Component
Folate polyglutamates
Folate derivatives with additional gamma-linked glutamate residues; not one vitamer.
11 recorded relationships. Experimental role, claim status and evidence remain attached to each record.
How nutrients influence it
Every nutrient with a recorded effect on this component, credited to the nutrient that acted rather than the chapter that recorded it. Open a nutrient to see the findings and the conditions they were measured under.
Other things that act on it
Enzymes, hormones, genes, and other components with a recorded effect. These are not nutrients, so they do not count toward the arrows above. Each finding names the chapter that recorded it.
How nutrients reach it in more than one step
Chains of two or more recorded steps that end here, grouped by the nutrient they start from. Each step is a separate finding, so a chain is a route a mechanism could take, not proof that it does.
Tracing routes…
What it does
Every recorded relationship this component is part of, grouped by its role. Plain wording comes first; the technical statement follows.
What it acts on
Tracer experiments detected no intact folate-polyglutamate transfer from mitochondria to cytosol in the tested human-FPGS-reconstituted hamster cells.
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
What acts on it
Partially purified human jejunal brush-border folate hydrolase progressively removed glutamates, producing predominantly monoglutamate after 120 minutes.
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 evidenceHuman GCPII structures and mutagenesis identified an arene-binding site that recognizes the folate portion of polyglutamate substrates.
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 evidenceGGH overexpression lowered long-chain folate-polyglutamate content in HCT116 cells.
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 evidenceGGH-targeted siRNA increased long-chain folate-polyglutamate content in HCT116 cells.
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
Where it participates (unsigned role)
Human cytosolic FPGS reconstitution supported persistent folate pools in AUXB1 cells; labeled folate loss was not measurable over three cell generations.
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 evidenceDihydrofolate was also an effective substrate for purified human cytosolic FPGS.
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 evidenceMitochondrial human FPGS maintained a separately retained mitochondrial folate-polyglutamate pool in reconstituted AUXB1 cells.
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 evidencePurified human cytosolic FPGS used tetrahydrofolate as an effective substrate for polyglutamate synthesis.
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 evidenceHuman GCPII crystal structures resolved two zinc ions at the catalytic center, bridged by water or hydroxide and Asp387.
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 evidenceSulfasalazine competitively inhibited human jejunal brush-border folate hydrolase, with reported Ki 0.13 mM.
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
The events it takes part in
A mechanism often involves more than two components. These are the full events, with every participant and its role.
Situations it appears in
Low-supply and faulty-machinery situations recorded in the chapters where this component plays a part.
In the sources
Preserved passages that mention this component, quoted exactly. Open one to read it in context.
Open hypotheses
Proposed ideas that involve this component. They are labeled as hypotheses and do not change any recorded statement.
This is a research prototype built from draft material. It is not medical advice, and its statements still await verification against the original studies.