Formate

evidence_access

Primary abstract

experimental_model

Cancer-cell nutrient and formate rescue experiment.

limitations

No extrapolation to treating cancer or supplement combinations in people.

nutrient_topic

Glycine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Glycine

plain_language

Another input changed whether supplied glycine could support growth.

primary_references

Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24813884/ · DOI 10.1016/j.celrep.2014.04.045

Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 186–192

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cancer-cell nutrient and formate rescue experiment. · source_derived_draft · unverified_draft

## glycine-formate-serine-deprived-rescue Another input changed whether supplied glycine could support growth. Formate restored nucleotide synthesis and growth in glycine-fed cells lacking serine. Model: Cancer-cell nutrient and formate rescue experiment. Limitations: No extrapolation to treating cancer or supplement combinations in people. Evidence access: Primary abstract Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24813884/ · DOI 10.1016/j.celrep.2014.04.045

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse developmental model and formate supplementation.

limitations

Does not establish treatment of human nonketotic hyperglycinemia or prove all disease features are formate-responsive.

nutrient_topic

Glycine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Glycine

plain_language

A downstream carbon donor bypassed part of the missing pathway.

primary_references

Glycine decarboxylase deficiency causes neural tube defects and features of non-ketotic hyperglycinemia in mice. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25736695/ · DOI 10.1038/ncomms7388

trigger_kind

machinery_impairment Imported condition classification; unverified.

Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 138–144

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse developmental model and formate supplementation. · source_derived_draft · unverified_draft

## glycine-gldc-formate-bypass A downstream carbon donor bypassed part of the missing pathway. Formate treatment normalized folate profiles, restored embryonic growth and prevented neural-tube defects in the tested Gldc-deficient mice. Model: Mouse developmental model and formate supplementation. Limitations: Does not establish treatment of human nonketotic hyperglycinemia or prove all disease features are formate-responsive. Evidence access: Primary full text Glycine decarboxylase deficiency causes neural tube defects and features of non-ketotic hyperglycinemia in mice. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25736695/ · DOI 10.1038/ncomms7388

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human leukemia cells, knockout and metabolite-rescue experiment.

limitations

Culture rescue is not a nutritional recommendation; this growth endpoint differs from zebrafish hemoglobin.

nutrient_topic

Glycine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Glycine

plain_language

Restoring a downstream one-carbon source worked where adding an amino acid did not.

primary_references

SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39856062/ · DOI 10.1038/s41467-025-56130-3

trigger_kind

machinery_impairment Imported condition classification; unverified.

Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 122–128

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human leukemia cells, knockout and metabolite-rescue experiment. · source_derived_draft · unverified_draft

## glycine-s38-formate-rescue Restoring a downstream one-carbon source worked where adding an amino acid did not. Formate at 1 mM rescued the low-B6 proliferation defect of SLC25A38-null K562 cells, while glycine, serine and folate did not under the tested conditions. Model: Human leukemia cells, knockout and metabolite-rescue experiment. Limitations: Culture rescue is not a nutritional recommendation; this growth endpoint differs from zebrafish hemoglobin. Evidence access: Primary full text SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39856062/ · DOI 10.1038/s41467-025-56130-3

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Demonstrates a formate-to-folate consequence downstream of a mitochondrial flavin-supply defect, not dietary folate deficiency.

evidence_spans

[{"source_bundle": "artifacts/riboflavin_metabolism_sources.json", "source_key": "PMC11072207", "locator": "HTML article p", "paragraph_index": 38, "char_start": 0, "char_end": 1062, "evidence_access": "full-text"}]

experimental_model

Slc25a32-null embryos and missense knock-in mice, isolated mitochondria and skeletal-muscle enzyme assays.

exposure

Dams received 0.1 mol/L sodium formate in drinking water; experimental context only.

limitations

Analyzed responder subgroup; does not prove normal folate metabolism or bypass every effect of Slc25a32 loss.

nutrient_topic

Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)

organism

Mus musculus

plain_language

Supplying a missing one-carbon donor changed the downstream folate profile.

primary_references

[peng-2022-slc25a32] Mitochondrial FAD shortage in SLC25A32 deficiency affects folate-mediated one-carbon metabolism (2022). https://pubmed.ncbi.nlm.nih.gov/35727412/ DOI: 10.1007/s00018-022-04404-0

tissue_or_cell_type

Whole E11.5 embryos

trigger_kind

machinery_impairment Imported condition classification; unverified.

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 902–914

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Slc25a32-null embryos and missense knock-in mice, isolated mitochondria and skeletal-muscle enzyme assays. · source_derived_draft · unverified_draft

### b2-met-formate-embryo-folate-rescue Maternal sodium formate supplementation increased embryo CH3-THF in Slc25a32-null offspring that completed neural tube closure. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Supplying a missing one-carbon donor changed the downstream folate profile. organism: Mus musculus tissue_or_cell_type: Whole E11.5 embryos experimental_model: Slc25a32-null embryos and missense knock-in mice, isolated mitochondria and skeletal-muscle enzyme assays. limitations: Analyzed responder subgroup; does not prove normal folate metabolism or bypass every effect of Slc25a32 loss. exposure: Dams received 0.1 mol/L sodium formate in drinking water; experimental context only. cross_nutrient: Demonstrates a formate-to-folate consequence downstream of a mitochondrial flavin-supply defect, not dietary folate deficiency. evidence_spans: [{"source_bundle": "artifacts/riboflavin_metabolism_sources.json", "source_key": "PMC11072207", "locator": "HTML article p", "paragraph_index": 38, "char_start": 0, "char_end": 1062, "evidence_access": "full-text"}] [peng-2022-slc25a32] Mitochondrial FAD shortage in SLC25A32 deficiency affects folate-mediated one-carbon metabolism (2022). https://pubmed.ncbi.nlm.nih.gov/35727412/ DOI: 10.1007/s00018-022-04404-0

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Connects a B2-related machinery defect to folate-dependent development through one-carbon availability.

evidence_spans

[{"source_bundle": "artifacts/riboflavin_metabolism_sources.json", "source_key": "PMC11072207", "locator": "HTML article p", "paragraph_index": 38, "char_start": 0, "char_end": 1062, "evidence_access": "full-text"}]

experimental_model

Slc25a32-null embryos and missense knock-in mice, isolated mitochondria and skeletal-muscle enzyme assays.

exposure

0.1 mol/L sodium formate in dam drinking water; 73 total embryos, nine litters.

limitations

Small animal intervention; incomplete rescue and no human treatment inference.

nutrient_topic

Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)

organism

Mus musculus

plain_language

One-carbon supplementation partly bypassed a developmental consequence in this mouse model.

primary_references

[peng-2022-slc25a32] Mitochondrial FAD shortage in SLC25A32 deficiency affects folate-mediated one-carbon metabolism (2022). https://pubmed.ncbi.nlm.nih.gov/35727412/ DOI: 10.1007/s00018-022-04404-0

tissue_or_cell_type

E11.5 embryos

trigger_kind

machinery_impairment Imported condition classification; unverified.

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 916–928

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Slc25a32-null embryos and missense knock-in mice, isolated mitochondria and skeletal-muscle enzyme assays. · source_derived_draft · unverified_draft

### b2-met-formate-embryo-neural-tube After maternal sodium formate treatment, 14 of 16 Slc25a32-null embryos completed neural tube closure in the reported nine-litter experiment. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: One-carbon supplementation partly bypassed a developmental consequence in this mouse model. organism: Mus musculus tissue_or_cell_type: E11.5 embryos experimental_model: Slc25a32-null embryos and missense knock-in mice, isolated mitochondria and skeletal-muscle enzyme assays. limitations: Small animal intervention; incomplete rescue and no human treatment inference. exposure: 0.1 mol/L sodium formate in dam drinking water; 73 total embryos, nine litters. cross_nutrient: Connects a B2-related machinery defect to folate-dependent development through one-carbon availability. evidence_spans: [{"source_bundle": "artifacts/riboflavin_metabolism_sources.json", "source_key": "PMC11072207", "locator": "HTML article p", "paragraph_index": 38, "char_start": 0, "char_end": 1062, "evidence_access": "full-text"}] [peng-2022-slc25a32] Mitochondrial FAD shortage in SLC25A32 deficiency affects folate-mediated one-carbon metabolism (2022). https://pubmed.ncbi.nlm.nih.gov/35727412/ DOI: 10.1007/s00018-022-04404-0

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Two-hour lung-only labeled-methanol exposure; repeated after diet-induced folate deficiency.

limitations

This was not aspartame feeding, and does not show aspartame causes folate depletion.

nutrient_topic

Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame

plain_language

Downstream handling depends on nutrient state and exposure route.

primary_references

Pharmacokinetics of inhaled [14C]methanol and methanol-derived [14C]formate in normal and folate-deficient cynomolgus monkeys. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7940538/ · DOI 10.1006/taap.1994.1202

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 154–160

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Two-hour lung-only labeled-methanol exposure; repeated after diet-induced folate deficiency. · source_derived_draft · unverified_draft

## aspartame-folate-methanol-context Downstream handling depends on nutrient state and exposure route. Four cynomolgus monkeys had higher labeled blood formate after 900 ppm methanol inhalation when folate-deficient than before depletion, while tracer-derived concentrations remained below endogenous formate. Model: Two-hour lung-only labeled-methanol exposure; repeated after diet-induced folate deficiency. Limitations: This was not aspartame feeding, and does not show aspartame causes folate depletion. Evidence access: Primary abstract Pharmacokinetics of inhaled [14C]methanol and methanol-derived [14C]formate in normal and folate-deficient cynomolgus monkeys. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7940538/ · DOI 10.1006/taap.1994.1202

evidence_access

Primary abstract

experimental_model

Four female monkeys; lung-only exposure for two hours at 10–900 ppm.

limitations

Not an aspartame feeding study; the route and systemic dose differ from digestion of a food sweetener.

nutrient_topic

Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame

plain_language

A traced precursor-product link connects two separate metabolite nodes.

primary_references

Pharmacokinetics of inhaled [14C]methanol and methanol-derived [14C]formate in normal and folate-deficient cynomolgus monkeys. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7940538/ · DOI 10.1006/taap.1994.1202

Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 354–360

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Four female monkeys; lung-only exposure for two hours at 10–900 ppm. · source_derived_draft · unverified_draft

## aspartame-methanol-formate-tracer A traced precursor-product link connects two separate metabolite nodes. Labeled methanol inhalation produced labeled blood formate in cynomolgus monkeys. Model: Four female monkeys; lung-only exposure for two hours at 10–900 ppm. Limitations: Not an aspartame feeding study; the route and systemic dose differ from digestion of a food sweetener. Evidence access: Primary abstract Pharmacokinetics of inhaled [14C]methanol and methanol-derived [14C]formate in normal and folate-deficient cynomolgus monkeys. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7940538/ · DOI 10.1006/taap.1994.1202

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

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

cross_nutrient

B1 cleavage is sequentially coupled to B5-derived CoA activation and B3-related NAD oxidation.

evidence

[{"paper_key": "foulon-2005-hacl1", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["abstract"], "locator": "Primary publication abstract", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}]

experimental_model

Intact/permeabilized rat hepatocytes and liver preparations.

limitations

Whole-pathway requirements cannot all be assigned to the isolated lyase.

nutrient

Thiamine (vitamin B1) · Thiamine (vitamin B1)

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Rattus norvegicus

plain_language

ATP activates the fatty acid upstream, while NAD supports later oxidation. Listing all pathway cofactors does not mean HACL itself consumes ATP or NAD.

primary_references

[foulon-2005-hacl1] Breakdown of 2-hydroxylated straight chain fatty acids via peroxisomal 2-hydroxyphytanoyl-CoA lyase: a revised pathway for the alpha-oxidation of straight chain fatty acids (2005). https://pubmed.ncbi.nlm.nih.gov/15644336/ DOI: 10.1074/jbc.m413362200

tissue_or_cell_type

Liver

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1003–1015

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Intact/permeabilized rat hepatocytes and liver preparations. · source_derived_draft · unverified_draft

### b1-alpha-oxidation-activation-before-cleavage Rat liver/hepatocyte pathway experiments supported activation of 2-hydroxy-fatty acid to its CoA ester before ThDP-dependent cleavage; whole-pathway assays required ATP, CoA, Mg2+, ThDP and NAD+. Condition category: normal nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: ATP activates the fatty acid upstream, while NAD supports later oxidation. Listing all pathway cofactors does not mean HACL itself consumes ATP or NAD. organism: Rattus norvegicus tissue_or_cell_type: Liver experimental_model: Intact/permeabilized rat hepatocytes and liver preparations. limitations: Whole-pathway requirements cannot all be assigned to the isolated lyase. evidence: [{"paper_key": "foulon-2005-hacl1", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["abstract"], "locator": "Primary publication abstract", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}] cross_nutrient: B1 cleavage is sequentially coupled to B5-derived CoA activation and B3-related NAD oxidation. nutrient: Thiamine (vitamin B1) [foulon-2005-hacl1] Breakdown of 2-hydroxylated straight chain fatty acids via peroxisomal 2-hydroxyphytanoyl-CoA lyase: a revised pathway for the alpha-oxidation of straight chain fatty acids (2005). https://pubmed.ncbi.nlm.nih.gov/15644336/ DOI: 10.1074/jbc.m413362200

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human melanoma cultures with shRNA and nutrient withdrawal/rescue.

limitations

A combined manipulation; not proof that ordinary dietary glycine alone controls a tumor.

nutrient_topic

Glycine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Glycine

plain_language

Removing both synthesis and external supply exposed a glycine dependency.

primary_references

Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22628656/ · DOI 10.1126/science.1218595

trigger_kind

machinery_impairment Imported condition classification; unverified.

Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 154–160

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human melanoma cultures with shRNA and nutrient withdrawal/rescue. · source_derived_draft · unverified_draft

## glycine-shmt2-glycine-dependence Removing both synthesis and external supply exposed a glycine dependency. SHMT2 silencing combined with removal of extracellular glycine halted LOX IMVI proliferation; adding glycine restored growth whereas formate did not. Model: Human melanoma cultures with shRNA and nutrient withdrawal/rescue. Limitations: A combined manipulation; not proof that ordinary dietary glycine alone controls a tumor. Evidence access: Primary full text Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22628656/ · DOI 10.1126/science.1218595

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

B2-dependent mitochondrial function supports glycine carbon entry into folate-related one-carbon supply.

evidence_spans

[{"source_bundle": "artifacts/riboflavin_metabolism_sources.json", "source_key": "PMC11072207", "locator": "HTML article p", "paragraph_index": 43, "char_start": 0, "char_end": 1215, "evidence_access": "full-text"}]

experimental_model

Slc25a32-null embryos and missense knock-in mice, isolated mitochondria and skeletal-muscle enzyme assays.

exposure

Slc25a32-null mitochondria supplied [1,2-13C2]-glycine.

limitations

Long isolated-mitochondrial assay; this is glycine-derived flux, not total cellular formate synthesis.

nutrient_topic

Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)

organism

Mus musculus

plain_language

The same genetic defect sharply reduced one-carbon output from glycine.

primary_references

[peng-2022-slc25a32] Mitochondrial FAD shortage in SLC25A32 deficiency affects folate-mediated one-carbon metabolism (2022). https://pubmed.ncbi.nlm.nih.gov/35727412/ DOI: 10.1007/s00018-022-04404-0

tissue_or_cell_type

Embryo mitochondria, 24-hour isotope incubation

trigger_kind

machinery_impairment Imported condition classification; unverified.

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 888–900

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Slc25a32-null embryos and missense knock-in mice, isolated mitochondria and skeletal-muscle enzyme assays. · source_derived_draft · unverified_draft

### b2-met-mouse-null-glycine-formate Isolated Slc25a32-null embryo mitochondria produced about 10.6% of control labeled formate from [13C2]-glycine over 24 hours. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The same genetic defect sharply reduced one-carbon output from glycine. organism: Mus musculus tissue_or_cell_type: Embryo mitochondria, 24-hour isotope incubation experimental_model: Slc25a32-null embryos and missense knock-in mice, isolated mitochondria and skeletal-muscle enzyme assays. limitations: Long isolated-mitochondrial assay; this is glycine-derived flux, not total cellular formate synthesis. exposure: Slc25a32-null mitochondria supplied [1,2-13C2]-glycine. cross_nutrient: B2-dependent mitochondrial function supports glycine carbon entry into folate-related one-carbon supply. evidence_spans: [{"source_bundle": "artifacts/riboflavin_metabolism_sources.json", "source_key": "PMC11072207", "locator": "HTML article p", "paragraph_index": 43, "char_start": 0, "char_end": 1215, "evidence_access": "full-text"}] [peng-2022-slc25a32] Mitochondrial FAD shortage in SLC25A32 deficiency affects folate-mediated one-carbon metabolism (2022). https://pubmed.ncbi.nlm.nih.gov/35727412/ DOI: 10.1007/s00018-022-04404-0

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Macrophage culture with serine restriction and metabolite add-back.

limitations

The delivered compound was cell-permeable GSH, not an assumed effect of oral glutathione.

nutrient_topic

L-Serine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Serine

plain_language

The limiting branch differs from the nucleotide requirement in dividing T cells.

primary_references

Serine Metabolism Supports Macrophage IL-1β Production. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30773464/ · DOI 10.1016/j.cmet.2019.01.014

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids and cross-nutrient mechanisms (2026-09-19) · lines 238–244

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Macrophage culture with serine restriction and metabolite add-back. · source_derived_draft · unverified_draft

## l-serine-macrophage-rescue The limiting branch differs from the nucleotide requirement in dividing T cells. Cell-permeable glutathione, but not formate, rescued IL-1beta mRNA expression under serine restriction in the macrophage experiments. Model: Macrophage culture with serine restriction and metabolite add-back. Limitations: The delivered compound was cell-permeable GSH, not an assumed effect of oral glutathione. Evidence access: Primary abstract Serine Metabolism Supports Macrophage IL-1β Production. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30773464/ · DOI 10.1016/j.cmet.2019.01.014

evidence_access

Primary abstract

experimental_model

Primary study of activated T cells with in-vivo pathogen-driven expansion experiments in mice.

limitations

Species and activation context limit translation to human supplementation. Correction record: PubMed indexes a published erratum, PMID 28178570 / DOI 10.1016/j.cmet.2017.01.014. The notice body was not accessible during this curation, so its specific scope and impact remain unverified. Do not treat the original study as having received comprehensive integrity clearance. https://pubmed.ncbi.nlm.nih.gov/28178570/

nutrient_topic

L-Serine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Serine

plain_language

Fuel availability alone does not meet every requirement for immune-cell division.

primary_references

Serine Is an Essential Metabolite for Effector T Cell Expansion. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28111214/ · DOI 10.1016/j.cmet.2016.12.011

L-Serine: synthesis, one-carbon metabolism, lipids and cross-nutrient mechanisms (2026-09-19) · lines 214–220

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary study of activated T cells with in-vivo pathogen-driven expansion experiments in mice. · source_derived_draft · unverified_draft

## l-serine-tcell-expansion Fuel availability alone does not meet every requirement for immune-cell division. Extracellular serine supported optimal activated T-cell expansion by providing glycine and one-carbon units for nucleotide biosynthesis; adequate glucose alone did not substitute. Model: Primary study of activated T cells with in-vivo pathogen-driven expansion experiments in mice. Limitations: Species and activation context limit translation to human supplementation. Correction record: PubMed indexes a published erratum, PMID 28178570 / DOI 10.1016/j.cmet.2017.01.014. The notice body was not accessible during this curation, so its specific scope and impact remain unverified. Do not treat the original study as having received comprehensive integrity clearance. https://pubmed.ncbi.nlm.nih.gov/28178570/ Evidence access: Primary abstract Serine Is an Essential Metabolite for Effector T Cell Expansion. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28111214/ · DOI 10.1016/j.cmet.2016.12.011

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Mouse dietary restriction and separate activated-cell formate add-back.

limitations

The culture rescue is not an in-vivo dietary rescue or a human treatment dose. Correction record: PubMed indexes a published erratum, PMID 28178570 / DOI 10.1016/j.cmet.2017.01.014. The notice body was not accessible during this curation, so its specific scope and impact remain unverified. Do not treat the original study as having received comprehensive integrity clearance. https://pubmed.ncbi.nlm.nih.gov/28178570/

nutrient_topic

L-Serine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · L-Serine

plain_language

Shortage can impair an induced response without eliminating resting immune cells.

primary_references

Serine Is an Essential Metabolite for Effector T Cell Expansion. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28111214/ · DOI 10.1016/j.cmet.2016.12.011

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

L-Serine: synthesis, one-carbon metabolism, lipids and cross-nutrient mechanisms (2026-09-19) · lines 222–228

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse dietary restriction and separate activated-cell formate add-back. · source_derived_draft · unverified_draft

## l-serine-tcell-restriction Shortage can impair an induced response without eliminating resting immune cells. Dietary serine restriction impaired pathogen-driven T-cell expansion in the mouse experiments without disrupting overall immune-cell homeostasis; formate rescued serine-deprived T cells in culture. Model: Mouse dietary restriction and separate activated-cell formate add-back. Limitations: The culture rescue is not an in-vivo dietary rescue or a human treatment dose. Correction record: PubMed indexes a published erratum, PMID 28178570 / DOI 10.1016/j.cmet.2017.01.014. The notice body was not accessible during this curation, so its specific scope and impact remain unverified. Do not treat the original study as having received comprehensive integrity clearance. https://pubmed.ncbi.nlm.nih.gov/28178570/ Evidence access: Primary abstract Serine Is an Essential Metabolite for Effector T Cell Expansion. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28111214/ · DOI 10.1016/j.cmet.2016.12.011

evidence_span

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experimental_model

Ligand bank screening in yeast, confirmed by calcium mobilisation, GTP-gamma-S binding and oocyte coexpression

exposure

Short chain carboxylic acid anions applied to recombinant GPR41 and GPR43

limitations

The deorphanising paper. Potencies come from recombinant systems, not from tissue, and the authors state plainly that the cognate physiological ligands are not clear.

nutrient_topic

Acetic acid research collection; topical membership is not evidence of a direct clinical effect, and the ingested acid is recorded separately from the circulating acetate anion. · Acetic acid

organism

Human and mouse receptors

plain_language

Acetate is not only fuel; it is the signal that identified this receptor.

primary_references

[acetate-p12496283] The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. (2003). https://pubmed.ncbi.nlm.nih.gov/12496283/ DOI: 10.1074/jbc.m211609200

tissue_or_cell_type

Transfected mammalian cells and Xenopus oocytes

Acetic acid: the ingested acid, the receptors acetate binds, the acetyl-CoA it becomes, and the acetyl groups that reach histones (2026-09-21) · lines 225–236

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Ligand bank screening in yeast, confirmed by calcium mobilisation, GTP-gamma-S binding and oocyte coexpression · source_derived_draft · unverified_draft

### acetate-acetate-activates-ffar2 The acetate anion was identified as an agonist of human GPR43 during ligand bank screening in yeast and confirmed after transient transfection using calcium mobilisation and GTP-gamma-S binding assays and by coexpression with GIRK potassium channels in Xenopus oocytes, with formate, propionate, butyrate and pentanoate also showing agonist activity. Condition category: normal nutrient_topic: Acetic acid research collection; topical membership is not evidence of a direct clinical effect, and the ingested acid is recorded separately from the circulating acetate anion. plain_language: Acetate is not only fuel; it is the signal that identified this receptor. organism: Human and mouse receptors tissue_or_cell_type: Transfected mammalian cells and Xenopus oocytes experimental_model: Ligand bank screening in yeast, confirmed by calcium mobilisation, GTP-gamma-S binding and oocyte coexpression limitations: The deorphanising paper. Potencies come from recombinant systems, not from tissue, and the authors state plainly that the cognate physiological ligands are not clear. exposure: Short chain carboxylic acid anions applied to recombinant GPR41 and GPR43 evidence_span: {"source_cache": "artifacts/acetate-research/12496283.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "83f7777cab02a7c69f063d21e26f895884724f46ad539ebc767d9e6f371bf64f", "start_char": 0, "end_char": 1291, "text_sha256": "83f7777cab02a7c69f063d21e26f895884724f46ad539ebc767d9e6f371bf64f"} [acetate-p12496283] The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. (2003). https://pubmed.ncbi.nlm.nih.gov/12496283/ DOI: 10.1074/jbc.m211609200

availability_state

biomarker_context Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Highest-dose subset of the loading study.

limitations

Limited sample, duration and assay; no inference about all metabolic disorders.

nutrient_topic

Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame

plain_language

Methanol appearance did not imply measured formate accumulation.

primary_references

Blood methanol concentrations in normal adult subjects administered abuse doses of aspartame. · 1981 · https://pubmed.ncbi.nlm.nih.gov/7230276/ · DOI 10.1080/15287398109529979

trigger_kind

biomarker_context Imported condition classification; unverified.

Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 130–136

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Highest-dose subset of the loading study. · source_derived_draft · unverified_draft

## aspartame-formate-loading Methanol appearance did not imply measured formate accumulation. Six adults receiving 200 mg/kg showed no significant increase in blood formate over baseline. Model: Highest-dose subset of the loading study. Limitations: Limited sample, duration and assay; no inference about all metabolic disorders. Evidence access: Primary abstract Blood methanol concentrations in normal adult subjects administered abuse doses of aspartame. · 1981 · https://pubmed.ncbi.nlm.nih.gov/7230276/ · DOI 10.1080/15287398109529979

evidence_access

Primary abstract

experimental_model

Six healthy young adults.

limitations

Normal range is protocol- and assay-dependent, not proof that no metabolism occurred.

nutrient_topic

Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame

plain_language

Products can be generated without a sustained high blood pool.

primary_references

Effect of repeated ingestion of aspartame-sweetened beverage on plasma amino acid, blood methanol, and blood formate concentrations in normal adults. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2566887/ · DOI 10.1016/0026-0495(89)90125-x

Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 114–120

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Six healthy young adults. · source_derived_draft · unverified_draft

## aspartame-repeated-metabolites Products can be generated without a sustained high blood pool. Methanol and formate remained within reported normal limits; plasma aspartate did not significantly rise in the eight-serving experiment. Model: Six healthy young adults. Limitations: Normal range is protocol- and assay-dependent, not proof that no metabolism occurred. Evidence access: Primary abstract Effect of repeated ingestion of aspartame-sweetened beverage on plasma amino acid, blood methanol, and blood formate concentrations in normal adults. · 1989 · https://pubmed.ncbi.nlm.nih.gov/2566887/ · DOI 10.1016/0026-0495(89)90125-x

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

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

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

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

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