 can consume one-carbon units instead of producing them.
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 and HCT116 cells
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 923–934
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Stable-isotope tracing · source_derived_draft · unverified_draft
### shmt1-reverse-flux-replete In nutrient-replete HEK293T and HCT116 cells, isotope tracing showed net SHMT1 flux toward serine synthesis. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: SHMT1 can consume one-carbon units instead of producing them. organism: Homo sapiens tissue_or_cell_type: HEK293T and HCT116 cells experimental_model: Stable-isotope tracing limitations: Not a universal direction across tissues or nutrition states. exposure: Assay conditions described in the linked primary study. cross_nutrient: Links existing B6-dependent SHMT chemistry to folate flux direction. [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
MTHFD1 accumulated in nuclei of S-phase HeLa and MCF7 cells.
Human MTHFD1 → Nucleus source_derived_draftungraded
Experimental context and source evidence
experimental_model
Cell-cycle localization experiments
exposure
Assay conditions described in the linked primary study.
limitations
Cultured-cell localization; not a whole-body folate biomarker.
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 enzyme moves toward the compartment where DNA is copied.
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 949–959
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell-cycle localization experiments · source_derived_draft · unverified_draft
### mthfd1-s-phase-localization MTHFD1 accumulated in nuclei of S-phase HeLa and MCF7 cells. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The enzyme moves toward the compartment where DNA is copied. organism: Homo sapiens tissue_or_cell_type: HeLa and MCF7 cells experimental_model: Cell-cycle localization experiments limitations: Cultured-cell localization; not a whole-body folate biomarker. exposure: Assay conditions described in the linked primary study. [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
Dietary folate depletion increased nuclear Mthfd1 more than twofold in mouse liver at the expense of cytosolic levels.
Mouse Mthfd1 protein → Nucleus source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Dietary depletion and liver fractionation
exposure
Assay conditions described in the linked primary study.
limitations
Nuclear protection is conditional; it does not prove indefinite resistance to deficiency.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Mus musculus
plain_language
The enzyme redistributed toward the nucleus as folate supply fell.
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
Liver
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 961–971
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Dietary depletion and liver fractionation · source_derived_draft · unverified_draft
### mouse-folate-depletion-mthfd1-enrichment Dietary folate depletion increased nuclear Mthfd1 more than twofold in mouse liver at the expense of cytosolic levels. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The enzyme redistributed toward the nucleus as folate supply fell. organism: Mus musculus tissue_or_cell_type: Liver experimental_model: Dietary depletion and liver fractionation limitations: Nuclear protection is conditional; it does not prove indefinite resistance to deficiency. exposure: Assay conditions described in the linked primary study. [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 TYMS uses 5,10-methylene-THF to convert dUMP to dTMP, producing dihydrofolate.
Human thymidylate synthase / TYMS → Deoxyuridine monophosphate source_derived_draftungraded
Experimental context and source evidence
experimental_model
Purified human TYMS reaction assays
exposure
Assay conditions described in the linked primary study.
limitations
Purified-enzyme chemistry does not specify cellular flux.
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
Folate supplies the carbon and reducing power to make a DNA base.
primary_references
[islam-2018] Bacterial versus human thymidylate synthase: Kinetics and functionality (2018). https://pubmed.ncbi.nlm.nih.gov/29715278/ DOI: 10.1371/journal.pone.0196506
tissue_or_cell_type
Cell-free
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 973–983
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human TYMS reaction assays · source_derived_draft · unverified_draft
### tyms-dump-methylation Human TYMS uses 5,10-methylene-THF to convert dUMP to dTMP, producing dihydrofolate. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Folate supplies the carbon and reducing power to make a DNA base. organism: Homo sapiens tissue_or_cell_type: Cell-free experimental_model: Purified human TYMS reaction assays limitations: Purified-enzyme chemistry does not specify cellular flux. exposure: Assay conditions described in the linked primary study. [islam-2018] Bacterial versus human thymidylate synthase: Kinetics and functionality (2018). https://pubmed.ncbi.nlm.nih.gov/29715278/ DOI: 10.1371/journal.pone.0196506
Complete structured claim and evidence
Added magnesium did not enhance human TYMS reaction rates under conditions where bacterial TYMS differed.
Mg2+ → Human thymidylate synthase / TYMS source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Species-specific boundary on a proposed magnesium-folate interaction.
experimental_model
Comparative enzyme kinetics
exposure
Assay conditions described in the linked primary study.
limitations
Assay-specific negative result, not proof of magnesium-independent DNA synthesis.
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
Magnesium effects on bacterial enzymes cannot be assumed for human TYMS.
primary_references
[islam-2018] Bacterial versus human thymidylate synthase: Kinetics and functionality (2018). https://pubmed.ncbi.nlm.nih.gov/29715278/ DOI: 10.1371/journal.pone.0196506
tissue_or_cell_type
Cell-free
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 985–996
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Comparative enzyme kinetics · source_derived_draft · unverified_draft
### human-tyms-magnesium-not-stimulatory Added magnesium did not enhance human TYMS reaction rates under conditions where bacterial TYMS differed. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Magnesium effects on bacterial enzymes cannot be assumed for human TYMS. organism: Homo sapiens tissue_or_cell_type: Cell-free experimental_model: Comparative enzyme kinetics limitations: Assay-specific negative result, not proof of magnesium-independent DNA synthesis. exposure: Assay conditions described in the linked primary study. cross_nutrient: Species-specific boundary on a proposed magnesium-folate interaction. [islam-2018] Bacterial versus human thymidylate synthase: Kinetics and functionality (2018). https://pubmed.ncbi.nlm.nih.gov/29715278/ DOI: 10.1371/journal.pone.0196506
Complete structured claim and evidence
The human GART transformylase domain binds a folate formyl donor and GAR-site acceptor in a ternary complex supporting GAR formylation to FGAR.
Human trifunctional GART → Glycinamide ribonucleotide source_derived_draftungraded
Experimental context and source evidence
experimental_model
X-ray crystallography
exposure
Assay conditions described in the linked primary study.
limitations
Structures used 10-formyl-dideazafolate and hydroxyacetamide ribonucleotide analogues.
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
Folate donates one carbon early in purine-base construction.
primary_references
[dahms-2005] The apo and ternary complex structures of a chemotherapeutic target: human glycinamide ribonucleotide transformylase (2005). https://pubmed.ncbi.nlm.nih.gov/16026156/ DOI: 10.1021/bi050307g
tissue_or_cell_type
Purified domain
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 998–1008
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · X-ray crystallography · source_derived_draft · unverified_draft
### gart-formyl-transfer The human GART transformylase domain binds a folate formyl donor and GAR-site acceptor in a ternary complex supporting GAR formylation to FGAR. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Folate donates one carbon early in purine-base construction. organism: Homo sapiens tissue_or_cell_type: Purified domain experimental_model: X-ray crystallography limitations: Structures used 10-formyl-dideazafolate and hydroxyacetamide ribonucleotide analogues. exposure: Assay conditions described in the linked primary study. [dahms-2005] The apo and ternary complex structures of a chemotherapeutic target: human glycinamide ribonucleotide transformylase (2005). https://pubmed.ncbi.nlm.nih.gov/16026156/ DOI: 10.1021/bi050307g
Complete structured claim and evidence
Purified human ATIC uses 10-formyl-THF for its AICAR formyltransferase reaction, yielding FAICAR.
Human bifunctional ATIC → 5-Aminoimidazole-4-carboxamide ribonucleotide source_derived_draftungraded
Experimental context and source evidence
experimental_model
Recombinant enzyme kinetics
exposure
Assay conditions described in the linked primary study.
limitations
Reported folate kinetics used a 6R/6S mixture.
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 second folate donation helps finish the purine ring.
primary_references
[rayl-1996] The human purH gene product, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase. Cloning, sequencing, expression, purification, kinetic analysis, and domain mapping (1996). https://pubmed.ncbi.nlm.nih.gov/8567683/ DOI: 10.1074/jbc.271.4.2225
tissue_or_cell_type
Cell-free
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1010–1020
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant enzyme kinetics · source_derived_draft · unverified_draft
### atic-aicar-formylation Purified human ATIC uses 10-formyl-THF for its AICAR formyltransferase reaction, yielding FAICAR. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A second folate donation helps finish the purine ring. organism: Homo sapiens tissue_or_cell_type: Cell-free experimental_model: Recombinant enzyme kinetics limitations: Reported folate kinetics used a 6R/6S mixture. exposure: Assay conditions described in the linked primary study. [rayl-1996] The human purH gene product, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase. Cloning, sequencing, expression, purification, kinetic analysis, and domain mapping (1996). https://pubmed.ncbi.nlm.nih.gov/8567683/ DOI: 10.1074/jbc.271.4.2225
Complete structured claim and evidence
Human ATIC has a separable IMP cyclohydrolase domain that converts FAICAR to IMP.
Human bifunctional ATIC → 5-Formamidoimidazole-4-carboxamide ribonucleotide source_derived_draftungraded
Experimental context and source evidence
experimental_model
Truncation-domain activity mapping
exposure
Assay conditions described in the linked primary study.
limitations
This second step does not consume another folate molecule.
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
After the folate donation, ATIC closes the purine ring.
primary_references
[rayl-1996] The human purH gene product, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase. Cloning, sequencing, expression, purification, kinetic analysis, and domain mapping (1996). https://pubmed.ncbi.nlm.nih.gov/8567683/ DOI: 10.1074/jbc.271.4.2225
tissue_or_cell_type
Cell-free
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1022–1032
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Truncation-domain activity mapping · source_derived_draft · unverified_draft
### atic-faicar-cyclization Human ATIC has a separable IMP cyclohydrolase domain that converts FAICAR to IMP. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: After the folate donation, ATIC closes the purine ring. organism: Homo sapiens tissue_or_cell_type: Cell-free experimental_model: Truncation-domain activity mapping limitations: This second step does not consume another folate molecule. exposure: Assay conditions described in the linked primary study. [rayl-1996] The human purH gene product, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase. Cloning, sequencing, expression, purification, kinetic analysis, and domain mapping (1996). https://pubmed.ncbi.nlm.nih.gov/8567683/ DOI: 10.1074/jbc.271.4.2225
Complete structured claim and evidence
A human ALDH1L2 construct carrying its N-terminal targeting region localized to mitochondria in transfected cells.
Human ALDH1L2 → Mitochondria source_derived_draftungraded
Experimental context and source evidence
experimental_model
Fluorescent protein localization
exposure
Assay conditions described in the linked primary study.
limitations
Localization alone does not measure carbon-disposal flux.
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
ALDH1L2 is the mitochondrial counterpart of cytosolic ALDH1L1.
primary_references
[krupenko-2010] ALDH1L2 is the mitochondrial homolog of 10-formyltetrahydrofolate dehydrogenase (2010). https://pubmed.ncbi.nlm.nih.gov/20498374/ DOI: 10.1074/jbc.m110.128843
tissue_or_cell_type
A549 cells; corroborating COS-7 host experiments
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1034–1044
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Fluorescent protein localization · source_derived_draft · unverified_draft
### aldh1l2-targeting A human ALDH1L2 construct carrying its N-terminal targeting region localized to mitochondria in transfected cells. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: ALDH1L2 is the mitochondrial counterpart of cytosolic ALDH1L1. organism: Homo sapiens tissue_or_cell_type: A549 cells; corroborating COS-7 host experiments experimental_model: Fluorescent protein localization limitations: Localization alone does not measure carbon-disposal flux. exposure: Assay conditions described in the linked primary study. [krupenko-2010] ALDH1L2 is the mitochondrial homolog of 10-formyltetrahydrofolate dehydrogenase (2010). https://pubmed.ncbi.nlm.nih.gov/20498374/ DOI: 10.1074/jbc.m110.128843
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
Ectopic ALDH1L1 expression in HuH-7 cells increased ZMP/AICAR ribotide, consistent with reduced formyl-donor availability for ATIC.
Human ALDH1L1 → 5-Aminoimidazole-4-carboxamide ribonucleotide source_derived_draftungraded
Experimental context and source evidence
experimental_model
Stable expression and metabolomics
exposure
Engineered ALDH1L1 expression.
limitations
Overexpression in one cancer line; substrate competition is the study interpretation.
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
Disposing of folate-bound carbon can slow a purine-building step.
primary_references
[sasaki-2023] One-carbon metabolizing enzyme ALDH1L1 influences mitochondrial metabolism through 5-aminoimidazole-4-carboxamide ribonucleotide accumulation and serine depletion, contributing to tumor suppression (2023). https://pubmed.ncbi.nlm.nih.gov/37596270/ DOI: 10.1038/s41598-023-38142-5
tissue_or_cell_type
HuH-7 hepatocellular carcinoma cells
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1072–1082
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Stable expression and metabolomics · source_derived_draft · unverified_draft
### aldh1l1-aicar-accumulation Ectopic ALDH1L1 expression in HuH-7 cells increased ZMP/AICAR ribotide, consistent with reduced formyl-donor availability for ATIC. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Disposing of folate-bound carbon can slow a purine-building step. organism: Homo sapiens tissue_or_cell_type: HuH-7 hepatocellular carcinoma cells experimental_model: Stable expression and metabolomics limitations: Overexpression in one cancer line; substrate competition is the study interpretation. exposure: Engineered ALDH1L1 expression. [sasaki-2023] One-carbon metabolizing enzyme ALDH1L1 influences mitochondrial metabolism through 5-aminoimidazole-4-carboxamide ribonucleotide accumulation and serine depletion, contributing to tumor suppression (2023). https://pubmed.ncbi.nlm.nih.gov/37596270/ DOI: 10.1038/s41598-023-38142-5
Complete structured claim and evidence
ALDH1L1-expressing HuH-7 cells had lower serine and higher glycine than controls.
Human ALDH1L1 → L-Serine source_derived_draftungraded
Experimental context and source evidence
experimental_model
Cell metabolomics
exposure
Engineered ALDH1L1 expression.
limitations
Pool changes alone do not quantify compartment-specific SHMT flux.
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
Changing folate-carbon disposal reshaped amino-acid pools.
primary_references
[sasaki-2023] One-carbon metabolizing enzyme ALDH1L1 influences mitochondrial metabolism through 5-aminoimidazole-4-carboxamide ribonucleotide accumulation and serine depletion, contributing to tumor suppression (2023). https://pubmed.ncbi.nlm.nih.gov/37596270/ DOI: 10.1038/s41598-023-38142-5
tissue_or_cell_type
HuH-7 cells
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1084–1094
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell metabolomics · source_derived_draft · unverified_draft
### aldh1l1-serine-glycine ALDH1L1-expressing HuH-7 cells had lower serine and higher glycine than controls. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Changing folate-carbon disposal reshaped amino-acid pools. organism: Homo sapiens tissue_or_cell_type: HuH-7 cells experimental_model: Cell metabolomics limitations: Pool changes alone do not quantify compartment-specific SHMT flux. exposure: Engineered ALDH1L1 expression. [sasaki-2023] One-carbon metabolizing enzyme ALDH1L1 influences mitochondrial metabolism through 5-aminoimidazole-4-carboxamide ribonucleotide accumulation and serine depletion, contributing to tumor suppression (2023). https://pubmed.ncbi.nlm.nih.gov/37596270/ DOI: 10.1038/s41598-023-38142-5
Complete structured claim and evidence
Isolated mouse embryonic mitochondria converted labeled glycine carbon into formate.
Glycine → Formate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Handoff to existing PLP-dependent glycine decarboxylase and lipoyl-GCSH/AMT folate transfer evidence; not new deficiency evidence.
experimental_model
Radiolabeled mitochondrial flux assay
exposure
Assay conditions described in the linked primary study.
limitations
No B6 or lipoate dietary perturbation tested.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Mus musculus
plain_language
Glycine cleavage can feed folate-bound carbon into mitochondrial formate production.
primary_references
[pike-2010] Mitochondrial C1-tetrahydrofolate synthase (MTHFD1L) supports the flow of mitochondrial one-carbon units into the methyl cycle in embryos (2010). https://pubmed.ncbi.nlm.nih.gov/19948730/ DOI: 10.1074/jbc.m109.079855
tissue_or_cell_type
Embryonic mitochondria
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1096–1107
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Radiolabeled mitochondrial flux assay · source_derived_draft · unverified_draft
### embryonic-glycine-formate Isolated mouse embryonic mitochondria converted labeled glycine carbon into formate. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Glycine cleavage can feed folate-bound carbon into mitochondrial formate production. organism: Mus musculus tissue_or_cell_type: Embryonic mitochondria experimental_model: Radiolabeled mitochondrial flux assay limitations: No B6 or lipoate dietary perturbation tested. exposure: Assay conditions described in the linked primary study. cross_nutrient: Handoff to existing PLP-dependent glycine decarboxylase and lipoyl-GCSH/AMT folate transfer evidence; not new deficiency evidence. [pike-2010] Mitochondrial C1-tetrahydrofolate synthase (MTHFD1L) supports the flow of mitochondrial one-carbon units into the methyl cycle in embryos (2010). https://pubmed.ncbi.nlm.nih.gov/19948730/ DOI: 10.1074/jbc.m109.079855
Complete structured claim and evidence
SHMT2-null Jurkat cells failed to maintain normal mitochondrial formylmethionyl-tRNA pools.
Human SHMT2 gene → Mitochondrial formylmethionyl-tRNA source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
CRISPR and tRNA assays
exposure
Assay conditions described in the linked primary study.
limitations
Several downstream mitochondrial consequences may coexist.
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
Mitochondrial serine breakdown helps prepare the tRNA that starts translation.
primary_references
[minton-2018] Serine Catabolism by SHMT2 Is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl-tRNAs (2018). https://pubmed.ncbi.nlm.nih.gov/29452640/ DOI: 10.1016/j.molcel.2018.01.024
tissue_or_cell_type
Jurkat cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1109–1119
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · CRISPR and tRNA assays · source_derived_draft · unverified_draft
### shmt2-loss-formyltrna SHMT2-null Jurkat cells failed to maintain normal mitochondrial formylmethionyl-tRNA pools. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Mitochondrial serine breakdown helps prepare the tRNA that starts translation. organism: Homo sapiens tissue_or_cell_type: Jurkat cells experimental_model: CRISPR and tRNA assays limitations: Several downstream mitochondrial consequences may coexist. exposure: Assay conditions described in the linked primary study. [minton-2018] Serine Catabolism by SHMT2 Is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl-tRNAs (2018). https://pubmed.ncbi.nlm.nih.gov/29452640/ DOI: 10.1016/j.molcel.2018.01.024
Complete structured claim and evidence
SHMT2 deletion reduced synthesis of mitochondrially encoded proteins while cytosolic protein labeling was preserved.
Human SHMT2 gene → Mitochondrial protein translation source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Radiolabeled protein synthesis
exposure
Assay conditions described in the linked primary study.
limitations
Cell-line response; no clinical supplementation conclusion.
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 translation defect was concentrated in mitochondria.
primary_references
[minton-2018] Serine Catabolism by SHMT2 Is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl-tRNAs (2018). https://pubmed.ncbi.nlm.nih.gov/29452640/ DOI: 10.1016/j.molcel.2018.01.024
tissue_or_cell_type
Jurkat cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1121–1131
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Radiolabeled protein synthesis · source_derived_draft · unverified_draft
### shmt2-loss-mito-translation SHMT2 deletion reduced synthesis of mitochondrially encoded proteins while cytosolic protein labeling was preserved. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The translation defect was concentrated in mitochondria. organism: Homo sapiens tissue_or_cell_type: Jurkat cells experimental_model: Radiolabeled protein synthesis limitations: Cell-line response; no clinical supplementation conclusion. exposure: Assay conditions described in the linked primary study. [minton-2018] Serine Catabolism by SHMT2 Is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl-tRNAs (2018). https://pubmed.ncbi.nlm.nih.gov/29452640/ DOI: 10.1016/j.molcel.2018.01.024
Complete structured claim and evidence
MTFMT uses mitochondrial 10-formyl-THF to generate formylmethionyl-tRNA needed for translation initiation.
Human mitochondrial methionyl-tRNA formyltransferase / MTFMT → Mitochondrial methionyl-tRNA source_derived_draftungraded
Experimental context and source evidence
experimental_model
Genetic and tRNA-formylation experiments
exposure
Assay conditions described in the linked primary study.
limitations
Does not imply that plasma folate directly reports mitochondrial 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
Folate supplies the small chemical tag used to start mitochondrial proteins.
primary_references
[minton-2018] Serine Catabolism by SHMT2 Is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl-tRNAs (2018). https://pubmed.ncbi.nlm.nih.gov/29452640/ DOI: 10.1016/j.molcel.2018.01.024
tissue_or_cell_type
Jurkat cells
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1133–1143
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Genetic and tRNA-formylation experiments · source_derived_draft · unverified_draft
### mtfmt-folate-formylation MTFMT uses mitochondrial 10-formyl-THF to generate formylmethionyl-tRNA needed for translation initiation. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Folate supplies the small chemical tag used to start mitochondrial proteins. organism: Homo sapiens tissue_or_cell_type: Jurkat cells experimental_model: Genetic and tRNA-formylation experiments limitations: Does not imply that plasma folate directly reports mitochondrial folate. exposure: Assay conditions described in the linked primary study. [minton-2018] Serine Catabolism by SHMT2 Is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl-tRNAs (2018). https://pubmed.ncbi.nlm.nih.gov/29452640/ DOI: 10.1016/j.molcel.2018.01.024
Complete structured claim and evidence
Shmt1-transgenic mouse liver had lower nuclear SHMT1/TYMS and lower nuclear de novo dTMP synthesis despite higher total enzyme abundance.
Mouse Shmt1 gene → Nuclear de novo thymidylate synthesis source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Transgene and isolated-nuclei assays
exposure
Assay conditions described in the linked primary study.
limitations
Overexpression phenotype must not be generalized to supplementation.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Mus musculus
plain_language
More enzyme in the whole cell did not mean more at DNA-replication sites.
primary_references
[macfarlane-2011] Nuclear localization of de novo thymidylate biosynthesis pathway is required to prevent uracil accumulation in DNA (2011). https://pubmed.ncbi.nlm.nih.gov/22057276/ DOI: 10.1074/jbc.m111.307629
tissue_or_cell_type
Liver nuclei
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1145–1155
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Transgene and isolated-nuclei assays · source_derived_draft · unverified_draft
### shmt1-transgene-nuclear-mislocalization Shmt1-transgenic mouse liver had lower nuclear SHMT1/TYMS and lower nuclear de novo dTMP synthesis despite higher total enzyme abundance. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: More enzyme in the whole cell did not mean more at DNA-replication sites. organism: Mus musculus tissue_or_cell_type: Liver nuclei experimental_model: Transgene and isolated-nuclei assays limitations: Overexpression phenotype must not be generalized to supplementation. exposure: Assay conditions described in the linked primary study. [macfarlane-2011] Nuclear localization of de novo thymidylate biosynthesis pathway is required to prevent uracil accumulation in DNA (2011). https://pubmed.ncbi.nlm.nih.gov/22057276/ DOI: 10.1074/jbc.m111.307629
Complete structured claim and evidence
Control-diet Shmt1-transgenic mice showed approximately twice the hepatic nuclear-DNA uracil of wild-type mice.
Mouse Shmt1 gene → Uracil incorporation in nuclear DNA source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_location
Table 2, control-diet comparison.
experimental_model
Nuclear DNA uracil measurement
exposure
Assay conditions described in the linked primary study.
limitations
Association within a transgenic model; control diet contains folate and choline.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Mus musculus
plain_language
Incorrect enzyme placement was accompanied by more uracil in DNA.
primary_references
[macfarlane-2011] Nuclear localization of de novo thymidylate biosynthesis pathway is required to prevent uracil accumulation in DNA (2011). https://pubmed.ncbi.nlm.nih.gov/22057276/ DOI: 10.1074/jbc.m111.307629
tissue_or_cell_type
Liver
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1157–1168
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Nuclear DNA uracil measurement · source_derived_draft · unverified_draft
### shmt1-transgene-dna-uracil Control-diet Shmt1-transgenic mice showed approximately twice the hepatic nuclear-DNA uracil of wild-type mice. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Incorrect enzyme placement was accompanied by more uracil in DNA. organism: Mus musculus tissue_or_cell_type: Liver experimental_model: Nuclear DNA uracil measurement limitations: Association within a transgenic model; control diet contains folate and choline. exposure: Assay conditions described in the linked primary study. evidence_location: Table 2, control-diet comparison. [macfarlane-2011] Nuclear localization of de novo thymidylate biosynthesis pathway is required to prevent uracil accumulation in DNA (2011). https://pubmed.ncbi.nlm.nih.gov/22057276/ DOI: 10.1074/jbc.m111.307629
Complete structured claim and evidence
Patient fibroblasts showed roughly half the formate-derived contribution to dTMP measured in control cells.
Human MTHFD1 gene → Nuclear de novo thymidylate synthesis source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Stable-isotope tracing
exposure
Assay conditions described in the linked primary study.
limitations
One genotype; isotope ratio is not a whole-body folate measurement.
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
This inherited enzyme defect reduced one carbon supply for a DNA base.
primary_references
[field-2015] Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis (2015). https://pubmed.ncbi.nlm.nih.gov/25548164/ DOI: 10.1073/pnas.1414555112
tissue_or_cell_type
WG3607 fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1170–1180
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Stable-isotope tracing · source_derived_draft · unverified_draft
### mthfd1-patient-dtmp Patient fibroblasts showed roughly half the formate-derived contribution to dTMP measured in control cells. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: This inherited enzyme defect reduced one carbon supply for a DNA base. organism: Homo sapiens tissue_or_cell_type: WG3607 fibroblasts experimental_model: Stable-isotope tracing limitations: One genotype; isotope ratio is not a whole-body folate measurement. exposure: Assay conditions described in the linked primary study. [field-2015] Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis (2015). https://pubmed.ncbi.nlm.nih.gov/25548164/ DOI: 10.1073/pnas.1414555112
Complete structured claim and evidence
MTHFD1-deficient patient fibroblasts contained more uracil in DNA than both control lines.
Human MTHFD1 gene → Uracil incorporation in nuclear DNA source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
DNA uracil assay
exposure
Assay conditions described in the linked primary study.
limitations
Fibroblast endpoint does not itself prove the cause of clinical immunodeficiency.
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 enzyme defect was accompanied by a DNA-base imbalance.
primary_references
[field-2015] Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis (2015). https://pubmed.ncbi.nlm.nih.gov/25548164/ DOI: 10.1073/pnas.1414555112
tissue_or_cell_type
WG3607 fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1182–1192
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · DNA uracil assay · source_derived_draft · unverified_draft
### mthfd1-patient-dna-uracil MTHFD1-deficient patient fibroblasts contained more uracil in DNA than both control lines. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The enzyme defect was accompanied by a DNA-base imbalance. organism: Homo sapiens tissue_or_cell_type: WG3607 fibroblasts experimental_model: DNA uracil assay limitations: Fibroblast endpoint does not itself prove the cause of clinical immunodeficiency. exposure: Assay conditions described in the linked primary study. [field-2015] Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis (2015). https://pubmed.ncbi.nlm.nih.gov/25548164/ DOI: 10.1073/pnas.1414555112
Complete structured claim and evidence
Formate incorporation through de novo purine synthesis was not significantly altered in these MTHFD1-deficient fibroblasts.
Human MTHFD1 gene → De novo purine nucleotide synthesis source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Formate suppression assay
exposure
Assay conditions described in the linked primary study.
limitations
Preservation in this genotype does not establish dispensability of MTHFD1.
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
Different folate-dependent pathways were not equally impaired.
primary_references
[field-2015] Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis (2015). https://pubmed.ncbi.nlm.nih.gov/25548164/ DOI: 10.1073/pnas.1414555112
tissue_or_cell_type
WG3607 fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1194–1204
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Formate suppression assay · source_derived_draft · unverified_draft
### mthfd1-patient-purine-preservation Formate incorporation through de novo purine synthesis was not significantly altered in these MTHFD1-deficient fibroblasts. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Different folate-dependent pathways were not equally impaired. organism: Homo sapiens tissue_or_cell_type: WG3607 fibroblasts experimental_model: Formate suppression assay limitations: Preservation in this genotype does not establish dispensability of MTHFD1. exposure: Assay conditions described in the linked primary study. [field-2015] Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis (2015). https://pubmed.ncbi.nlm.nih.gov/25548164/ DOI: 10.1073/pnas.1414555112
Complete structured claim and evidence
Tested cancer cells and IMR90 fibroblasts released most serine-derived one-carbon units as formate rather than retaining them for biosynthesis.
L-Serine → Cellular formate release source_derived_draftungraded
Experimental context and source evidence
experimental_model
Stable-isotope and exchange-rate measurements
exposure
Assay conditions described in the linked primary study.
limitations
Fractions depend on culture conditions.
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 can make more one-carbon units than they use locally.
primary_references
[meiser-2016] Serine one-carbon catabolism with formate overflow (2016). https://pubmed.ncbi.nlm.nih.gov/27819051/ DOI: 10.1126/sciadv.1601273
tissue_or_cell_type
Cultured cancer cells and lung fibroblasts
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1206–1216
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Stable-isotope and exchange-rate measurements · source_derived_draft · unverified_draft
### serine-formate-overflow Tested cancer cells and IMR90 fibroblasts released most serine-derived one-carbon units as formate rather than retaining them for biosynthesis. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cells can make more one-carbon units than they use locally. organism: Homo sapiens tissue_or_cell_type: Cultured cancer cells and lung fibroblasts experimental_model: Stable-isotope and exchange-rate measurements limitations: Fractions depend on culture conditions. exposure: Assay conditions described in the linked primary study. [meiser-2016] Serine one-carbon catabolism with formate overflow (2016). https://pubmed.ncbi.nlm.nih.gov/27819051/ DOI: 10.1126/sciadv.1601273
Complete structured claim and evidence
MTHFD1L knockdown lowered formate release in the tested human cells.
Human MTHFD1L gene → Cellular formate release source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
experimental_model
Knockdown and extracellular metabolite assay
exposure
Assay conditions described in the linked primary study.
limitations
Does not establish the transporter responsible for formate exchange.
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
Mitochondrial MTHFD1L helps release carbon as formate.
primary_references
[meiser-2016] Serine one-carbon catabolism with formate overflow (2016). https://pubmed.ncbi.nlm.nih.gov/27819051/ DOI: 10.1126/sciadv.1601273
tissue_or_cell_type
Cancer cell lines and IMR90 fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1218–1228
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Knockdown and extracellular metabolite assay · source_derived_draft · unverified_draft
### mthfd1l-formate-release MTHFD1L knockdown lowered formate release in the tested human cells. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Mitochondrial MTHFD1L helps release carbon as formate. organism: Homo sapiens tissue_or_cell_type: Cancer cell lines and IMR90 fibroblasts experimental_model: Knockdown and extracellular metabolite assay limitations: Does not establish the transporter responsible for formate exchange. exposure: Assay conditions described in the linked primary study. [meiser-2016] Serine one-carbon catabolism with formate overflow (2016). https://pubmed.ncbi.nlm.nih.gov/27819051/ DOI: 10.1126/sciadv.1601273
Complete structured claim and evidence
Biochemical experiments identified QDPR activity that repairs oxidatively damaged tetrahydrofolate.
Human quinoid dihydropteridine reductase / QDPR → Oxidative degradation of reduced folates source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Shared QDPR machinery connects biopterin and folate redox maintenance.
experimental_model
Biochemical enzyme experiments
exposure
Assay conditions described in the linked primary study.
limitations
Repair capacity is finite; no human dietary requirement was determined.
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
An enzyme also used in biopterin metabolism helps preserve reduced folate.
primary_references
[zheng-2018] Mitochondrial One-Carbon Pathway Supports Cytosolic Folate Integrity in Cancer Cells (2018). https://pubmed.ncbi.nlm.nih.gov/30500537/ DOI: 10.1016/j.cell.2018.09.041
tissue_or_cell_type
Cell-free and cancer-cell experiments
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1230–1241
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Biochemical enzyme experiments · source_derived_draft · unverified_draft
### qdpr-folate-repair Biochemical experiments identified QDPR activity that repairs oxidatively damaged tetrahydrofolate. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: An enzyme also used in biopterin metabolism helps preserve reduced folate. organism: Homo sapiens tissue_or_cell_type: Cell-free and cancer-cell experiments experimental_model: Biochemical enzyme experiments limitations: Repair capacity is finite; no human dietary requirement was determined. exposure: Assay conditions described in the linked primary study. cross_nutrient: Shared QDPR machinery connects biopterin and folate redox maintenance. [zheng-2018] Mitochondrial One-Carbon Pathway Supports Cytosolic Folate Integrity in Cancer Cells (2018). https://pubmed.ncbi.nlm.nih.gov/30500537/ DOI: 10.1016/j.cell.2018.09.041
Complete structured claim and evidence
Purified human liver MTHFS converts 5-formyl-THF into 5,10-methenyl-THF.
Human methenyltetrahydrofolate synthetase / MTHFS → 5-Formyltetrahydrofolate source_derived_draftungraded
Experimental context and source evidence
experimental_model
Purified liver enzyme
exposure
Purified human liver enzyme and folate substrates; initial-velocity measurements.
limitations
An enzyme assay does not establish clinical benefit from folinic acid.
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
This enzyme moves folinic acid into the methenyl-folate pool.
primary_references
[bertrand-1987] Human liver methenyltetrahydrofolate synthetase: improved purification and increased affinity for folate polyglutamate substrates (1987). https://pubmed.ncbi.nlm.nih.gov/3801490/ DOI: 10.1016/0167-4838(87)90004-5
tissue_or_cell_type
Liver-derived, cell-free
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1243–1253
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified liver enzyme · source_derived_draft · unverified_draft
### mthfs-folinic-acid-conversion Purified human liver MTHFS converts 5-formyl-THF into 5,10-methenyl-THF. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: This enzyme moves folinic acid into the methenyl-folate pool. organism: Homo sapiens tissue_or_cell_type: Liver-derived, cell-free experimental_model: Purified liver enzyme limitations: An enzyme assay does not establish clinical benefit from folinic acid. exposure: Purified human liver enzyme and folate substrates; initial-velocity measurements. [bertrand-1987] Human liver methenyltetrahydrofolate synthetase: improved purification and increased affinity for folate polyglutamate substrates (1987). https://pubmed.ncbi.nlm.nih.gov/3801490/ DOI: 10.1016/0167-4838(87)90004-5
Complete structured claim and evidence
The purified human liver MTHFS reaction requires ATP and Mg2+ and is an ADP-forming cyclo-ligase reaction.
ATP → Human methenyltetrahydrofolate synthetase / MTHFS source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Magnesium and ATP support folate interconversion.
experimental_model
Purified liver enzyme
exposure
Controlled enzyme assay with ATP and magnesium.
limitations
Cofactor dependence does not establish a dietary magnesium threshold.
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
ATP supplies energy for this magnesium-dependent folate conversion.
primary_references
[bertrand-1987] Human liver methenyltetrahydrofolate synthetase: improved purification and increased affinity for folate polyglutamate substrates (1987). https://pubmed.ncbi.nlm.nih.gov/3801490/ DOI: 10.1016/0167-4838(87)90004-5
tissue_or_cell_type
Liver-derived, cell-free
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1255–1266
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified liver enzyme · source_derived_draft · unverified_draft
### mthfs-atp-magnesium-dependence The purified human liver MTHFS reaction requires ATP and Mg2+ and is an ADP-forming cyclo-ligase reaction. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: ATP supplies energy for this magnesium-dependent folate conversion. organism: Homo sapiens tissue_or_cell_type: Liver-derived, cell-free experimental_model: Purified liver enzyme limitations: Cofactor dependence does not establish a dietary magnesium threshold. exposure: Controlled enzyme assay with ATP and magnesium. cross_nutrient: Magnesium and ATP support folate interconversion. [bertrand-1987] Human liver methenyltetrahydrofolate synthetase: improved purification and increased affinity for folate polyglutamate substrates (1987). https://pubmed.ncbi.nlm.nih.gov/3801490/ DOI: 10.1016/0167-4838(87)90004-5
Complete structured claim and evidence
Patient 1 fibroblast lysate had no detectable MTHFS activity in the reported product-formation assay.
Human MTHFS gene → Human methenyltetrahydrofolate synthetase / MTHFS source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_location
Results 3.3 and Figure 4.
experimental_model
Fibroblast lysate enzyme assay
exposure
Lysate enzyme assay versus control; Figure 4.
limitations
Assay-specific nondetection does not prove zero activity in every tissue or separate the two alleles.
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
These patient cells could not measurably perform the tested folate conversion.
primary_references
[rodan-2018] 5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination (2018). https://pubmed.ncbi.nlm.nih.gov/30031689/ DOI: 10.1016/j.ymgme.2018.06.006
tissue_or_cell_type
Patient 1 skin fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1268–1279
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Fibroblast lysate enzyme assay · source_derived_draft · unverified_draft
### mthfs-patient1-enzyme-activity Patient 1 fibroblast lysate had no detectable MTHFS activity in the reported product-formation assay. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: These patient cells could not measurably perform the tested folate conversion. organism: Homo sapiens tissue_or_cell_type: Patient 1 skin fibroblasts experimental_model: Fibroblast lysate enzyme assay limitations: Assay-specific nondetection does not prove zero activity in every tissue or separate the two alleles. exposure: Lysate enzyme assay versus control; Figure 4. evidence_location: Results 3.3 and Figure 4. [rodan-2018] 5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination (2018). https://pubmed.ncbi.nlm.nih.gov/30031689/ DOI: 10.1016/j.ymgme.2018.06.006
Complete structured claim and evidence
Patient 1 fibroblasts accumulated about 30-fold more 5-formyl-THF than control cells.
Human MTHFS gene → 5-Formyltetrahydrofolate source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_location
Results 3.4 and Figure 5.
experimental_model
Cellular folate mass spectrometry
exposure
Patient 1183-01 versus EC/BJ control fibroblasts; Figure 5.
limitations
Substrate accumulation does not establish that it causes the neurologic phenotype.
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 substrate built up in cells with impaired MTHFS.
primary_references
[rodan-2018] 5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination (2018). https://pubmed.ncbi.nlm.nih.gov/30031689/ DOI: 10.1016/j.ymgme.2018.06.006
tissue_or_cell_type
Patient 1 skin fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1281–1292
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cellular folate mass spectrometry · source_derived_draft · unverified_draft
### mthfs-patient1-folinic-accumulation Patient 1 fibroblasts accumulated about 30-fold more 5-formyl-THF than control cells. Condition category: machinery_impairment nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The substrate built up in cells with impaired MTHFS. organism: Homo sapiens tissue_or_cell_type: Patient 1 skin fibroblasts experimental_model: Cellular folate mass spectrometry limitations: Substrate accumulation does not establish that it causes the neurologic phenotype. exposure: Patient 1183-01 versus EC/BJ control fibroblasts; Figure 5. evidence_location: Results 3.4 and Figure 5. [rodan-2018] 5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination (2018). https://pubmed.ncbi.nlm.nih.gov/30031689/ DOI: 10.1016/j.ymgme.2018.06.006
Complete structured claim and evidence
The FT activity of rat FTCD transfers the FIGLU formimino group to THF, yielding 5-formimino-THF and glutamate.
Rat formiminotransferase cyclodeaminase / FTCD → N-Formimino-L-glutamate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Histidine degradation supplies a folate-bound carbon group.
evidence_location
Introduction reaction definition; Figure 1 and FT-domain structural analysis.
experimental_model
Recombinant protein structure and functional analysis
exposure
Recombinant rat FTCD; FT-domain structural analysis.
limitations
Rat enzyme; no human histidine-loading response is inferred.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Rattus norvegicus
plain_language
This step brings histidine-derived carbon into folate chemistry.
primary_references
[mao-2004] Structure of the bifunctional and Golgi-associated formiminotransferase cyclodeaminase octamer (2004). https://pubmed.ncbi.nlm.nih.gov/15272307/ DOI: 10.1038/sj.emboj.7600327
tissue_or_cell_type
Cell-free
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1294–1306
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant protein structure and functional analysis · source_derived_draft · unverified_draft
### rat-ftcd-formimino-transfer The FT activity of rat FTCD transfers the FIGLU formimino group to THF, yielding 5-formimino-THF and glutamate. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: This step brings histidine-derived carbon into folate chemistry. organism: Rattus norvegicus tissue_or_cell_type: Cell-free experimental_model: Recombinant protein structure and functional analysis limitations: Rat enzyme; no human histidine-loading response is inferred. exposure: Recombinant rat FTCD; FT-domain structural analysis. cross_nutrient: Histidine degradation supplies a folate-bound carbon group. evidence_location: Introduction reaction definition; Figure 1 and FT-domain structural analysis. [mao-2004] Structure of the bifunctional and Golgi-associated formiminotransferase cyclodeaminase octamer (2004). https://pubmed.ncbi.nlm.nih.gov/15272307/ DOI: 10.1038/sj.emboj.7600327
Complete structured claim and evidence
Rat FTCD cyclodeaminase converts 5-formimino-THF to 5,10-methenyl-THF with ammonia release.
Rat formiminotransferase cyclodeaminase / FTCD → 5-Formiminotetrahydrofolate source_derived_draftungraded
Experimental context and source evidence
evidence_location
Cyclodeaminase active-site results and enzyme assay methods.
experimental_model
Recombinant protein catalytic assay and mutagenesis
exposure
Recombinant rat FTCD and CD-site mutants.
limitations
Rat enzyme; human catalytic rates are not measured.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Rattus norvegicus
plain_language
A second enzyme domain converts the transferred group into methenyl-folate.
primary_references
[mao-2004] Structure of the bifunctional and Golgi-associated formiminotransferase cyclodeaminase octamer (2004). https://pubmed.ncbi.nlm.nih.gov/15272307/ DOI: 10.1038/sj.emboj.7600327
tissue_or_cell_type
Cell-free
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1308–1319
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant protein catalytic assay and mutagenesis · source_derived_draft · unverified_draft
### rat-ftcd-cyclodeamination Rat FTCD cyclodeaminase converts 5-formimino-THF to 5,10-methenyl-THF with ammonia release. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A second enzyme domain converts the transferred group into methenyl-folate. organism: Rattus norvegicus tissue_or_cell_type: Cell-free experimental_model: Recombinant protein catalytic assay and mutagenesis limitations: Rat enzyme; human catalytic rates are not measured. exposure: Recombinant rat FTCD and CD-site mutants. evidence_location: Cyclodeaminase active-site results and enzyme assay methods. [mao-2004] Structure of the bifunctional and Golgi-associated formiminotransferase cyclodeaminase octamer (2004). https://pubmed.ncbi.nlm.nih.gov/15272307/ DOI: 10.1038/sj.emboj.7600327
Complete structured claim and evidence
The NAD+-dependent rat MTHFD2L assay also requires phosphate in the presence of magnesium.
Inorganic phosphate (Pi; protonation depends on pH) → Rat mitochondrial MTHFD2L source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Direct magnesium/phosphate requirement in folate oxidation.
experimental_model
Cofactor omission/addition assays
exposure
Assay conditions described in the linked primary study.
limitations
No dietary magnesium threshold follows from these assays.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Rattus norvegicus
plain_language
Phosphate is another required partner in the NAD-linked reaction.
primary_references
[shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573
tissue_or_cell_type
Cell-free
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1321–1332
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cofactor omission/addition assays · source_derived_draft · unverified_draft
### rat-mthfd2l-phosphate-nad-requirement The NAD+-dependent rat MTHFD2L assay also requires phosphate in the presence of magnesium. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Phosphate is another required partner in the NAD-linked reaction. organism: Rattus norvegicus tissue_or_cell_type: Cell-free experimental_model: Cofactor omission/addition assays limitations: No dietary magnesium threshold follows from these assays. exposure: Assay conditions described in the linked primary study. cross_nutrient: Direct magnesium/phosphate requirement in folate oxidation. [shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573
Complete structured claim and evidence
Inorganic phosphate inhibits the NADP+-dependent dehydrogenase activity of rat MTHFD2L.
Inorganic phosphate (Pi; protonation depends on pH) → Rat mitochondrial MTHFD2L source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Direct magnesium/phosphate requirement in folate oxidation.
experimental_model
Cofactor omission/addition assays
exposure
Assay conditions described in the linked primary study.
limitations
No dietary magnesium threshold follows from these assays.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Rattus norvegicus
plain_language
The same phosphate has the opposite effect with the alternative electron carrier.
primary_references
[shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573
tissue_or_cell_type
Cell-free
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1334–1345
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cofactor omission/addition assays · source_derived_draft · unverified_draft
### rat-mthfd2l-phosphate-nadp-inhibition Inorganic phosphate inhibits the NADP+-dependent dehydrogenase activity of rat MTHFD2L. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same phosphate has the opposite effect with the alternative electron carrier. organism: Rattus norvegicus tissue_or_cell_type: Cell-free experimental_model: Cofactor omission/addition assays limitations: No dietary magnesium threshold follows from these assays. exposure: Assay conditions described in the linked primary study. cross_nutrient: Direct magnesium/phosphate requirement in folate oxidation. [shin-2014] Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014). https://pubmed.ncbi.nlm.nih.gov/24733394/ DOI: 10.1074/jbc.m114.555573
Complete structured claim and evidence
Nuclear folate levels resisted depletion despite more than 50% lower total cellular folate in folate-depleted mouse liver.
Folate (vitamin B9) → Nucleus source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Dietary depletion and liver fractionation
exposure
Assay conditions described in the linked primary study.
limitations
Nuclear protection is conditional; it does not prove indefinite resistance to deficiency.
nutrient_topic
Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)
organism
Mus musculus
plain_language
The nucleus retained folate even when whole-cell stores fell.
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
Liver
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1347–1357
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Dietary depletion and liver fractionation · source_derived_draft · unverified_draft
### mouse-folate-depletion-nuclear-retention Nuclear folate levels resisted depletion despite more than 50% lower total cellular folate in folate-depleted mouse liver. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The nucleus retained folate even when whole-cell stores fell. organism: Mus musculus tissue_or_cell_type: Liver experimental_model: Dietary depletion and liver fractionation limitations: Nuclear protection is conditional; it does not prove indefinite resistance to deficiency. exposure: Assay conditions described in the linked primary study. [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
The MRC trial recorded 6 NTD-affected pregnancies in folic-acid groups and 21 in groups without folic acid: relative risk 0.28 (95% CI 0.12–0.71).
Folic acid → Neural-tube defect incidence source_derived_draftungraded
Experimental context and source evidence
experimental_model
Randomized double-blind factorial trial at 33 centers in seven countries; 1817 women with a previous NTD-affected pregnancy, 1195 informative pregnancies.
exposure
Folic acid 4 mg/day, seven other vitamins, both or neither from randomization to 12 weeks of pregnancy. Historical trial exposure.
limitations
Not every NTD was prevented. Early stopping can inflate an effect estimate; the report also supplied an adjusted estimate. The trial did not isolate a cellular mechanism.
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
Adding folic acid before and early in pregnancy prevented many recurrences in this high-risk trial.
primary_references
[fol-mrc1991] Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group (1991). https://pubmed.ncbi.nlm.nih.gov/1677062/ DOI: 10.1016/0140-6736(91)90133-A
tissue_or_cell_type
Pregnancy and fetal developmental outcomes
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1359–1369
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized double-blind factorial trial at 33 centers in seven countries; 1817 women with a previous NTD-affected pregnancy, 1195 informative pregnancies. · source_derived_draft · unverified_draft
### fol-ntd-recurrence-randomized The MRC trial recorded 6 NTD-affected pregnancies in folic-acid groups and 21 in groups without folic acid: relative risk 0.28 (95% CI 0.12–0.71). Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding folic acid before and early in pregnancy prevented many recurrences in this high-risk trial. organism: Homo sapiens tissue_or_cell_type: Pregnancy and fetal developmental outcomes experimental_model: Randomized double-blind factorial trial at 33 centers in seven countries; 1817 women with a previous NTD-affected pregnancy, 1195 informative pregnancies. limitations: Not every NTD was prevented. Early stopping can inflate an effect estimate; the report also supplied an adjusted estimate. The trial did not isolate a cellular mechanism. exposure: Folic acid 4 mg/day, seven other vitamins, both or neither from randomization to 12 weeks of pregnancy. Historical trial exposure. [fol-mrc1991] Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group (1991). https://pubmed.ncbi.nlm.nih.gov/1677062/ DOI: 10.1016/0140-6736(91)90133-A
Complete structured claim and evidence
The Hungarian trial observed zero NTDs among 2104 known-outcome multivitamin pregnancies and six among 2052 trace-element pregnancies (P=0.029).
Folic acid → Neural-tube defect incidence source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Cointervention with multiple vitamins and minerals is retained explicitly.
experimental_model
Randomized Hungarian first-occurrence prevention trial; known outcomes in 2104 multivitamin and 2052 trace-element recipients.
exposure
Multivitamin including 0.8 mg folic acid versus trace elements with low vitamin C; at least one month before conception through second missed period or later.
limitations
The randomized comparison cannot assign its entire effect to folic acid alone or demonstrate equivalence of other folate formulations.
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 supplement containing folic acid reduced first occurrences, but it also contained other vitamins and minerals.
primary_references
[fol-czeizel1992] Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation (1992). https://pubmed.ncbi.nlm.nih.gov/1307234/ DOI: 10.1056/nejm199212243272602
tissue_or_cell_type
Pregnancy and fetal developmental outcomes
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1371–1382
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized Hungarian first-occurrence prevention trial; known outcomes in 2104 multivitamin and 2052 trace-element recipients. · source_derived_draft · unverified_draft
### fol-ntd-first-occurrence-multivitamin The Hungarian trial observed zero NTDs among 2104 known-outcome multivitamin pregnancies and six among 2052 trace-element pregnancies (P=0.029). Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The supplement containing folic acid reduced first occurrences, but it also contained other vitamins and minerals. organism: Homo sapiens tissue_or_cell_type: Pregnancy and fetal developmental outcomes experimental_model: Randomized Hungarian first-occurrence prevention trial; known outcomes in 2104 multivitamin and 2052 trace-element recipients. limitations: The randomized comparison cannot assign its entire effect to folic acid alone or demonstrate equivalence of other folate formulations. exposure: Multivitamin including 0.8 mg folic acid versus trace elements with low vitamin C; at least one month before conception through second missed period or later. cross_nutrient: Cointervention with multiple vitamins and minerals is retained explicitly. [fol-czeizel1992] Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation (1992). https://pubmed.ncbi.nlm.nih.gov/1307234/ DOI: 10.1056/nejm199212243272602
Complete structured claim and evidence
Among women registered before the last menstrual period, NTD rates with periconceptional folic acid use versus no use were 1.0 versus 4.8 per 1000 in northern China and 0.6 versus 1.0 per 1000 in southern China; denominators were pregnancies of at least 20 weeks gestation.
Folic acid → Neural-tube defect incidence source_derived_draftungraded
Experimental context and source evidence
experimental_model
Prospective nonrandomized community intervention in northern and southern China, 1993–1995.
exposure
400 micrograms/day folic acid alone from premarital examination through first trimester; actual use and adherence recorded.
limitations
Nonrandomized adherence and use can be confounded. Regional effect sizes do not define a universal biological response.
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 observed benefit appeared in regions with different starting risks.
primary_references
[fol-berry1999] Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention (1999). https://pubmed.ncbi.nlm.nih.gov/10559448/ DOI: 10.1056/nejm199911113412001
tissue_or_cell_type
Community pregnancy outcomes
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1384–1394
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Prospective nonrandomized community intervention in northern and southern China, 1993–1995. · source_derived_draft · unverified_draft
### fol-china-periconception-ntd Among women registered before the last menstrual period, NTD rates with periconceptional folic acid use versus no use were 1.0 versus 4.8 per 1000 in northern China and 0.6 versus 1.0 per 1000 in southern China; denominators were pregnancies of at least 20 weeks gestation. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The observed benefit appeared in regions with different starting risks. organism: Homo sapiens tissue_or_cell_type: Community pregnancy outcomes experimental_model: Prospective nonrandomized community intervention in northern and southern China, 1993–1995. limitations: Nonrandomized adherence and use can be confounded. Regional effect sizes do not define a universal biological response. exposure: 400 micrograms/day folic acid alone from premarital examination through first trimester; actual use and adherence recorded. [fol-berry1999] Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention (1999). https://pubmed.ncbi.nlm.nih.gov/10559448/ DOI: 10.1056/nejm199911113412001
Complete structured claim and evidence
The Bayesian model estimated 25.4 NTDs per 10000 births at RBC folate 500 nmol/L, with risk substantially lower above approximately 1000 nmol/L; this was an estimated population relation.
Erythrocyte folate concentration → Neural-tube defect incidence source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
experimental_model
Bayesian model combining the Chinese prevention cohort (247831 participants) and a separate blood-response trial (1194 women).
exposure
Estimated RBC folate at neural-tube closure; modeled population risk, not a prospective test of an individual threshold.
limitations
Estimated concentration at neural-tube closure, assay context and model assumptions matter. Reuses the Chinese intervention cohort; not an independent prevention trial.
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
Red-cell folate helped model population risk; it was not a pass/fail test for an individual pregnancy.
primary_references
[fol-crider2014] Population red blood cell folate concentrations for prevention of neural tube defects: Bayesian model (2014). https://pubmed.ncbi.nlm.nih.gov/25073783/ DOI: 10.1136/bmj.g4554
tissue_or_cell_type
Human blood or whole-person clinical endpoints
trigger_kind
biomarker_context Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1396–1406
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bayesian model combining the Chinese prevention cohort (247831 participants) and a separate blood-response trial (1194 women). · source_derived_draft · unverified_draft
### fol-rbc-population-risk-model The Bayesian model estimated 25.4 NTDs per 10000 births at RBC folate 500 nmol/L, with risk substantially lower above approximately 1000 nmol/L; this was an estimated population relation. Condition category: biomarker_context nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Red-cell folate helped model population risk; it was not a pass/fail test for an individual pregnancy. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Bayesian model combining the Chinese prevention cohort (247831 participants) and a separate blood-response trial (1194 women). limitations: Estimated concentration at neural-tube closure, assay context and model assumptions matter. Reuses the Chinese intervention cohort; not an independent prevention trial. exposure: Estimated RBC folate at neural-tube closure; modeled population risk, not a prospective test of an individual threshold. [fol-crider2014] Population red blood cell folate concentrations for prevention of neural tube defects: Bayesian model (2014). https://pubmed.ncbi.nlm.nih.gov/25073783/ DOI: 10.1136/bmj.g4554
Complete structured claim and evidence
Controlled depletion lowered plasma folate and significantly raised plasma homocysteine in eight postmenopausal women.
Folate (vitamin B9) → Homocysteine source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
Folate and B12 meet at methionine synthase; this experiment manipulated folate intake.
experimental_model
Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion.
exposure
Five weeks 56 micrograms/day folate, four weeks 111, then three weeks 286–516 using folic acid added to a low-folate diet.
limitations
A concentration is not direct enzyme flux; B12 status, kidney function and other inputs also affect this marker.
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 shortage made a connected methionine-recycling marker rise.
primary_references
[fol-jacob1998] Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women (1998). https://pubmed.ncbi.nlm.nih.gov/9649607/ DOI: 10.1093/jn/128.7.1204
tissue_or_cell_type
Human blood or whole-person clinical endpoints
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1408–1419
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion. · source_derived_draft · unverified_draft
### fol-depletion-homocysteine Controlled depletion lowered plasma folate and significantly raised plasma homocysteine in eight postmenopausal women. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A shortage made a connected methionine-recycling marker rise. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion. limitations: A concentration is not direct enzyme flux; B12 status, kidney function and other inputs also affect this marker. exposure: Five weeks 56 micrograms/day folate, four weeks 111, then three weeks 286–516 using folic acid added to a low-folate diet. cross_nutrient: Folate and B12 meet at methionine synthase; this experiment manipulated folate intake. [fol-jacob1998] Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women (1998). https://pubmed.ncbi.nlm.nih.gov/9649607/ DOI: 10.1093/jn/128.7.1204
Complete structured claim and evidence
Lymphocyte DNA hypomethylation developed during the depletion periods and reversed during folate repletion of 286–516 micrograms/day.
Folate (vitamin B9) → Lymphocyte genomic DNA methylation source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion.
exposure
Five weeks 56 micrograms/day folate, four weeks 111, then three weeks 286–516 using folic acid added to a low-folate diet.
limitations
No specific oncogene activation, tumor formation or whole-body methylation failure was measured.
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 methylation readout changed with folate intake in these blood cells.
primary_references
[fol-jacob1998] Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women (1998). https://pubmed.ncbi.nlm.nih.gov/9649607/ DOI: 10.1093/jn/128.7.1204
tissue_or_cell_type
Human lymphocytes
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1421–1431
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion. · source_derived_draft · unverified_draft
### fol-depletion-lymphocyte-methylation Lymphocyte DNA hypomethylation developed during the depletion periods and reversed during folate repletion of 286–516 micrograms/day. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The methylation readout changed with folate intake in these blood cells. organism: Homo sapiens tissue_or_cell_type: Human lymphocytes experimental_model: Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion. limitations: No specific oncogene activation, tumor formation or whole-body methylation failure was measured. exposure: Five weeks 56 micrograms/day folate, four weeks 111, then three weeks 286–516 using folic acid added to a low-folate diet. [fol-jacob1998] Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women (1998). https://pubmed.ncbi.nlm.nih.gov/9649607/ DOI: 10.1093/jn/128.7.1204
Complete structured claim and evidence
During repletion, elevated homocysteine decreased with total folate intake 516 but not 286 micrograms/day, while the DNA methylation readout improved across 286–516 micrograms/day.
Folic acid → Homocysteine source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion.
exposure
Five weeks 56 micrograms/day folate, four weeks 111, then three weeks 286–516 using folic acid added to a low-folate diet.
limitations
Historical experimental intakes in eight participants do not establish a universal requirement or treatment regimen.
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
Different folate-related measurements did not recover identically.
primary_references
[fol-jacob1998] Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women (1998). https://pubmed.ncbi.nlm.nih.gov/9649607/ DOI: 10.1093/jn/128.7.1204
tissue_or_cell_type
Human blood or whole-person clinical endpoints
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1433–1443
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion. · source_derived_draft · unverified_draft
### fol-repletion-endpoint-difference During repletion, elevated homocysteine decreased with total folate intake 516 but not 286 micrograms/day, while the DNA methylation readout improved across 286–516 micrograms/day. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Different folate-related measurements did not recover identically. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion. limitations: Historical experimental intakes in eight participants do not establish a universal requirement or treatment regimen. exposure: Five weeks 56 micrograms/day folate, four weeks 111, then three weeks 286–516 using folic acid added to a low-folate diet. [fol-jacob1998] Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women (1998). https://pubmed.ncbi.nlm.nih.gov/9649607/ DOI: 10.1093/jn/128.7.1204
Complete structured claim and evidence
In vitro incorporation of labeled SAM methyl groups into extracted leukocyte DNA increased after depletion (P=0.0025), consistent with lower pre-existing methylation.
Folate (vitamin B9) → Leukocyte DNA methyl-acceptance assay source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Thirty-three women aged 60–85 in depletion, thirty in four repletion groups.
exposure
Seven weeks 118 micrograms/day folate, followed by seven weeks 200 or 415 micrograms/day with different food/supplement combinations.
limitations
The assay interpretation is distinct from measuring intracellular SAM or methylation at specific genes.
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 assay found more available sites for adding methyl groups to the extracted DNA.
primary_references
[fol-rampersaud2000] Genomic DNA methylation decreases in response to moderate folate depletion in elderly women (2000). https://pubmed.ncbi.nlm.nih.gov/11010943/ DOI: 10.1093/ajcn/72.4.998
tissue_or_cell_type
Human leukocyte DNA, ex-vivo assay
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1445–1455
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Thirty-three women aged 60–85 in depletion, thirty in four repletion groups. · source_derived_draft · unverified_draft
### fol-elderly-dna-methyl-acceptance In vitro incorporation of labeled SAM methyl groups into extracted leukocyte DNA increased after depletion (P=0.0025), consistent with lower pre-existing methylation. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The assay found more available sites for adding methyl groups to the extracted DNA. organism: Homo sapiens tissue_or_cell_type: Human leukocyte DNA, ex-vivo assay experimental_model: Thirty-three women aged 60–85 in depletion, thirty in four repletion groups. limitations: The assay interpretation is distinct from measuring intracellular SAM or methylation at specific genes. exposure: Seven weeks 118 micrograms/day folate, followed by seven weeks 200 or 415 micrograms/day with different food/supplement combinations. [fol-rampersaud2000] Genomic DNA methylation decreases in response to moderate folate depletion in elderly women (2000). https://pubmed.ncbi.nlm.nih.gov/11010943/ DOI: 10.1093/ajcn/72.4.998
Complete structured claim and evidence
No repletion group showed a significant change from postdepletion methyl-acceptance values over seven weeks.
Folate (vitamin B9) → Leukocyte DNA methyl-acceptance assay source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Thirty-three women aged 60–85 in depletion, thirty in four repletion groups.
exposure
Seven weeks 118 micrograms/day folate, followed by seven weeks 200 or 415 micrograms/day with different food/supplement combinations.
limitations
Different age, intake and assay design from the eight-woman study; no claim of an unexplained scientific contradiction.
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
Returning folate did not quickly normalize this particular readout.
primary_references
[fol-rampersaud2000] Genomic DNA methylation decreases in response to moderate folate depletion in elderly women (2000). https://pubmed.ncbi.nlm.nih.gov/11010943/ DOI: 10.1093/ajcn/72.4.998
tissue_or_cell_type
Human leukocyte DNA, ex-vivo assay
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1457–1467
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Thirty-three women aged 60–85 in depletion, thirty in four repletion groups. · source_derived_draft · unverified_draft
### fol-elderly-methylation-repletion-null No repletion group showed a significant change from postdepletion methyl-acceptance values over seven weeks. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Returning folate did not quickly normalize this particular readout. organism: Homo sapiens tissue_or_cell_type: Human leukocyte DNA, ex-vivo assay experimental_model: Thirty-three women aged 60–85 in depletion, thirty in four repletion groups. limitations: Different age, intake and assay design from the eight-woman study; no claim of an unexplained scientific contradiction. exposure: Seven weeks 118 micrograms/day folate, followed by seven weeks 200 or 415 micrograms/day with different food/supplement combinations. [fol-rampersaud2000] Genomic DNA methylation decreases in response to moderate folate depletion in elderly women (2000). https://pubmed.ncbi.nlm.nih.gov/11010943/ DOI: 10.1093/ajcn/72.4.998
Complete structured claim and evidence
Folate-deficient participants had roughly eightfold higher measured blood DNA uracil than controls in the 1997 study.
Folate (vitamin B9) → Uracil content of blood-cell DNA source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Selected splenectomized human volunteers: 22 at baseline, 19 supplementation completers; additional blood/marrow samples and Crohn case analyzed separately.
exposure
Folic acid 5 mg/day for eight weeks; blood DNA uracil and erythrocyte/reticulocyte micronuclei.
limitations
Enriched selection by micronucleus frequency and older assay methodology limit extrapolation. The full repair-to-break sequence was a mechanistic interpretation.
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
Insufficient folate was associated with more of an inappropriate DNA base in the measured samples.
primary_references
[fol-blount1997] Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage (1997). https://pubmed.ncbi.nlm.nih.gov/9096386/ DOI: 10.1073/pnas.94.7.3290
tissue_or_cell_type
Human blood-cell DNA
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1469–1479
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Selected splenectomized human volunteers: 22 at baseline, 19 supplementation completers; additional blood/marrow samples and Crohn case analyzed separately. · source_derived_draft · unverified_draft
### fol-low-status-blood-dna-uracil Folate-deficient participants had roughly eightfold higher measured blood DNA uracil than controls in the 1997 study. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Insufficient folate was associated with more of an inappropriate DNA base in the measured samples. organism: Homo sapiens tissue_or_cell_type: Human blood-cell DNA experimental_model: Selected splenectomized human volunteers: 22 at baseline, 19 supplementation completers; additional blood/marrow samples and Crohn case analyzed separately. limitations: Enriched selection by micronucleus frequency and older assay methodology limit extrapolation. The full repair-to-break sequence was a mechanistic interpretation. exposure: Folic acid 5 mg/day for eight weeks; blood DNA uracil and erythrocyte/reticulocyte micronuclei. [fol-blount1997] Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage (1997). https://pubmed.ncbi.nlm.nih.gov/9096386/ DOI: 10.1073/pnas.94.7.3290
Complete structured claim and evidence
Blood DNA uracil declined after folic-acid supplementation in study completers, including the initially low-folate subgroup.
Folic acid → Uracil content of blood-cell DNA source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Selected splenectomized human volunteers: 22 at baseline, 19 supplementation completers; additional blood/marrow samples and Crohn case analyzed separately.
exposure
Folic acid 5 mg/day for eight weeks; blood DNA uracil and erythrocyte/reticulocyte micronuclei.
limitations
Before/after study with small subgroups and attrition; not a randomized cancer outcome trial.
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
Restoring folate was followed by improvement in the DNA-base readout.
primary_references
[fol-blount1997] Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage (1997). https://pubmed.ncbi.nlm.nih.gov/9096386/ DOI: 10.1073/pnas.94.7.3290
tissue_or_cell_type
Human blood-cell DNA
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1481–1491
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Selected splenectomized human volunteers: 22 at baseline, 19 supplementation completers; additional blood/marrow samples and Crohn case analyzed separately. · source_derived_draft · unverified_draft
### fol-uracil-repletion-response Blood DNA uracil declined after folic-acid supplementation in study completers, including the initially low-folate subgroup. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Restoring folate was followed by improvement in the DNA-base readout. organism: Homo sapiens tissue_or_cell_type: Human blood-cell DNA experimental_model: Selected splenectomized human volunteers: 22 at baseline, 19 supplementation completers; additional blood/marrow samples and Crohn case analyzed separately. limitations: Before/after study with small subgroups and attrition; not a randomized cancer outcome trial. exposure: Folic acid 5 mg/day for eight weeks; blood DNA uracil and erythrocyte/reticulocyte micronuclei. [fol-blount1997] Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage (1997). https://pubmed.ncbi.nlm.nih.gov/9096386/ DOI: 10.1073/pnas.94.7.3290
Complete structured claim and evidence
Elevated micronucleus frequencies associated with low folate were reduced following supplementation.
Folic acid → Erythrocyte micronucleus frequency source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Selected splenectomized human volunteers: 22 at baseline, 19 supplementation completers; additional blood/marrow samples and Crohn case analyzed separately.
exposure
Folic acid 5 mg/day for eight weeks; blood DNA uracil and erythrocyte/reticulocyte micronuclei.
limitations
Micronuclei in circulating erythrocytes are strongly affected by splenic clearance; do not apply this assay relation unchanged to everyone.
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 separate marker of chromosome damage also improved.
primary_references
[fol-blount1997] Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage (1997). https://pubmed.ncbi.nlm.nih.gov/9096386/ DOI: 10.1073/pnas.94.7.3290
tissue_or_cell_type
Human erythrocytes and reticulocytes
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1493–1503
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Selected splenectomized human volunteers: 22 at baseline, 19 supplementation completers; additional blood/marrow samples and Crohn case analyzed separately. · source_derived_draft · unverified_draft
### fol-micronuclei-repletion-response Elevated micronucleus frequencies associated with low folate were reduced following supplementation. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A separate marker of chromosome damage also improved. organism: Homo sapiens tissue_or_cell_type: Human erythrocytes and reticulocytes experimental_model: Selected splenectomized human volunteers: 22 at baseline, 19 supplementation completers; additional blood/marrow samples and Crohn case analyzed separately. limitations: Micronuclei in circulating erythrocytes are strongly affected by splenic clearance; do not apply this assay relation unchanged to everyone. exposure: Folic acid 5 mg/day for eight weeks; blood DNA uracil and erythrocyte/reticulocyte micronuclei. [fol-blount1997] Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage (1997). https://pubmed.ncbi.nlm.nih.gov/9096386/ DOI: 10.1073/pnas.94.7.3290
Complete structured claim and evidence
In the single-subject study, serum folate became abnormally low by day 219; RBC folate abnormality was reported at day 413 in the abstract/discussion and day 420 in the Results.
Folate (vitamin B9) → Erythrocyte folate concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Single initially folate-replete 58-year-old male self-experiment with serial blood assays and marrow examinations.
exposure
Prolonged severe folate restriction, major energy restriction/weight loss, and multiple other nutrient supplements; replete diet plus folic acid during recovery.
limitations
Assay-dependent observations in a highly supplemented, initially replete individual with severe weight loss; these timings are not typical-person predictions. The paper gives inconsistent day counts for the RBC laboratory-limit crossing; both locations are retained.
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
Different blood compartments showed the shortage at different times.
primary_references
[fol-golding2014] Severe experimental folate deficiency in a human subject - a longitudinal study of biochemical and haematological responses as megaloblastic anaemia develops (2014). https://pubmed.ncbi.nlm.nih.gov/25332850/ DOI: 10.1186/2193-1801-3-442
tissue_or_cell_type
Human blood or whole-person clinical endpoints
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1505–1515
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Single initially folate-replete 58-year-old male self-experiment with serial blood assays and marrow examinations. · source_derived_draft · unverified_draft
### fol-severe-marker-sequence In the single-subject study, serum folate became abnormally low by day 219; RBC folate abnormality was reported at day 413 in the abstract/discussion and day 420 in the Results. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Different blood compartments showed the shortage at different times. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Single initially folate-replete 58-year-old male self-experiment with serial blood assays and marrow examinations. limitations: Assay-dependent observations in a highly supplemented, initially replete individual with severe weight loss; these timings are not typical-person predictions. The paper gives inconsistent day counts for the RBC laboratory-limit crossing; both locations are retained. exposure: Prolonged severe folate restriction, major energy restriction/weight loss, and multiple other nutrient supplements; replete diet plus folic acid during recovery. [fol-golding2014] Severe experimental folate deficiency in a human subject - a longitudinal study of biochemical and haematological responses as megaloblastic anaemia develops (2014). https://pubmed.ncbi.nlm.nih.gov/25332850/ DOI: 10.1186/2193-1801-3-442
Complete structured claim and evidence
Macrocytic anemia was documented after 469 days of restriction in the self-experiment.
Folate (vitamin B9) → Macrocytic anemia source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Single initially folate-replete 58-year-old male self-experiment with serial blood assays and marrow examinations.
exposure
Prolonged severe folate restriction, major energy restriction/weight loss, and multiple other nutrient supplements; replete diet plus folic acid during recovery.
limitations
One subject, calorie restriction and multiple co-supplements; cannot calculate a population time-to-anemia distribution.
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 red-cell disorder appeared after the blood folate changes.
primary_references
[fol-golding2014] Severe experimental folate deficiency in a human subject - a longitudinal study of biochemical and haematological responses as megaloblastic anaemia develops (2014). https://pubmed.ncbi.nlm.nih.gov/25332850/ DOI: 10.1186/2193-1801-3-442
tissue_or_cell_type
Human blood or whole-person clinical endpoints
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1517–1527
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Single initially folate-replete 58-year-old male self-experiment with serial blood assays and marrow examinations. · source_derived_draft · unverified_draft
### fol-severe-macrocytic-anemia Macrocytic anemia was documented after 469 days of restriction in the self-experiment. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The red-cell disorder appeared after the blood folate changes. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Single initially folate-replete 58-year-old male self-experiment with serial blood assays and marrow examinations. limitations: One subject, calorie restriction and multiple co-supplements; cannot calculate a population time-to-anemia distribution. exposure: Prolonged severe folate restriction, major energy restriction/weight loss, and multiple other nutrient supplements; replete diet plus folic acid during recovery. [fol-golding2014] Severe experimental folate deficiency in a human subject - a longitudinal study of biochemical and haematological responses as megaloblastic anaemia develops (2014). https://pubmed.ncbi.nlm.nih.gov/25332850/ DOI: 10.1186/2193-1801-3-442
Complete structured claim and evidence
Marrow examination at day 575 confirmed megaloblastic anemia; blood counts recovered during the subsequent replete-diet/supplement phase.
Folate (vitamin B9) → Megaloblastic anemia source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Single initially folate-replete 58-year-old male self-experiment with serial blood assays and marrow examinations.
exposure
Prolonged severe folate restriction, major energy restriction/weight loss, and multiple other nutrient supplements; replete diet plus folic acid during recovery.
limitations
Major energy restriction and weight loss confound isolated nutrient attribution. Other nutrients were supplemented; neither liver folate content nor a unique recovery dose was directly established.
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 shortage eventually coincided with abnormal marrow-cell maturation and reversible blood-count changes.
primary_references
[fol-golding2014] Severe experimental folate deficiency in a human subject - a longitudinal study of biochemical and haematological responses as megaloblastic anaemia develops (2014). https://pubmed.ncbi.nlm.nih.gov/25332850/ DOI: 10.1186/2193-1801-3-442
tissue_or_cell_type
Human bone marrow and peripheral blood
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1529–1539
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Single initially folate-replete 58-year-old male self-experiment with serial blood assays and marrow examinations. · source_derived_draft · unverified_draft
### fol-severe-marrow-megaloblastosis Marrow examination at day 575 confirmed megaloblastic anemia; blood counts recovered during the subsequent replete-diet/supplement phase. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The shortage eventually coincided with abnormal marrow-cell maturation and reversible blood-count changes. organism: Homo sapiens tissue_or_cell_type: Human bone marrow and peripheral blood experimental_model: Single initially folate-replete 58-year-old male self-experiment with serial blood assays and marrow examinations. limitations: Major energy restriction and weight loss confound isolated nutrient attribution. Other nutrients were supplemented; neither liver folate content nor a unique recovery dose was directly established. exposure: Prolonged severe folate restriction, major energy restriction/weight loss, and multiple other nutrient supplements; replete diet plus folic acid during recovery. [fol-golding2014] Severe experimental folate deficiency in a human subject - a longitudinal study of biochemical and haematological responses as megaloblastic anaemia develops (2014). https://pubmed.ncbi.nlm.nih.gov/25332850/ DOI: 10.1186/2193-1801-3-442
Complete structured claim and evidence
Within the low-B12 group, serum folate above 59 nmol/L was associated with higher anemia odds than lower folate (OR 3.1; 95% CI 1.5–6.6).
Serum folate concentration → Anemia source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
cross_nutrient
B12 status modifies interpretation of a folate measurement.
experimental_model
Cross-sectional NHANES 1999–2002 sample of 1459 older adults with normal creatinine and specified clinical exclusions. Anemia analysis n=1458.
exposure
Measured serum folate and B12/MMA; low B12 defined as serum B12 <148 pmol/L or MMA >210 nmol/L; high folate >59 nmol/L.
limitations
Cross-sectional confounding and reverse causation remain possible. Total serum folate does not identify unmetabolized folic acid or supplement dose.
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 high folate blood value did not cancel the anemia association in people with low B12.
primary_references
[fol-morris2007] Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification (2007). https://pubmed.ncbi.nlm.nih.gov/17209196/ DOI: 10.1093/ajcn/85.1.193
tissue_or_cell_type
Human blood or whole-person clinical endpoints
trigger_kind
biomarker_context Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1541–1552
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cross-sectional NHANES 1999–2002 sample of 1459 older adults with normal creatinine and specified clinical exclusions. Anemia analysis n=1458. · source_derived_draft · unverified_draft
### fol-b12-low-high-folate-anemia Within the low-B12 group, serum folate above 59 nmol/L was associated with higher anemia odds than lower folate (OR 3.1; 95% CI 1.5–6.6). Condition category: biomarker_context nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A high folate blood value did not cancel the anemia association in people with low B12. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Cross-sectional NHANES 1999–2002 sample of 1459 older adults with normal creatinine and specified clinical exclusions. Anemia analysis n=1458. limitations: Cross-sectional confounding and reverse causation remain possible. Total serum folate does not identify unmetabolized folic acid or supplement dose. exposure: Measured serum folate and B12/MMA; low B12 defined as serum B12 <148 pmol/L or MMA >210 nmol/L; high folate >59 nmol/L. cross_nutrient: B12 status modifies interpretation of a folate measurement. [fol-morris2007] Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification (2007). https://pubmed.ncbi.nlm.nih.gov/17209196/ DOI: 10.1093/ajcn/85.1.193
Complete structured claim and evidence
High folate within low B12 status was associated with greater odds of cognitive impairment defined by Digit Symbol-Coding score below 34 (OR 2.6; 95% CI 1.1–6.1).
Serum folate concentration → Digit Symbol-Coding performance source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
cross_nutrient
Does not prove folic acid worsens neurologic injury or that methylfolate resolves B12 deficiency.
experimental_model
Cross-sectional NHANES 1999–2002 sample of 1459 older adults with normal creatinine and specified clinical exclusions. Cognitive analysis n=1302.
exposure
Measured serum folate and B12/MMA; low B12 defined as serum B12 <148 pmol/L or MMA >210 nmol/L; high folate >59 nmol/L.
limitations
An association in one test is not causal dementia evidence. In B12-normal participants, high folate was associated with lower impairment odds.
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 observed folate–cognition relationship depended on B12 status.
primary_references
[fol-morris2007] Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification (2007). https://pubmed.ncbi.nlm.nih.gov/17209196/ DOI: 10.1093/ajcn/85.1.193
tissue_or_cell_type
Human blood or whole-person clinical endpoints
trigger_kind
biomarker_context Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1554–1565
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cross-sectional NHANES 1999–2002 sample of 1459 older adults with normal creatinine and specified clinical exclusions. Cognitive analysis n=1302. · source_derived_draft · unverified_draft
### fol-b12-low-high-folate-cognition High folate within low B12 status was associated with greater odds of cognitive impairment defined by Digit Symbol-Coding score below 34 (OR 2.6; 95% CI 1.1–6.1). Condition category: biomarker_context nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The observed folate–cognition relationship depended on B12 status. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Cross-sectional NHANES 1999–2002 sample of 1459 older adults with normal creatinine and specified clinical exclusions. Cognitive analysis n=1302. limitations: An association in one test is not causal dementia evidence. In B12-normal participants, high folate was associated with lower impairment odds. exposure: Measured serum folate and B12/MMA; low B12 defined as serum B12 <148 pmol/L or MMA >210 nmol/L; high folate >59 nmol/L. cross_nutrient: Does not prove folic acid worsens neurologic injury or that methylfolate resolves B12 deficiency. [fol-morris2007] Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification (2007). https://pubmed.ncbi.nlm.nih.gov/17209196/ DOI: 10.1093/ajcn/85.1.193
Complete structured claim and evidence
In low-serum-B12 strata, circulating total homocysteine increased as folate increased above approximately 20 nmol/L; the relationship ran oppositely in B12-replete strata.
Serum folate concentration → Homocysteine source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
cross_nutrient
The measured interaction concerns B12 status and total folate, not all folate formulations equally.
experimental_model
Cross-sectional adult NHANES III 1991–1994 (4940) and NHANES 1999–2002 (5473) analyses, exclusions for several confounders.
exposure
Measured serum folate, B12, total homocysteine and MMA; stratification at serum B12 148 pmol/L; no randomized folate exposure.
limitations
No direct enzyme-flux measurement or causal proof of folate toxicity. Survey subsets and B12 definitions differ from the older-adult cognition analysis.
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
More circulating folate did not guarantee a better B12-related marker.
primary_references
[fol-selhub2007] In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations (2007). https://pubmed.ncbi.nlm.nih.gov/18056804/ DOI: 10.1073/pnas.0709487104
tissue_or_cell_type
Human blood or whole-person clinical endpoints
trigger_kind
biomarker_context Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1567–1578
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cross-sectional adult NHANES III 1991–1994 (4940) and NHANES 1999–2002 (5473) analyses, exclusions for several confounders. · source_derived_draft · unverified_draft
### fol-b12-interaction-homocysteine In low-serum-B12 strata, circulating total homocysteine increased as folate increased above approximately 20 nmol/L; the relationship ran oppositely in B12-replete strata. Condition category: biomarker_context nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: More circulating folate did not guarantee a better B12-related marker. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Cross-sectional adult NHANES III 1991–1994 (4940) and NHANES 1999–2002 (5473) analyses, exclusions for several confounders. limitations: No direct enzyme-flux measurement or causal proof of folate toxicity. Survey subsets and B12 definitions differ from the older-adult cognition analysis. exposure: Measured serum folate, B12, total homocysteine and MMA; stratification at serum B12 148 pmol/L; no randomized folate exposure. cross_nutrient: The measured interaction concerns B12 status and total folate, not all folate formulations equally. [fol-selhub2007] In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations (2007). https://pubmed.ncbi.nlm.nih.gov/18056804/ DOI: 10.1073/pnas.0709487104
Complete structured claim and evidence
In low-serum-B12 strata, circulating methylmalonic acid increased as folate increased above approximately 20 nmol/L; the relationship ran oppositely in B12-replete strata.
Serum folate concentration → Methylmalonic acid source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
cross_nutrient
The measured interaction concerns B12 status and total folate, not all folate formulations equally.
experimental_model
Cross-sectional adult NHANES III 1991–1994 (4940) and NHANES 1999–2002 (5473) analyses, exclusions for several confounders.
exposure
Measured serum folate, B12, total homocysteine and MMA; stratification at serum B12 148 pmol/L; no randomized folate exposure.
limitations
No direct enzyme-flux measurement or causal proof of folate toxicity. Survey subsets and B12 definitions differ from the older-adult cognition analysis.
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
More circulating folate did not guarantee a better B12-related marker.
primary_references
[fol-selhub2007] In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations (2007). https://pubmed.ncbi.nlm.nih.gov/18056804/ DOI: 10.1073/pnas.0709487104
tissue_or_cell_type
Human blood or whole-person clinical endpoints
trigger_kind
biomarker_context Imported condition classification; unverified.
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1580–1591
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cross-sectional adult NHANES III 1991–1994 (4940) and NHANES 1999–2002 (5473) analyses, exclusions for several confounders. · source_derived_draft · unverified_draft
### fol-b12-interaction-mma In low-serum-B12 strata, circulating methylmalonic acid increased as folate increased above approximately 20 nmol/L; the relationship ran oppositely in B12-replete strata. Condition category: biomarker_context nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: More circulating folate did not guarantee a better B12-related marker. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Cross-sectional adult NHANES III 1991–1994 (4940) and NHANES 1999–2002 (5473) analyses, exclusions for several confounders. limitations: No direct enzyme-flux measurement or causal proof of folate toxicity. Survey subsets and B12 definitions differ from the older-adult cognition analysis. exposure: Measured serum folate, B12, total homocysteine and MMA; stratification at serum B12 148 pmol/L; no randomized folate exposure. cross_nutrient: The measured interaction concerns B12 status and total folate, not all folate formulations equally. [fol-selhub2007] In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations (2007). https://pubmed.ncbi.nlm.nih.gov/18056804/ DOI: 10.1073/pnas.0709487104
Complete structured claim and evidence
First stroke occurred in 2.7% with enalapril–folic acid versus 3.4% with enalapril alone (HR 0.79; 95% CI 0.68–0.93).
Folic acid → Stroke incidence source_derived_draftungraded
Experimental context and source evidence
experimental_model
Double-blind randomized CSPPT: 20702 Chinese adults with hypertension and no previous stroke or myocardial infarction, stratified by MTHFR C677T genotype.
exposure
Enalapril 10 mg plus folic acid 0.8 mg/day versus enalapril alone; median 4.5 years.
limitations
Not a trial in all populations or secondary prevention; no proof of a single homocysteine-mediated mechanism.
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
Adding folic acid improved the first-stroke endpoint in this particular hypertensive population.
primary_references
[fol-csppt2015] Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial (2015). https://pubmed.ncbi.nlm.nih.gov/25771069/ DOI: 10.1001/jama.2015.2274
tissue_or_cell_type
Human blood or whole-person clinical endpoints
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1593–1603
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized CSPPT: 20702 Chinese adults with hypertension and no previous stroke or myocardial infarction, stratified by MTHFR C677T genotype. · source_derived_draft · unverified_draft
### fol-csppt-first-stroke First stroke occurred in 2.7% with enalapril–folic acid versus 3.4% with enalapril alone (HR 0.79; 95% CI 0.68–0.93). Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding folic acid improved the first-stroke endpoint in this particular hypertensive population. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Double-blind randomized CSPPT: 20702 Chinese adults with hypertension and no previous stroke or myocardial infarction, stratified by MTHFR C677T genotype. limitations: Not a trial in all populations or secondary prevention; no proof of a single homocysteine-mediated mechanism. exposure: Enalapril 10 mg plus folic acid 0.8 mg/day versus enalapril alone; median 4.5 years. [fol-csppt2015] Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial (2015). https://pubmed.ncbi.nlm.nih.gov/25771069/ DOI: 10.1001/jama.2015.2274
Complete structured claim and evidence
First ischemic stroke was lower with combined treatment (HR 0.76; 95% CI 0.64–0.91); hemorrhagic stroke, MI and all-cause death did not differ significantly.
Folic acid → Ischemic stroke incidence source_derived_draftungraded
Experimental context and source evidence
experimental_model
Double-blind randomized CSPPT: 20702 Chinese adults with hypertension and no previous stroke or myocardial infarction, stratified by MTHFR C677T genotype.
exposure
Enalapril 10 mg plus folic acid 0.8 mg/day versus enalapril alone; median 4.5 years.
limitations
Secondary endpoints, event frequency and confidence intervals matter; null results do not prove identical risks.
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 benefit was endpoint-specific, rather than a uniform reduction in every vascular event.
primary_references
[fol-csppt2015] Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial (2015). https://pubmed.ncbi.nlm.nih.gov/25771069/ DOI: 10.1001/jama.2015.2274
tissue_or_cell_type
Human blood or whole-person clinical endpoints
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1605–1615
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized CSPPT: 20702 Chinese adults with hypertension and no previous stroke or myocardial infarction, stratified by MTHFR C677T genotype. · source_derived_draft · unverified_draft
### fol-csppt-ischemic-stroke First ischemic stroke was lower with combined treatment (HR 0.76; 95% CI 0.64–0.91); hemorrhagic stroke, MI and all-cause death did not differ significantly. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The benefit was endpoint-specific, rather than a uniform reduction in every vascular event. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Double-blind randomized CSPPT: 20702 Chinese adults with hypertension and no previous stroke or myocardial infarction, stratified by MTHFR C677T genotype. limitations: Secondary endpoints, event frequency and confidence intervals matter; null results do not prove identical risks. exposure: Enalapril 10 mg plus folic acid 0.8 mg/day versus enalapril alone; median 4.5 years. [fol-csppt2015] Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial (2015). https://pubmed.ncbi.nlm.nih.gov/25771069/ DOI: 10.1001/jama.2015.2274
Complete structured claim and evidence
Mean homocysteine fell 2.4 micromol/L with the combined B vitamins and rose 0.8 micromol/L with placebo.
Folic acid → Homocysteine source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
Directly records the combined B6/B12/folic-acid exposure.
experimental_model
Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years.
exposure
Folic acid 2.5 mg, B6 50 mg and B12 1 mg/day together versus placebo; combined intervention, not isolated folate.
limitations
Folate, B6 and B12 were administered together; their individual contributions cannot be separated.
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 biochemical target changed in the trial.
primary_references
[fol-hope2006] Homocysteine lowering with folic acid and B vitamins in vascular disease (2006). https://pubmed.ncbi.nlm.nih.gov/16531613/ DOI: 10.1056/nejmoa060900
tissue_or_cell_type
Human blood or whole-person clinical endpoints
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1617–1628
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years. · source_derived_draft · unverified_draft
### fol-hope2-homocysteine Mean homocysteine fell 2.4 micromol/L with the combined B vitamins and rose 0.8 micromol/L with placebo. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The biochemical target changed in the trial. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years. limitations: Folate, B6 and B12 were administered together; their individual contributions cannot be separated. exposure: Folic acid 2.5 mg, B6 50 mg and B12 1 mg/day together versus placebo; combined intervention, not isolated folate. cross_nutrient: Directly records the combined B6/B12/folic-acid exposure. [fol-hope2006] Homocysteine lowering with folic acid and B vitamins in vascular disease (2006). https://pubmed.ncbi.nlm.nih.gov/16531613/ DOI: 10.1056/nejmoa060900
Complete structured claim and evidence
The primary cardiovascular death/MI/stroke composite occurred in 18.8% versus 19.8% (RR 0.95; 95% CI 0.84–1.07), without a significant treatment effect.
Folic acid → Major cardiovascular event incidence source_derived_draftungraded
Experimental context and source evidence
experimental_model
Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years.
exposure
Folic acid 2.5 mg, B6 50 mg and B12 1 mg/day together versus placebo; combined intervention, not isolated folate.
limitations
Distinct population, regimen and endpoint from CSPPT; this is an outcome boundary, not a contradiction to a biochemical reaction.
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
Improving homocysteine did not establish benefit for the primary clinical endpoint.
primary_references
[fol-hope2006] Homocysteine lowering with folic acid and B vitamins in vascular disease (2006). https://pubmed.ncbi.nlm.nih.gov/16531613/ DOI: 10.1056/nejmoa060900
tissue_or_cell_type
Human blood or whole-person clinical endpoints
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1630–1640
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years. · source_derived_draft · unverified_draft
### fol-hope2-primary-outcome-null The primary cardiovascular death/MI/stroke composite occurred in 18.8% versus 19.8% (RR 0.95; 95% CI 0.84–1.07), without a significant treatment effect. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Improving homocysteine did not establish benefit for the primary clinical endpoint. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years. limitations: Distinct population, regimen and endpoint from CSPPT; this is an outcome boundary, not a contradiction to a biochemical reaction. exposure: Folic acid 2.5 mg, B6 50 mg and B12 1 mg/day together versus placebo; combined intervention, not isolated folate. [fol-hope2006] Homocysteine lowering with folic acid and B vitamins in vascular disease (2006). https://pubmed.ncbi.nlm.nih.gov/16531613/ DOI: 10.1056/nejmoa060900
Complete structured claim and evidence
The stroke endpoint was lower with combined vitamins (RR 0.75; 95% CI 0.59–0.97), despite the null primary composite.
Folic acid → Stroke incidence source_derived_draftungraded
Experimental context and source evidence
experimental_model
Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years.
exposure
Folic acid 2.5 mg, B6 50 mg and B12 1 mg/day together versus placebo; combined intervention, not isolated folate.
limitations
Interpret secondary/component findings alongside the trial hierarchy and the reported increase in unstable-angina hospitalizations; not a general cardiovascular protection claim.
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
One clinical component improved while the combined primary outcome did not.
primary_references
[fol-hope2006] Homocysteine lowering with folic acid and B vitamins in vascular disease (2006). https://pubmed.ncbi.nlm.nih.gov/16531613/ DOI: 10.1056/nejmoa060900
tissue_or_cell_type
Human blood or whole-person clinical endpoints
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1642–1652
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years. · source_derived_draft · unverified_draft
### fol-hope2-stroke-secondary The stroke endpoint was lower with combined vitamins (RR 0.75; 95% CI 0.59–0.97), despite the null primary composite. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: One clinical component improved while the combined primary outcome did not. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years. limitations: Interpret secondary/component findings alongside the trial hierarchy and the reported increase in unstable-angina hospitalizations; not a general cardiovascular protection claim. exposure: Folic acid 2.5 mg, B6 50 mg and B12 1 mg/day together versus placebo; combined intervention, not isolated folate. [fol-hope2006] Homocysteine lowering with folic acid and B vitamins in vascular disease (2006). https://pubmed.ncbi.nlm.nih.gov/16531613/ DOI: 10.1056/nejmoa060900
Complete structured claim and evidence
At the first surveillance interval, adenoma recurrence was 44.1% with folic acid and 42.4% with placebo (RR 1.04; 95% CI 0.90–1.20).
Folic acid → Colorectal adenoma recurrence source_derived_draftungraded
Experimental context and source evidence
experimental_model
Randomized double-blind factorial trial in 1021 adults with recent colorectal adenomas; independently randomized aspirin exposure.
exposure
Folic acid 1 mg/day versus placebo; colonoscopy at first three-year interval and a later surveillance interval.
limitations
Participants already had adenomas; not a study of ordinary food folate or primary cancer prevention in everyone.
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 supplement did not prevent recurrent adenomas in this trial.
primary_references
[fol-cole2007] Folic acid for the prevention of colorectal adenomas: a randomized clinical trial (2007). https://pubmed.ncbi.nlm.nih.gov/17551129/ DOI: 10.1001/jama.297.21.2351
tissue_or_cell_type
Human blood or whole-person clinical endpoints
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1654–1664
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized double-blind factorial trial in 1021 adults with recent colorectal adenomas; independently randomized aspirin exposure. · source_derived_draft · unverified_draft
### fol-adenoma-recurrence-null At the first surveillance interval, adenoma recurrence was 44.1% with folic acid and 42.4% with placebo (RR 1.04; 95% CI 0.90–1.20). Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The supplement did not prevent recurrent adenomas in this trial. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Randomized double-blind factorial trial in 1021 adults with recent colorectal adenomas; independently randomized aspirin exposure. limitations: Participants already had adenomas; not a study of ordinary food folate or primary cancer prevention in everyone. exposure: Folic acid 1 mg/day versus placebo; colonoscopy at first three-year interval and a later surveillance interval. [fol-cole2007] Folic acid for the prevention of colorectal adenomas: a randomized clinical trial (2007). https://pubmed.ncbi.nlm.nih.gov/17551129/ DOI: 10.1001/jama.297.21.2351
Complete structured claim and evidence
Among 607 participants with a second follow-up, advanced lesions occurred in 11.6% versus 6.9% (RR 1.67; 95% CI 1.00–2.80; P=0.05).
Folic acid → Advanced colorectal lesion incidence source_derived_draftungraded
Experimental context and source evidence
experimental_model
Randomized double-blind factorial trial in 1021 adults with recent colorectal adenomas; independently randomized aspirin exposure.
exposure
Folic acid 1 mg/day versus placebo; colonoscopy at first three-year interval and a later surveillance interval.
limitations
Secondary endpoint with substantial follow-up attrition and uncertainty; cannot establish that food folate causes cancer or identify the cellular mechanism.
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 later follow-up raised a possible adverse signal that must remain visible.
primary_references
[fol-cole2007] Folic acid for the prevention of colorectal adenomas: a randomized clinical trial (2007). https://pubmed.ncbi.nlm.nih.gov/17551129/ DOI: 10.1001/jama.297.21.2351
tissue_or_cell_type
Human blood or whole-person clinical endpoints
Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1666–1676
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized double-blind factorial trial in 1021 adults with recent colorectal adenomas; independently randomized aspirin exposure. · source_derived_draft · unverified_draft
### fol-advanced-lesion-later-signal Among 607 participants with a second follow-up, advanced lesions occurred in 11.6% versus 6.9% (RR 1.67; 95% CI 1.00–2.80; P=0.05). Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The later follow-up raised a possible adverse signal that must remain visible. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Randomized double-blind factorial trial in 1021 adults with recent colorectal adenomas; independently randomized aspirin exposure. limitations: Secondary endpoint with substantial follow-up attrition and uncertainty; cannot establish that food folate causes cancer or identify the cellular mechanism. exposure: Folic acid 1 mg/day versus placebo; colonoscopy at first three-year interval and a later surveillance interval. [fol-cole2007] Folic acid for the prevention of colorectal adenomas: a randomized clinical trial (2007). https://pubmed.ncbi.nlm.nih.gov/17551129/ DOI: 10.1001/jama.297.21.2351
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.

Inherited PCFT loss in the Qiu family

Condition: machinery_impairment · Biallelic loss-of-function mutation in the studied family

Normal role: PCFT enables proton-coupled folate entry.

Recorded consequence: Hereditary folate malabsorption

Scope: Original affected family

Low folate changes EGCG sensitivity in cultured lymphoma cells

Condition: nutrient_deficiency · Folate depletion in the experimental culture.

Normal role: The intact pathway and nutrient conditions support the comparator response.

Recorded consequence: Increased growth-inhibitory sensitivity; this does not define human EGCG-induced folate deficiency.

Scope: Preclinical experiment; inspect linked evidence.

FOLR1 nonsense variants in two siblings

Condition: machinery_impairment · Compound-heterozygous Q118X/C175X variants

Normal role: FOLR1 supports delivery into the CSF.

Recorded consequence: Very low CSF folate despite unremarkable peripheral folate

Scope: Two siblings

Restoring FOLR1 in patient fibroblasts

Condition: machinery_impairment · FOLR1 Q118X/C175X patient cells followed by wild-type receptor transfection

Normal role: Surface receptor binds folate.

Recorded consequence: Specific folate binding restored

Scope: Cell assay

Folate shortage changes downstream methanol handling

Condition: nutrient_deficiency · Diet-induced folate deficiency then labeled methanol inhalation.

Normal role: Folate-dependent metabolism contributes to formate handling.

Recorded consequence: Higher methanol-derived labeled formate than before depletion.

Scope: Four cynomolgus monkeys.

Mitochondrial-only FPGS in AUXB1 cells

Condition: machinery_impairment · Endogenous Fpgs defect with only mitochondrial FPGS restored

Normal role: Both compartments require folate retention machinery.

Recorded consequence: Glycine requirement corrected while cytosolic support remains incomplete

Scope: Engineered cells

Increased GGH in HCT116 cells

Condition: machinery_impairment · Sense-GGH transfection

Normal role: GGH trims folate polyglutamate tails.

Recorded consequence: Reduced long-chain folate polyglutamate pools

Scope: HCT116 culture

Reduced GGH in HCT116 cells

Condition: machinery_impairment · GGH-targeted siRNA

Normal role: GGH trims folate polyglutamate tails.

Recorded consequence: Higher long-chain folate-polyglutamate pools

Scope: HCT116 culture

UMFA measurement in NHANES 2007-2008

Condition: biomarker_context · Cross-sectional sampling under different fasting and intake conditions

Normal role: Serum assays distinguish unchanged folic acid from reduced folates.

Recorded consequence: Frequent UMFA detection

Scope: US participants at least one year old

MTR loss with physiological folates

Condition: machinery_impairment · MTR knockout

Normal role: MTR returns methylfolate to THF.

Recorded consequence: Methylfolate trapping

Scope: Specified tumour cultures

When alcohol blocks folate absorption

Condition: nutrient_deficiency · Chronic ethanol ingestion.

Normal role: Intestinal folate uptake is carrier-mediated, pH-dependent and electroneutral, using the reduced folate carrier and the proton-coupled folate transporter.

Recorded consequence: Intestinal and renal uptake fall through altered transport kinetics and reduced transporter expression, on top of dietary inadequacy and increased renal excretion.

Scope: Human and animal folate transport studies

MTR loss in cblG fibroblasts

Condition: machinery_impairment · cblG MTR loss of function

Normal role: MTR recycles methylfolate.

Recorded consequence: Folate redistribution

Scope: WG4215 versus MCH058 cells

Hypomorphic Mtrr gene trap

Condition: machinery_impairment · Homozygous gene-trap insertion

Normal role: MTRR sustains MTR.

Recorded consequence: Perturbed remethylation

Scope: Mtrr gt/gt mice

Loss of betaine remethylation

Condition: machinery_impairment · Bhmt deletion

Normal role: BHMT recycles homocysteine.

Recorded consequence: Altered methyl metabolites

Scope: Bhmt-null mice

Folate feeding with absent BHMT

Condition: machinery_impairment · Bhmt knockout plus 0, 2 or 20 mg folate/kg diet

Normal role: MTR and BHMT provide different routes.

Recorded consequence: Incomplete compensation

Scope: Four-week feeding

Low folate with low choline

Condition: nutrient_deficiency · 4-5 weeks combined restriction

Normal role: Folate and choline supply intersecting methyl routes.

Recorded consequence: Reduced choline markers

Scope: Separate male/female cohorts

MTHFR variant and choline allocation

Condition: machinery_impairment · MTHFR rs1801133 variant allele

Normal role: Folate metabolism intersects with choline use.

Recorded consequence: Altered tracer partition

Scope: 480/930 mg choline/day; adequate folate

Folate depletion in young women

Condition: nutrient_deficiency · 115 micrograms DFE/day for seven weeks

Normal role: Folate supports one-carbon supply.

Recorded consequence: Assay-dependent methylation response

Scope: Age 20-30; 19 TT, 22 CC

CRISPR MTHFD2 knockout

Condition: machinery_impairment · CRISPR MTHFD2 knockout