Vitamin B12 (cobalamins)

availability_state

biomarker_context Imported condition classification; unverified.

cross_nutrient

Folate and B12 both participate in homocysteine remethylation.

experimental_model

Selected clear-cut deficiency series: 434 B12 episodes in 406 patients and 123 folate episodes in 119 patients.

exposure

Serum MMA and total homocysteine assays; elevation defined above three standard deviations of the reference mean.

limitations

Circulating concentration is not a direct MTR activity measurement.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

This marker is shared by connected nutrient pathways, so it cannot identify B12 deficiency by itself.

primary_references

[b12-savage1994] Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies (1994). https://pubmed.ncbi.nlm.nih.gov/8154512/ DOI: 10.1016/0002-9343(94)90149-x

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

biomarker_context Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1474–1485

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Selected clear-cut deficiency series: 434 B12 episodes in 406 patients and 123 folate episodes in 119 patients. · source_derived_draft · unverified_draft

### b12-deficiency-homocysteine-frequency Total homocysteine was elevated in 95.9% of the B12-deficiency episodes; it was also elevated in 91% of the folate-deficiency episodes. Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This marker is shared by connected nutrient pathways, so it cannot identify B12 deficiency by itself. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Selected clear-cut deficiency series: 434 B12 episodes in 406 patients and 123 folate episodes in 119 patients. limitations: Circulating concentration is not a direct MTR activity measurement. exposure: Serum MMA and total homocysteine assays; elevation defined above three standard deviations of the reference mean. cross_nutrient: Folate and B12 both participate in homocysteine remethylation. [b12-savage1994] Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies (1994). https://pubmed.ncbi.nlm.nih.gov/8154512/ DOI: 10.1016/0002-9343(94)90149-x

availability_state

biomarker_context Imported condition classification; unverified.

experimental_model

Selected clear-cut deficiency series: 434 B12 episodes in 406 patients and 123 folate episodes in 119 patients.

exposure

Serum MMA and total homocysteine assays; elevation defined above three standard deviations of the reference mean.

limitations

Selected established deficiency overestimates performance for some borderline screening settings; renal insufficiency or hypovolemia can also raise MMA.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

A metabolite connected to the mitochondrial B12 pathway often provided an additional clue.

primary_references

[b12-savage1994] Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies (1994). https://pubmed.ncbi.nlm.nih.gov/8154512/ DOI: 10.1016/0002-9343(94)90149-x

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

biomarker_context Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1462–1472

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Selected clear-cut deficiency series: 434 B12 episodes in 406 patients and 123 folate episodes in 119 patients. · source_derived_draft · unverified_draft

### b12-deficiency-mma-frequency MMA was elevated in 98.4% of 434 clear-cut B12-deficiency episodes in the diagnostic series. Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A metabolite connected to the mitochondrial B12 pathway often provided an additional clue. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Selected clear-cut deficiency series: 434 B12 episodes in 406 patients and 123 folate episodes in 119 patients. limitations: Selected established deficiency overestimates performance for some borderline screening settings; renal insufficiency or hypovolemia can also raise MMA. exposure: Serum MMA and total homocysteine assays; elevation defined above three standard deviations of the reference mean. [b12-savage1994] Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies (1994). https://pubmed.ncbi.nlm.nih.gov/8154512/ DOI: 10.1016/0002-9343(94)90149-x

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Specific candidate mechanism connecting B12 function to iron utilization.

experimental_model

Before/after series of 75 patients diagnosed with cobalamin deficiency.

exposure

Blood counts and iron-status measurements before and after cobalamin therapy; regimen is not extracted from the abstract.

limitations

Proposed explanation, not a directly measured isotope flux or demonstrated cellular mediator in this study.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

If red-cell production is impaired, available iron and productive iron use need not move together.

primary_references

[b12-solmaz2015] Cobalamin deficiency can mask depleted body iron reserves (2015). https://pubmed.ncbi.nlm.nih.gov/25825568/ DOI: 10.1007/s12288-014-0417-x

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1611–1622

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Before/after series of 75 patients diagnosed with cobalamin deficiency. · source_derived_draft · unverified_draft

### b12-ineffective-erythropoiesis-iron-hypothesis The authors proposed that ineffective erythropoiesis during cobalamin deficiency reduces iron use by erythroblasts, helping explain the before/after iron results. Condition category: nutrient_deficiency nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: If red-cell production is impaired, available iron and productive iron use need not move together. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Before/after series of 75 patients diagnosed with cobalamin deficiency. limitations: Proposed explanation, not a directly measured isotope flux or demonstrated cellular mediator in this study. exposure: Blood counts and iron-status measurements before and after cobalamin therapy; regimen is not extracted from the abstract. cross_nutrient: Specific candidate mechanism connecting B12 function to iron utilization. [b12-solmaz2015] Cobalamin deficiency can mask depleted body iron reserves (2015). https://pubmed.ncbi.nlm.nih.gov/25825568/ DOI: 10.1007/s12288-014-0417-x

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Clinical series: 141 consecutive patients with neuropsychiatric abnormalities attributed to cobalamin deficiency; 40 lacked anemia or macrocytosis.

exposure

Clinical evaluation and cobalamin replacement; observational response series.

limitations

The reported 28% is not the percentage with both tests normal. Selected patients do not estimate population prevalence.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Normal red-cell size or hematocrit did not exclude the neurologic presentation.

primary_references

[b12-lindenbaum1988] Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis (1988). https://pubmed.ncbi.nlm.nih.gov/3374544/ DOI: 10.1056/nejm198806303182604

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1426–1436

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Clinical series: 141 consecutive patients with neuropsychiatric abnormalities attributed to cobalamin deficiency; 40 lacked anemia or macrocytosis. · source_derived_draft · unverified_draft

### b12-neuro-normal-blood-counts Of 141 neurologic B12-deficiency patients, 34 had normal hematocrit, 25 normal mean cell volume, and 19 both; 40 lacked at least one of these two abnormalities. Condition category: nutrient_deficiency nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Normal red-cell size or hematocrit did not exclude the neurologic presentation. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Clinical series: 141 consecutive patients with neuropsychiatric abnormalities attributed to cobalamin deficiency; 40 lacked anemia or macrocytosis. limitations: The reported 28% is not the percentage with both tests normal. Selected patients do not estimate population prevalence. exposure: Clinical evaluation and cobalamin replacement; observational response series. [b12-lindenbaum1988] Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis (1988). https://pubmed.ncbi.nlm.nih.gov/3374544/ DOI: 10.1056/nejm198806303182604

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Retrospective clinical series: 153 neurologic B12-deficiency episodes in 143 patients at two New York hospitals over 17 years.

exposure

Cobalamin treatment and clinical follow-up; 121 episodes had adequate neurologic response assessment.

limitations

Related investigators and hospital settings may overlap earlier clinical series. No guaranteed reversibility or universal time limit.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Treatment response and full recovery are different outcomes.

primary_references

[b12-healton1991] Neurologic aspects of cobalamin deficiency (1991). https://pubmed.ncbi.nlm.nih.gov/1648656/ DOI: 10.1097/00005792-199107000-00001

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1450–1460

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Retrospective clinical series: 153 neurologic B12-deficiency episodes in 143 patients at two New York hospitals over 17 years. · source_derived_draft · unverified_draft

### b12-neuro-recovery-incomplete In 121 adequately followed episodes, all responded and 57 (47.1%) recovered completely; post-treatment involvement was related to pretreatment severity and symptom duration. Condition category: nutrient_deficiency nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Treatment response and full recovery are different outcomes. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Retrospective clinical series: 153 neurologic B12-deficiency episodes in 143 patients at two New York hospitals over 17 years. limitations: Related investigators and hospital settings may overlap earlier clinical series. No guaranteed reversibility or universal time limit. exposure: Cobalamin treatment and clinical follow-up; 121 episodes had adequate neurologic response assessment. [b12-healton1991] Neurologic aspects of cobalamin deficiency (1991). https://pubmed.ncbi.nlm.nih.gov/1648656/ DOI: 10.1097/00005792-199107000-00001

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Clinical series: 141 consecutive patients with neuropsychiatric abnormalities attributed to cobalamin deficiency; 40 lacked anemia or macrocytosis.

exposure

Clinical evaluation and cobalamin replacement; observational response series.

limitations

Uncontrolled selected series; response does not mean complete recovery or prove that every neuropsychiatric symptom is caused by B12.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

A blood count could look unremarkable while a B12-responsive nervous-system problem was present.

primary_references

[b12-lindenbaum1988] Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis (1988). https://pubmed.ncbi.nlm.nih.gov/3374544/ DOI: 10.1056/nejm198806303182604

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1438–1448

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Clinical series: 141 consecutive patients with neuropsychiatric abnormalities attributed to cobalamin deficiency; 40 lacked anemia or macrocytosis. · source_derived_draft · unverified_draft

### b12-neuro-treatment-response Among the 40 patients lacking at least one blood-count abnormality, one died in the first week; all 39 remaining patients showed neuropsychiatric improvement following cobalamin therapy. Condition category: nutrient_deficiency nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A blood count could look unremarkable while a B12-responsive nervous-system problem was present. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Clinical series: 141 consecutive patients with neuropsychiatric abnormalities attributed to cobalamin deficiency; 40 lacked anemia or macrocytosis. limitations: Uncontrolled selected series; response does not mean complete recovery or prove that every neuropsychiatric symptom is caused by B12. exposure: Clinical evaluation and cobalamin replacement; observational response series. [b12-lindenbaum1988] Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis (1988). https://pubmed.ncbi.nlm.nih.gov/3374544/ DOI: 10.1056/nejm198806303182604

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Retains the iron/B12 interaction without claiming either nutrient universally replaces the other.

experimental_model

Before/after series of 75 patients diagnosed with cobalamin deficiency.

exposure

Blood counts and iron-status measurements before and after cobalamin therapy; regimen is not extracted from the abstract.

limitations

A diagnostic reclassification is not proof of newly caused iron depletion.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

An accompanying iron shortage could become easier to recognize during recovery.

primary_references

[b12-solmaz2015] Cobalamin deficiency can mask depleted body iron reserves (2015). https://pubmed.ncbi.nlm.nih.gov/25825568/ DOI: 10.1007/s12288-014-0417-x

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1598–1609

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Before/after series of 75 patients diagnosed with cobalamin deficiency. · source_derived_draft · unverified_draft

### b12-repletion-iron-deficiency-detection Iron deficiency was identified in 7 of 75 patients before cobalamin therapy and 37 of 75 afterward. Condition category: nutrient_deficiency nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: An accompanying iron shortage could become easier to recognize during recovery. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Before/after series of 75 patients diagnosed with cobalamin deficiency. limitations: A diagnostic reclassification is not proof of newly caused iron depletion. exposure: Blood counts and iron-status measurements before and after cobalamin therapy; regimen is not extracted from the abstract. cross_nutrient: Retains the iron/B12 interaction without claiming either nutrient universally replaces the other. [b12-solmaz2015] Cobalamin deficiency can mask depleted body iron reserves (2015). https://pubmed.ncbi.nlm.nih.gov/25825568/ DOI: 10.1007/s12288-014-0417-x

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

B12-associated ineffective blood-cell production can complicate iron-status interpretation.

experimental_model

Before/after series of 75 patients diagnosed with cobalamin deficiency.

exposure

Blood counts and iron-status measurements before and after cobalamin therapy; regimen is not extracted from the abstract.

limitations

Before/after observations cannot isolate iron utilization from all other changes.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Restoring B12 changed how the blood iron results looked.

primary_references

[b12-solmaz2015] Cobalamin deficiency can mask depleted body iron reserves (2015). https://pubmed.ncbi.nlm.nih.gov/25825568/ DOI: 10.1007/s12288-014-0417-x

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1585–1596

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Before/after series of 75 patients diagnosed with cobalamin deficiency. · source_derived_draft · unverified_draft

### b12-repletion-iron-readouts After cobalamin therapy, mean serum iron fell from 126.4 to 59.1 micrograms/dL, ferritin from 192.5 to 44.9 ng/mL and transferrin saturation from 47.2% to 17.5%. Condition category: nutrient_deficiency nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Restoring B12 changed how the blood iron results looked. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Before/after series of 75 patients diagnosed with cobalamin deficiency. limitations: Before/after observations cannot isolate iron utilization from all other changes. exposure: Blood counts and iron-status measurements before and after cobalamin therapy; regimen is not extracted from the abstract. cross_nutrient: B12-associated ineffective blood-cell production can complicate iron-status interpretation. [b12-solmaz2015] Cobalamin deficiency can mask depleted body iron reserves (2015). https://pubmed.ncbi.nlm.nih.gov/25825568/ DOI: 10.1007/s12288-014-0417-x

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

evidence_location

Full text Results: vitamin B12 supplementation; Figure 4g-u

experimental_model

Differentiating ECHDC1-knockout mouse L929 adipocytes (Figure 4g-u)

exposure

ECHDC1 knockout; 2.5 micromolar supplementary B12 during differentiation

limitations

GC-MS abundance endpoint; do not infer unchanged synthesis flux or universal myelin effects.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Mus musculus

plain_language

Lower precursor pools did not translate into a large branched-fat reduction in this mouse-cell model. The cells had ECHDC1 deleted.

primary_references

[dewulf-2019-l929-b12] The synthesis of branched-chain fatty acids is limited by enzymatic decarboxylation of ethyl- and methylmalonyl-CoA. (2019). https://pubmed.ncbi.nlm.nih.gov/31416829/ DOI: 10.1042/bcj20190500

tissue_or_cell_type

Adipocytes

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1286–1298

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Differentiating ECHDC1-knockout mouse L929 adipocytes (Figure 4g-u) · source_derived_draft · unverified_draft

### l929-b12-limited-lipid-response Despite lower acyl-CoA pools, B12 supplementation barely changed measured methyl-branched fatty acids in ECHDC1-knockout L929 adipocytes. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Lower precursor pools did not translate into a large branched-fat reduction in this mouse-cell model. The cells had ECHDC1 deleted. organism: Mus musculus tissue_or_cell_type: Adipocytes experimental_model: Differentiating ECHDC1-knockout mouse L929 adipocytes (Figure 4g-u) limitations: GC-MS abundance endpoint; do not infer unchanged synthesis flux or universal myelin effects. exposure: ECHDC1 knockout; 2.5 micromolar supplementary B12 during differentiation cross_nutrient: false evidence_location: Full text Results: vitamin B12 supplementation; Figure 4g-u [dewulf-2019-l929-b12] The synthesis of branched-chain fatty acids is limited by enzymatic decarboxylation of ethyl- and methylmalonyl-CoA. (2019). https://pubmed.ncbi.nlm.nih.gov/31416829/ DOI: 10.1042/bcj20190500

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

evidence_location

Full text Results: vitamin B12 supplementation; Figure 4g-u

experimental_model

Differentiating ECHDC1-knockout mouse L929 adipocytes (Figure 4g-u)

exposure

ECHDC1 knockout; 2.5 micromolar supplementary B12 during differentiation

limitations

Whole-cell LC-MS pools; no compartment or epimer resolution and no direct pathway flux measurement.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Mus musculus

plain_language

B12 addition sharply lowered this measured precursor pool in cultured mouse adipocytes. The cells had ECHDC1 deleted.

primary_references

[dewulf-2019-l929-b12] The synthesis of branched-chain fatty acids is limited by enzymatic decarboxylation of ethyl- and methylmalonyl-CoA. (2019). https://pubmed.ncbi.nlm.nih.gov/31416829/ DOI: 10.1042/bcj20190500

tissue_or_cell_type

Adipocytes

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1258–1270

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Differentiating ECHDC1-knockout mouse L929 adipocytes (Figure 4g-u) · source_derived_draft · unverified_draft

### l929-b12-lowers-methylmalonyl-pool Adding 2.5 micromolar B12 during ECHDC1-knockout L929 adipocyte differentiation lowered whole-cell methylmalonyl-CoA approximately 20-fold. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: B12 addition sharply lowered this measured precursor pool in cultured mouse adipocytes. The cells had ECHDC1 deleted. organism: Mus musculus tissue_or_cell_type: Adipocytes experimental_model: Differentiating ECHDC1-knockout mouse L929 adipocytes (Figure 4g-u) limitations: Whole-cell LC-MS pools; no compartment or epimer resolution and no direct pathway flux measurement. exposure: ECHDC1 knockout; 2.5 micromolar supplementary B12 during differentiation cross_nutrient: false evidence_location: Full text Results: vitamin B12 supplementation; Figure 4g-u [dewulf-2019-l929-b12] The synthesis of branched-chain fatty acids is limited by enzymatic decarboxylation of ethyl- and methylmalonyl-CoA. (2019). https://pubmed.ncbi.nlm.nih.gov/31416829/ DOI: 10.1042/bcj20190500

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

evidence_location

Full text Results: vitamin B12 supplementation; Figure 4g-u

experimental_model

Differentiating ECHDC1-knockout mouse L929 adipocytes (Figure 4g-u)

exposure

ECHDC1 knockout; 2.5 micromolar supplementary B12 during differentiation

limitations

Whole-cell LC-MS pools; no compartment or epimer resolution and no direct pathway flux measurement.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Mus musculus

plain_language

In the same mouse-cell experiment, B12 also lowered the upstream propionyl-CoA pool. The cells had ECHDC1 deleted.

primary_references

[dewulf-2019-l929-b12] The synthesis of branched-chain fatty acids is limited by enzymatic decarboxylation of ethyl- and methylmalonyl-CoA. (2019). https://pubmed.ncbi.nlm.nih.gov/31416829/ DOI: 10.1042/bcj20190500

tissue_or_cell_type

Adipocytes

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1272–1284

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Differentiating ECHDC1-knockout mouse L929 adipocytes (Figure 4g-u) · source_derived_draft · unverified_draft

### l929-b12-lowers-propionyl-pool B12 supplementation lowered the measured propionyl-CoA pool approximately fourfold in differentiating ECHDC1-knockout L929 adipocytes. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: In the same mouse-cell experiment, B12 also lowered the upstream propionyl-CoA pool. The cells had ECHDC1 deleted. organism: Mus musculus tissue_or_cell_type: Adipocytes experimental_model: Differentiating ECHDC1-knockout mouse L929 adipocytes (Figure 4g-u) limitations: Whole-cell LC-MS pools; no compartment or epimer resolution and no direct pathway flux measurement. exposure: ECHDC1 knockout; 2.5 micromolar supplementary B12 during differentiation cross_nutrient: false evidence_location: Full text Results: vitamin B12 supplementation; Figure 4g-u [dewulf-2019-l929-b12] The synthesis of branched-chain fatty acids is limited by enzymatic decarboxylation of ethyl- and methylmalonyl-CoA. (2019). https://pubmed.ncbi.nlm.nih.gov/31416829/ DOI: 10.1042/bcj20190500

cross_nutrient

false

evidence_location

Results: Figures 3, 4, 5; Experimental procedures: liposomes and transport assays

experimental_model

Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression

exposure

100 micromolar lumenal cobalamin, external ATP, 37 C

limitations

Artificial membrane orientation models lysosomal export; exact cobalamin upper ligand was not specified in retrieved methods.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

ABCD4 used ATP-dependent machinery to move B12 across a membrane.

primary_references

[kitai-2021-abcd4-transport] The lysosomal protein ABCD4 can transport vitamin B12 across liposomal membranes in vitro (2021). https://pubmed.ncbi.nlm.nih.gov/33845046/ DOI: 10.1016/j.jbc.2021.100654

tissue_or_cell_type

Cell-free membrane system

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 613–625

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression · source_derived_draft · unverified_draft

### b12-abcd4-atp-export Reconstituted human ABCD4 moved cobalamin from liposome interior to exterior with external ATP; the ATPase-defective K427A control lacked this activity. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: ABCD4 used ATP-dependent machinery to move B12 across a membrane. organism: Homo sapiens tissue_or_cell_type: Cell-free membrane system experimental_model: Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression limitations: Artificial membrane orientation models lysosomal export; exact cobalamin upper ligand was not specified in retrieved methods. exposure: 100 micromolar lumenal cobalamin, external ATP, 37 C cross_nutrient: false evidence_location: Results: Figures 3, 4, 5; Experimental procedures: liposomes and transport assays [kitai-2021-abcd4-transport] The lysosomal protein ABCD4 can transport vitamin B12 across liposomal membranes in vitro (2021). https://pubmed.ncbi.nlm.nih.gov/33845046/ DOI: 10.1016/j.jbc.2021.100654

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

evidence_location

Results: Figures 3, 4, 5; Experimental procedures: liposomes and transport assays

experimental_model

Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression

exposure

Variant versus wild-type ABCD4 proteoliposomes

limitations

Disease-related variant tested outside cells; ATP hydrolysis and transport are distinct measured endpoints.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

The variant disrupted B12 movement across the membrane.

primary_references

[kitai-2021-abcd4-transport] The lysosomal protein ABCD4 can transport vitamin B12 across liposomal membranes in vitro (2021). https://pubmed.ncbi.nlm.nih.gov/33845046/ DOI: 10.1016/j.jbc.2021.100654

tissue_or_cell_type

Cell-free membrane system

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 641–653

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression · source_derived_draft · unverified_draft

### b12-abcd4-n141k-transport Purified human ABCD4 N141K lost detectable cobalamin transport in liposomes, despite ATPase activity comparable with wild type. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The variant disrupted B12 movement across the membrane. organism: Homo sapiens tissue_or_cell_type: Cell-free membrane system experimental_model: Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression limitations: Disease-related variant tested outside cells; ATP hydrolysis and transport are distinct measured endpoints. exposure: Variant versus wild-type ABCD4 proteoliposomes cross_nutrient: false evidence_location: Results: Figures 3, 4, 5; Experimental procedures: liposomes and transport assays [kitai-2021-abcd4-transport] The lysosomal protein ABCD4 can transport vitamin B12 across liposomal membranes in vitro (2021). https://pubmed.ncbi.nlm.nih.gov/33845046/ DOI: 10.1016/j.jbc.2021.100654

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

evidence_location

Results: Figures 3, 4, 5; Experimental procedures: liposomes and transport assays

experimental_model

Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression

exposure

Variant versus wild-type ABCD4 proteoliposomes

limitations

Disease-related variant tested outside cells; ATP hydrolysis and transport are distinct measured endpoints.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

The variant disrupted B12 movement across the membrane.

primary_references

[kitai-2021-abcd4-transport] The lysosomal protein ABCD4 can transport vitamin B12 across liposomal membranes in vitro (2021). https://pubmed.ncbi.nlm.nih.gov/33845046/ DOI: 10.1016/j.jbc.2021.100654

tissue_or_cell_type

Cell-free membrane system

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 655–667

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression · source_derived_draft · unverified_draft

### b12-abcd4-y319c-transport Purified human ABCD4 Y319C lost detectable cobalamin transport in liposomes, together with loss of ATPase activity. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The variant disrupted B12 movement across the membrane. organism: Homo sapiens tissue_or_cell_type: Cell-free membrane system experimental_model: Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression limitations: Disease-related variant tested outside cells; ATP hydrolysis and transport are distinct measured endpoints. exposure: Variant versus wild-type ABCD4 proteoliposomes cross_nutrient: false evidence_location: Results: Figures 3, 4, 5; Experimental procedures: liposomes and transport assays [kitai-2021-abcd4-transport] The lysosomal protein ABCD4 can transport vitamin B12 across liposomal membranes in vitro (2021). https://pubmed.ncbi.nlm.nih.gov/33845046/ DOI: 10.1016/j.jbc.2021.100654

cross_nutrient

false

experimental_model

In vitro egg-yolk cobalamin-binding protein mixed with human saliva/gastric juice

exposure

Acidified human saliva/gastric juice with egg-yolk-bound radiocobalamin

limitations

Food-specific biochemical model; this pH threshold is not a clinical blood threshold or proof that all foods behave identically. Pepsin preparation species was not specified in the inspected abstract.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

The first observed carrier was haptocorrin.

primary_references

[carmel-1990-food-transfer] Transfer of cobalamin from the cobalamin-binding protein of egg yolk to R binder of human saliva and gastric juice. (1990). https://pubmed.ncbi.nlm.nih.gov/2110915/ DOI: 10.1016/0016-5085(90)91076-i

tissue_or_cell_type

Gastric luminal digestion model

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 114–125

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · In vitro egg-yolk cobalamin-binding protein mixed with human saliva/gastric juice · source_derived_draft · unverified_draft

### b12-abs-food-haptocorrin-capture In egg-yolk transfer assays, human R binder accepted released cobalamin, whereas direct transfer to intrinsic factor was not detected and R-binder-deficient gastric juice failed to accept it. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The first observed carrier was haptocorrin. organism: Homo sapiens tissue_or_cell_type: Gastric luminal digestion model experimental_model: In vitro egg-yolk cobalamin-binding protein mixed with human saliva/gastric juice limitations: Food-specific biochemical model; this pH threshold is not a clinical blood threshold or proof that all foods behave identically. Pepsin preparation species was not specified in the inspected abstract. exposure: Acidified human saliva/gastric juice with egg-yolk-bound radiocobalamin cross_nutrient: false [carmel-1990-food-transfer] Transfer of cobalamin from the cobalamin-binding protein of egg yolk to R binder of human saliva and gastric juice. (1990). https://pubmed.ncbi.nlm.nih.gov/2110915/ DOI: 10.1016/0016-5085(90)91076-i

cross_nutrient

false

experimental_model

Purified human salivary R protein and gastric intrinsic factor in vitro

exposure

pH 2 or 8; purified protein competition

limitations

Reconstituted binding/protease conditions; measured competition does not quantify absorption in an intact person. Individual protease isoforms and reagent species not resolved in abstract.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Haptocorrin outcompeted intrinsic factor, especially in acid.

primary_references

[allen-1978-proteases] Effect of proteolytic enzymes on the binding of cobalamin to R protein and intrinsic factor. In vitro evidence that a failure to partially degrade R protein is responsible for cobalamin malabsorption in pancreatic insufficiency. (1978). https://pubmed.ncbi.nlm.nih.gov/22556/ DOI: 10.1172/jci108924

tissue_or_cell_type

Salivary/gastric and intestinal luminal binding models

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 153–164

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human salivary R protein and gastric intrinsic factor in vitro · source_derived_draft · unverified_draft

### b12-abs-haptocorrin-affinity Human salivary R protein bound cobalamin with 50-fold higher affinity than human intrinsic factor at pH 2 and threefold higher affinity at pH 8. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Haptocorrin outcompeted intrinsic factor, especially in acid. organism: Homo sapiens tissue_or_cell_type: Salivary/gastric and intestinal luminal binding models experimental_model: Purified human salivary R protein and gastric intrinsic factor in vitro limitations: Reconstituted binding/protease conditions; measured competition does not quantify absorption in an intact person. Individual protease isoforms and reagent species not resolved in abstract. exposure: pH 2 or 8; purified protein competition cross_nutrient: false [allen-1978-proteases] Effect of proteolytic enzymes on the binding of cobalamin to R protein and intrinsic factor. In vitro evidence that a failure to partially degrade R protein is responsible for cobalamin malabsorption in pancreatic insufficiency. (1978). https://pubmed.ncbi.nlm.nih.gov/22556/ DOI: 10.1172/jci108924

cross_nutrient

false

evidence_location

Results: Figures 3, 4, 5; Experimental procedures: liposomes and transport assays

experimental_model

Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression

exposure

LMBD1-only versus ABCD4-containing proteoliposomes

limitations

Assay-specific absence of activity does not negate LMBD1’s cellular targeting role.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

The escort alone did not transport B12 in this membrane assay.

primary_references

[kitai-2021-abcd4-transport] The lysosomal protein ABCD4 can transport vitamin B12 across liposomal membranes in vitro (2021). https://pubmed.ncbi.nlm.nih.gov/33845046/ DOI: 10.1016/j.jbc.2021.100654

tissue_or_cell_type

Cell-free membrane system

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 627–639

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression · source_derived_draft · unverified_draft

### b12-lmbd1-no-direct-transport LMBD1-only proteoliposomes had no detectable cobalamin transport in the same reconstitution system in which ABCD4 transported cobalamin. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The escort alone did not transport B12 in this membrane assay. organism: Homo sapiens tissue_or_cell_type: Cell-free membrane system experimental_model: Purified human ABCD4/LMBD1 in synthetic liposomes after yeast expression limitations: Assay-specific absence of activity does not negate LMBD1’s cellular targeting role. exposure: LMBD1-only versus ABCD4-containing proteoliposomes cross_nutrient: false evidence_location: Results: Figures 3, 4, 5; Experimental procedures: liposomes and transport assays [kitai-2021-abcd4-transport] The lysosomal protein ABCD4 can transport vitamin B12 across liposomal membranes in vitro (2021). https://pubmed.ncbi.nlm.nih.gov/33845046/ DOI: 10.1016/j.jbc.2021.100654

evidence_span

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experimental_model

Long-duration high-copper feeding study

exposure

Nine men; prolonged high copper intake including 7 mg/day supplementation phase

limitations

Small intervention with biomarker outcomes; it does not establish copper as a human methionine-synthase cofactor, B-vitamin depletion, or benefit from high copper intake.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human young men

plain_language

Several vitamin-related blood markers shifted, but that does not identify a new copper-dependent methylation enzyme.

primary_references

[copper-p15325682] Effect of long-term, high-copper intake on the concentrations of plasma homocysteine and B vitamins in young men. (2004). https://pubmed.ncbi.nlm.nih.gov/15325682/ DOI: 10.1016/j.nut.2004.05.011

tissue_or_cell_type

Plasma homocysteine, folate, B12 and PLP

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1183–1194

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Long-duration high-copper feeding study · source_derived_draft · unverified_draft

### copper-copper-homocysteine-folate High copper intake in nine men produced small decreases in plasma homocysteine and folate, without changes in B12 or PLP measures. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: Several vitamin-related blood markers shifted, but that does not identify a new copper-dependent methylation enzyme. organism: Human young men tissue_or_cell_type: Plasma homocysteine, folate, B12 and PLP experimental_model: Long-duration high-copper feeding study limitations: Small intervention with biomarker outcomes; it does not establish copper as a human methionine-synthase cofactor, B-vitamin depletion, or benefit from high copper intake. exposure: Nine men; prolonged high copper intake including 7 mg/day supplementation phase evidence_span: {"source_cache": "artifacts/copper-research/15325682.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4b6a41a9645d006de2098c2ca83f5aaeab2f1d4d76608b1131dc47d0e2e4148a", "start_char": 0, "end_char": 1606, "text_sha256": "4b6a41a9645d006de2098c2ca83f5aaeab2f1d4d76608b1131dc47d0e2e4148a"} [copper-p15325682] Effect of long-term, high-copper intake on the concentrations of plasma homocysteine and B vitamins in young men. (2004). https://pubmed.ncbi.nlm.nih.gov/15325682/ DOI: 10.1016/j.nut.2004.05.011

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

true

evidence_location

Primary abstract, cubilin sequestration and human urinary loss.

experimental_model

Human inherited cubilin dysfunction; supporting receptor experiments

exposure

Inherited CUBN dysfunction; patient details/doses not specified in retrieved abstract.

limitations

This shared B12/D transport machinery does not mean dietary B12 deficiency causes urinary D loss. Genotype-phenotype evidence is observational.

nutrient

Vitamin D2 and D3 · Vitamin D2 and D3

nutrient_topic

Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin D2 and D3

organism

Homo sapiens

plain_language

Cubilin defects can cause loss of vitamin D precursor through urine.

primary_references

[nykjaer2001] Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3). (2001). https://pubmed.ncbi.nlm.nih.gov/11717447/ DOI: 10.1073/pnas.241516998

tissue_or_cell_type

kidney proximal tubule and urine

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin D2 and D3: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 257–270

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human inherited cubilin dysfunction; supporting receptor experiments · source_derived_draft · unverified_draft

### vd-act-cubilin-human-loss Human patients with mutations causing cubilin dysfunction excreted calcifediol in urine, supporting the cubilin-dependent renal carrier-retrieval pathway. Condition category: machinery_impairment nutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cubilin defects can cause loss of vitamin D precursor through urine. organism: Homo sapiens tissue_or_cell_type: kidney proximal tubule and urine experimental_model: Human inherited cubilin dysfunction; supporting receptor experiments limitations: This shared B12/D transport machinery does not mean dietary B12 deficiency causes urinary D loss. Genotype-phenotype evidence is observational. exposure: Inherited CUBN dysfunction; patient details/doses not specified in retrieved abstract. cross_nutrient: true evidence_location: Primary abstract, cubilin sequestration and human urinary loss. nutrient: Vitamin D2 and D3 [nykjaer2001] Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3). (2001). https://pubmed.ncbi.nlm.nih.gov/11717447/ DOI: 10.1073/pnas.241516998

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

evidence_location

Abstract

experimental_model

Human cblJ disease and cellular characterization

exposure

Inherited ABCD4 mutations

limitations

Primary abstract supports the release defect; mutation-specific magnitudes were not extracted.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

An inherited transporter defect can trap B12 in lysosomes.

primary_references

[coelho-2012-abcd4] Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism (2012). https://pubmed.ncbi.nlm.nih.gov/22922874/ DOI: 10.1038/ng.2386

tissue_or_cell_type

Patient-derived cultured cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 557–569

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human cblJ disease and cellular characterization · source_derived_draft · unverified_draft

### b12-abcd4-defect-export The human disorder assigned to pathogenic ABCD4 mutations showed failure of lysosomal vitamin B12 release, resembling the cblF cellular defect. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: An inherited transporter defect can trap B12 in lysosomes. organism: Homo sapiens tissue_or_cell_type: Patient-derived cultured cells experimental_model: Human cblJ disease and cellular characterization limitations: Primary abstract supports the release defect; mutation-specific magnitudes were not extracted. exposure: Inherited ABCD4 mutations cross_nutrient: false evidence_location: Abstract [coelho-2012-abcd4] Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism (2012). https://pubmed.ncbi.nlm.nih.gov/22922874/ DOI: 10.1038/ng.2386

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

evidence_location

Figure 4c

experimental_model

HEK293T human tagged-protein interface mutagenesis

exposure

ABCD4-HA Y482A plus LMBD1-GFP-Flag versus wild type

limitations

Experimental Y482A substitution and overexpression; no claim that this is a disease allele or a direct flux measurement.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Changing the transporter’s interface weakened its association with the escort.

primary_references

[liu-2026-abcd4-interface] Structural basis for LMBD1-dependent trafficking and cobalamin export of ABCD4 (2026). https://pubmed.ncbi.nlm.nih.gov/42303638/ DOI: 10.1038/s41467-026-74552-5

tissue_or_cell_type

Human embryonic kidney-derived cell line

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 949–961

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HEK293T human tagged-protein interface mutagenesis · source_derived_draft · unverified_draft

### b12-abcd4-y482a-binding Human ABCD4 Y482A showed markedly impaired association with LMBD1 in HEK293T co-immunoprecipitation compared with wild-type ABCD4. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Changing the transporter’s interface weakened its association with the escort. organism: Homo sapiens tissue_or_cell_type: Human embryonic kidney-derived cell line experimental_model: HEK293T human tagged-protein interface mutagenesis limitations: Experimental Y482A substitution and overexpression; no claim that this is a disease allele or a direct flux measurement. exposure: ABCD4-HA Y482A plus LMBD1-GFP-Flag versus wild type cross_nutrient: false evidence_location: Figure 4c [liu-2026-abcd4-interface] Structural basis for LMBD1-dependent trafficking and cobalamin export of ABCD4 (2026). https://pubmed.ncbi.nlm.nih.gov/42303638/ DOI: 10.1038/s41467-026-74552-5

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

evidence_location

Supplementary Figure 12a,b

experimental_model

HEK293T human tagged-protein interface mutagenesis

exposure

ABCD4-HA Y482A plus LMBD1-GFP-Flag versus wild type

limitations

Experimental Y482A substitution and overexpression; no claim that this is a disease allele or a direct flux measurement.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

The interface variant failed to reach lysosomes normally.

primary_references

[liu-2026-abcd4-interface] Structural basis for LMBD1-dependent trafficking and cobalamin export of ABCD4 (2026). https://pubmed.ncbi.nlm.nih.gov/42303638/ DOI: 10.1038/s41467-026-74552-5

tissue_or_cell_type

Human embryonic kidney-derived cell line

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 963–975

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HEK293T human tagged-protein interface mutagenesis · source_derived_draft · unverified_draft

### b12-abcd4-y482a-targeting Human ABCD4 Y482A coexpressed with LMBD1 in HEK293T cells showed a reticular distribution without normal LAMP1 overlap. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The interface variant failed to reach lysosomes normally. organism: Homo sapiens tissue_or_cell_type: Human embryonic kidney-derived cell line experimental_model: HEK293T human tagged-protein interface mutagenesis limitations: Experimental Y482A substitution and overexpression; no claim that this is a disease allele or a direct flux measurement. exposure: ABCD4-HA Y482A plus LMBD1-GFP-Flag versus wild type cross_nutrient: false evidence_location: Supplementary Figure 12a,b [liu-2026-abcd4-interface] Structural basis for LMBD1-dependent trafficking and cobalamin export of ABCD4 (2026). https://pubmed.ncbi.nlm.nih.gov/42303638/ DOI: 10.1038/s41467-026-74552-5

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Human AMN double-signal mutant plus rat cubilin 1-1389 in CHO-K1 cells

exposure

Both cytoplasmic motifs disrupted; wild-type and single-motif mutants as comparators

limitations

Engineered trafficking defect, not a patient genotype. Surface binding and intracellular entry are separate readouts.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Human AMN; rat cubilin; Chinese hamster host cells; human/porcine IF reagents

plain_language

A receptor can reach the surface yet fail to internalize its cargo.

primary_references

[pedersen-2010-amn-endocytosis] AMN directs endocytosis of the intrinsic factor-vitamin B(12) receptor cubam by engaging ARH or Dab2. (2010). https://pubmed.ncbi.nlm.nih.gov/20088845/ DOI: 10.1111/j.1600-0854.2010.01042.x

tissue_or_cell_type

Engineered receptor internalization model

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 491–502

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human AMN double-signal mutant plus rat cubilin 1-1389 in CHO-K1 cells · source_derived_draft · unverified_draft

### b12-abs-amn-endocytic-signal-loss Disruption of both human AMN FXNPXF motifs impaired IF-B12 internalization and degradation in CHO-K1 cells despite preserved cubam surface expression. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A receptor can reach the surface yet fail to internalize its cargo. organism: Human AMN; rat cubilin; Chinese hamster host cells; human/porcine IF reagents tissue_or_cell_type: Engineered receptor internalization model experimental_model: Human AMN double-signal mutant plus rat cubilin 1-1389 in CHO-K1 cells limitations: Engineered trafficking defect, not a patient genotype. Surface binding and intracellular entry are separate readouts. exposure: Both cytoplasmic motifs disrupted; wild-type and single-motif mutants as comparators cross_nutrient: false [pedersen-2010-amn-endocytosis] AMN directs endocytosis of the intrinsic factor-vitamin B(12) receptor cubam by engaging ARH or Dab2. (2010). https://pubmed.ncbi.nlm.nih.gov/20088845/ DOI: 10.1111/j.1600-0854.2010.01042.x

cross_nutrient

false

experimental_model

Human AMN plus rat cubilin minireceptor in CHO-K1 cells

exposure

Labeled human/porcine IF-B12 at 37 degrees C over 1-8 hours

limitations

Reconstituted mixed-species system. Cell-associated radiolabel includes surface-bound cargo and must not be equated with internalized ligand.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Human AMN; rat cubilin; Chinese hamster host cells; human/porcine IF reagents

plain_language

Amnionless supplies signals that bring receptor-bound B12 into cells.

primary_references

[pedersen-2010-amn-endocytosis] AMN directs endocytosis of the intrinsic factor-vitamin B(12) receptor cubam by engaging ARH or Dab2. (2010). https://pubmed.ncbi.nlm.nih.gov/20088845/ DOI: 10.1111/j.1600-0854.2010.01042.x

tissue_or_cell_type

Engineered plasma-membrane endocytosis model

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 478–489

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human AMN plus rat cubilin minireceptor in CHO-K1 cells · source_derived_draft · unverified_draft

### b12-abs-amn-endocytosis Human AMN coexpressed with rat cubilin 1-1389 enabled IF-B12 internalization in CHO-K1 cells; either intact FXNPXF cytoplasmic motif supported uptake. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Amnionless supplies signals that bring receptor-bound B12 into cells. organism: Human AMN; rat cubilin; Chinese hamster host cells; human/porcine IF reagents tissue_or_cell_type: Engineered plasma-membrane endocytosis model experimental_model: Human AMN plus rat cubilin minireceptor in CHO-K1 cells limitations: Reconstituted mixed-species system. Cell-associated radiolabel includes surface-bound cargo and must not be equated with internalized ligand. exposure: Labeled human/porcine IF-B12 at 37 degrees C over 1-8 hours cross_nutrient: false [pedersen-2010-amn-endocytosis] AMN directs endocytosis of the intrinsic factor-vitamin B(12) receptor cubam by engaging ARH or Dab2. (2010). https://pubmed.ncbi.nlm.nih.gov/20088845/ DOI: 10.1111/j.1600-0854.2010.01042.x

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Two affected siblings and family carriers; urinary receptor characterization

exposure

Inherited compound AMN nonsense/splice genotype

limitations

Urinary receptor activity is a localization-related readout; it is not direct intestinal flux. Heterozygous relatives were unaffected.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Faulty amnionless reduced available receptor without changing its affinity.

primary_references

[namour-2011-amn] Luminal expression of cubilin is impaired in Imerslund-Grasbeck syndrome with compound AMN mutations in intron 3 and exon 7. (2011). https://pubmed.ncbi.nlm.nih.gov/21750092/ DOI: 10.3324/haematol.2011.043984

tissue_or_cell_type

Renal epithelial receptor expression

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 296–307

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two affected siblings and family carriers; urinary receptor characterization · source_derived_draft · unverified_draft

### b12-abs-amn-human-receptor Two siblings with AMN p.Gln248Ter/c.208-2A>G compound heterozygosity had markedly reduced urinary cubilin receptor activity despite preserved intrinsic-factor binding affinity and no CUBN mutation. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Faulty amnionless reduced available receptor without changing its affinity. organism: Homo sapiens tissue_or_cell_type: Renal epithelial receptor expression experimental_model: Two affected siblings and family carriers; urinary receptor characterization limitations: Urinary receptor activity is a localization-related readout; it is not direct intestinal flux. Heterozygous relatives were unaffected. exposure: Inherited compound AMN nonsense/splice genotype cross_nutrient: false [namour-2011-amn] Luminal expression of cubilin is impaired in Imerslund-Grasbeck syndrome with compound AMN mutations in intron 3 and exon 7. (2011). https://pubmed.ncbi.nlm.nih.gov/21750092/ DOI: 10.3324/haematol.2011.043984

cross_nutrient

false

experimental_model

Rat N-terminal mini-cubilin plus human AMN; HEK293T, MDCK, human RPTEC and HCT116

exposure

Recombinant coexpression versus single transfection

limitations

Mixed-species truncated construct lacks the complete CUB5-8 IF-binding region; surface expression is not direct B12 uptake.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Rattus norvegicus construct; Homo sapiens AMN; human/canine host cells

plain_language

Amnionless helped the experimental receptor reach the cell surface.

primary_references

[udagawa-2018-glycosylation] Amnionless-mediated glycosylation is crucial for cell surface targeting of cubilin in renal and intestinal cells. (2018). https://pubmed.ncbi.nlm.nih.gov/29402915/ DOI: 10.1038/s41598-018-20731-4

tissue_or_cell_type

Cultured renal and colorectal epithelial cells

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 322–333

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat N-terminal mini-cubilin plus human AMN; HEK293T, MDCK, human RPTEC and HCT116 · source_derived_draft · unverified_draft

### b12-abs-amn-trafficking-rat-construct Human AMN coexpression allowed rat mini-cubilin to reach the plasma membrane in HEK293T and other tested renal/intestinal cell models, whereas mini-cubilin alone remained intracellular. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Amnionless helped the experimental receptor reach the cell surface. organism: Rattus norvegicus construct; Homo sapiens AMN; human/canine host cells tissue_or_cell_type: Cultured renal and colorectal epithelial cells experimental_model: Rat N-terminal mini-cubilin plus human AMN; HEK293T, MDCK, human RPTEC and HCT116 limitations: Mixed-species truncated construct lacks the complete CUB5-8 IF-binding region; surface expression is not direct B12 uptake. exposure: Recombinant coexpression versus single transfection cross_nutrient: false [udagawa-2018-glycosylation] Amnionless-mediated glycosylation is crucial for cell surface targeting of cubilin in renal and intestinal cells. (2018). https://pubmed.ncbi.nlm.nih.gov/29402915/ DOI: 10.1038/s41598-018-20731-4

cross_nutrient

false

experimental_model

Double-blind crossover in 14 healthy humans using 57Co-labeled rabbit liver

exposure

Short-term omeprazole versus placebo; dose not in inspected abstract

limitations

Short-term food tracer experiment, not a long-term deficiency outcome.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Suppressing acid delayed early stomach release in this experiment.

primary_references

[kittang-1987-anacidity] Effect of gastric anacidity on the release of cobalamins from food and their subsequent binding to R-protein. (1987). https://pubmed.ncbi.nlm.nih.gov/3423731/ DOI: 10.3109/00365528708991952

tissue_or_cell_type

Stomach lumen

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 127–138

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind crossover in 14 healthy humans using 57Co-labeled rabbit liver · source_derived_draft · unverified_draft

### b12-abs-anacidity-gastric In 14 healthy volunteers, omeprazole-induced anacidity slightly reduced release of orally administered labeled liver cobalamins in gastric aspirates at 5 and 30 minutes versus placebo. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Suppressing acid delayed early stomach release in this experiment. organism: Homo sapiens tissue_or_cell_type: Stomach lumen experimental_model: Double-blind crossover in 14 healthy humans using 57Co-labeled rabbit liver limitations: Short-term food tracer experiment, not a long-term deficiency outcome. exposure: Short-term omeprazole versus placebo; dose not in inspected abstract cross_nutrient: false [kittang-1987-anacidity] Effect of gastric anacidity on the release of cobalamins from food and their subsequent binding to R-protein. (1987). https://pubmed.ncbi.nlm.nih.gov/3423731/ DOI: 10.3109/00365528708991952

cross_nutrient

false

experimental_model

Double-blind crossover in 14 healthy humans using 57Co-labeled rabbit liver

exposure

Short-term omeprazole versus placebo

limitations

Luminal release is not systemic absorption; this observation cannot exclude long-term effects on status.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Most liver-bound B12 was still released by the jejunum.

primary_references

[kittang-1987-anacidity] Effect of gastric anacidity on the release of cobalamins from food and their subsequent binding to R-protein. (1987). https://pubmed.ncbi.nlm.nih.gov/3423731/ DOI: 10.3109/00365528708991952

tissue_or_cell_type

Upper jejunal lumen

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 140–151

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind crossover in 14 healthy humans using 57Co-labeled rabbit liver · source_derived_draft · unverified_draft

### b12-abs-anacidity-jejunum In the same crossover experiment, jejunal release of labeled liver cobalamins was near 90% after either omeprazole or placebo, despite earlier gastric effects. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Most liver-bound B12 was still released by the jejunum. organism: Homo sapiens tissue_or_cell_type: Upper jejunal lumen experimental_model: Double-blind crossover in 14 healthy humans using 57Co-labeled rabbit liver limitations: Luminal release is not systemic absorption; this observation cannot exclude long-term effects on status. exposure: Short-term omeprazole versus placebo cross_nutrient: false [kittang-1987-anacidity] Effect of gastric anacidity on the release of cobalamins from food and their subsequent binding to R-protein. (1987). https://pubmed.ncbi.nlm.nih.gov/3423731/ DOI: 10.3109/00365528708991952

cross_nutrient

true

experimental_model

21 adults with type 2 diabetes; 14 switched to metformin, then received calcium

exposure

Oral calcium after three months of metformin; dose not specified in inspected abstract

limitations

Small sequential comparative intervention. Serum holo-TC is an indirect absorption readout and does not directly prove membrane calcium antagonism.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Calcium increased the circulating B12-carrier marker after metformin.

primary_references

[bauman-2000-calcium] Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. (2000). https://pubmed.ncbi.nlm.nih.gov/10977010/ DOI: 10.2337/diacare.23.9.1227

tissue_or_cell_type

Circulating holo-transcobalamin

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 439–450

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 21 adults with type 2 diabetes; 14 switched to metformin, then received calcium · source_derived_draft · unverified_draft

### b12-abs-bauman-calcium-holotc In the comparative diabetes study, adding oral calcium after three months of metformin reversed the decline in serum holo-transcobalamin. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium increased the circulating B12-carrier marker after metformin. organism: Homo sapiens tissue_or_cell_type: Circulating holo-transcobalamin experimental_model: 21 adults with type 2 diabetes; 14 switched to metformin, then received calcium limitations: Small sequential comparative intervention. Serum holo-TC is an indirect absorption readout and does not directly prove membrane calcium antagonism. exposure: Oral calcium after three months of metformin; dose not specified in inspected abstract cross_nutrient: true [bauman-2000-calcium] Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. (2000). https://pubmed.ncbi.nlm.nih.gov/10977010/ DOI: 10.2337/diacare.23.9.1227

cross_nutrient

true

experimental_model

Recombinant human proteins; crystal complex at 3.3 angstrom

exposure

Purified complex containing calcium ions

limitations

Does not define a dietary calcium intake target or prove nutritional calcium deficiency causes B12 malabsorption.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Calcium helps intrinsic factor dock with the B12 receptor.

primary_references

[andersen-2010-if-cubn] Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes. (2010). https://pubmed.ncbi.nlm.nih.gov/20237569/ DOI: 10.1038/nature08874

tissue_or_cell_type

Extracellular ileal receptor binding site

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 257–268

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human proteins; crystal complex at 3.3 angstrom · source_derived_draft · unverified_draft

### b12-abs-calcium-recognition In the human IF-cobalamin/CUB5-8 structure, calcium-dependent contacts connect cubilin ligand-binding domains to intrinsic factor, providing a molecular basis for calcium-dependent recognition. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium helps intrinsic factor dock with the B12 receptor. organism: Homo sapiens tissue_or_cell_type: Extracellular ileal receptor binding site experimental_model: Recombinant human proteins; crystal complex at 3.3 angstrom limitations: Does not define a dietary calcium intake target or prove nutritional calcium deficiency causes B12 malabsorption. exposure: Purified complex containing calcium ions cross_nutrient: true [andersen-2010-if-cubn] Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes. (2010). https://pubmed.ncbi.nlm.nih.gov/20237569/ DOI: 10.1038/nature08874

cross_nutrient

true

experimental_model

Seven healthy adult completers; three experimental days separated by one-month washouts

exposure

Metformin 850 mg plus calcium 500 mg and carbon-13 cyanocobalamin

limitations

Small acute tracer pilot in healthy adults; cannot establish prevention of chronic deficiency or identify the exact molecular metformin target. Doses describe the experiment, not advice.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Calcium coadministration reversed the tracer reduction in this pilot.

primary_references

[muralidharan-2024-calcium] Effect of calcium supplementation on reversing metformin-based inhibition of vitamin B12 bioavailability in healthy adults using a [13C] cyanocobalamin tracer - A pilot study. (2024). https://pubmed.ncbi.nlm.nih.gov/38901951/ DOI: 10.1016/j.clnesp.2024.04.024

tissue_or_cell_type

Intestinal absorption assessed from serial venous tracer measurements

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 465–476

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Seven healthy adult completers; three experimental days separated by one-month washouts · source_derived_draft · unverified_draft

### b12-abs-calcium-tracer-rescue Adding calcium 500 mg to metformin 850 mg raised mean tracer bioavailability from 30.8% to 46.4% in seven healthy completers (p=0.003). Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium coadministration reversed the tracer reduction in this pilot. organism: Homo sapiens tissue_or_cell_type: Intestinal absorption assessed from serial venous tracer measurements experimental_model: Seven healthy adult completers; three experimental days separated by one-month washouts limitations: Small acute tracer pilot in healthy adults; cannot establish prevention of chronic deficiency or identify the exact molecular metformin target. Doses describe the experiment, not advice. exposure: Metformin 850 mg plus calcium 500 mg and carbon-13 cyanocobalamin cross_nutrient: true [muralidharan-2024-calcium] Effect of calcium supplementation on reversing metformin-based inhibition of vitamin B12 bioavailability in healthy adults using a [13C] cyanocobalamin tracer - A pilot study. (2024). https://pubmed.ncbi.nlm.nih.gov/38901951/ DOI: 10.1016/j.clnesp.2024.04.024

cross_nutrient

false

experimental_model

Human receptor identification and functional characterization

exposure

TC-cobalamin complex presented to receptor

limitations

No universal uptake rate, tissue sufficiency threshold, or assertion that this is the sole B12 entry route.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

CD320 brings carrier-bound B12 into cells.

primary_references

[quadros-2009-cd320] The protein and the gene encoding the receptor for the cellular uptake of transcobalamin-bound cobalamin. (2009). https://pubmed.ncbi.nlm.nih.gov/18779389/ DOI: 10.1182/blood-2008-05-158949

tissue_or_cell_type

Plasma-membrane endocytosis

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 374–385

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human receptor identification and functional characterization · source_derived_draft · unverified_draft

### b12-abs-cd320-cellular-delivery The human receptor identified as CD320 binds transcobalamin-cobalamin at the plasma membrane and internalizes the carrier-vitamin complex by endocytosis. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: CD320 brings carrier-bound B12 into cells. organism: Homo sapiens tissue_or_cell_type: Plasma-membrane endocytosis experimental_model: Human receptor identification and functional characterization limitations: No universal uptake rate, tissue sufficiency threshold, or assertion that this is the sole B12 entry route. exposure: TC-cobalamin complex presented to receptor cross_nutrient: false [quadros-2009-cd320] The protein and the gene encoding the receptor for the cellular uptake of transcobalamin-bound cobalamin. (2009). https://pubmed.ncbi.nlm.nih.gov/18779389/ DOI: 10.1182/blood-2008-05-158949

cross_nutrient

false

experimental_model

Human placental protein purification and recombinant receptor-domain analysis

exposure

Holo-TC binding to native or recombinant CD320

limitations

Binding-domain result does not show the cytoplasmic tail is dispensable for endocytosis.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

The outside portion of CD320 recognizes B12-loaded transcobalamin.

primary_references

[quadros-2009-cd320] The protein and the gene encoding the receptor for the cellular uptake of transcobalamin-bound cobalamin. (2009). https://pubmed.ncbi.nlm.nih.gov/18779389/ DOI: 10.1182/blood-2008-05-158949

tissue_or_cell_type

Placental plasma membrane/extracellular receptor domain

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 361–372

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human placental protein purification and recombinant receptor-domain analysis · source_derived_draft · unverified_draft

### b12-abs-cd320-holo-binding Purified human placental receptor and recombinant CD320 extracellular domain bound transcobalamin-cobalamin; high-affinity binding did not require the cytoplasmic domain or membrane orientation. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The outside portion of CD320 recognizes B12-loaded transcobalamin. organism: Homo sapiens tissue_or_cell_type: Placental plasma membrane/extracellular receptor domain experimental_model: Human placental protein purification and recombinant receptor-domain analysis limitations: Binding-domain result does not show the cytoplasmic tail is dispensable for endocytosis. exposure: Holo-TC binding to native or recombinant CD320 cross_nutrient: false [quadros-2009-cd320] The protein and the gene encoding the receptor for the cellular uptake of transcobalamin-bound cobalamin. (2009). https://pubmed.ncbi.nlm.nih.gov/18779389/ DOI: 10.1182/blood-2008-05-158949

cross_nutrient

false

experimental_model

Affinity purification and gel filtration of human kidney membrane proteins

exposure

IF-cobalamin affinity chromatography; nondenaturing versus denaturing separation

limitations

Native renal purification establishes association; intestinal uptake rate is not measured by this experiment.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Cubilin and amnionless form a stable receptor pair.

primary_references

[fyfe-2004-cubam] The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless. (2004). https://pubmed.ncbi.nlm.nih.gov/14576052/ DOI: 10.1182/blood-2003-08-2852

tissue_or_cell_type

Renal epithelial membranes

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 218–229

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Affinity purification and gel filtration of human kidney membrane proteins · source_derived_draft · unverified_draft

### b12-abs-cubam-association Human renal cubilin and AMN copurified and coeluted as a tightly associated complex that required denaturing conditions for separation. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cubilin and amnionless form a stable receptor pair. organism: Homo sapiens tissue_or_cell_type: Renal epithelial membranes experimental_model: Affinity purification and gel filtration of human kidney membrane proteins limitations: Native renal purification establishes association; intestinal uptake rate is not measured by this experiment. exposure: IF-cobalamin affinity chromatography; nondenaturing versus denaturing separation cross_nutrient: false [fyfe-2004-cubam] The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless. (2004). https://pubmed.ncbi.nlm.nih.gov/14576052/ DOI: 10.1182/blood-2003-08-2852

cross_nutrient

true

experimental_model

Human kidney cubilin-AMN purification with chelation

exposure

EDTA present during coelution

limitations

Chelation result concerns CUBN-AMN association, not IF-cobalamin docking or whole-body calcium deficiency.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Calcium dependence concerns ligand binding, not every receptor interaction.

primary_references

[fyfe-2004-cubam] The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless. (2004). https://pubmed.ncbi.nlm.nih.gov/14576052/ DOI: 10.1182/blood-2003-08-2852

tissue_or_cell_type

Renal epithelial receptor complex

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 231–242

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human kidney cubilin-AMN purification with chelation · source_derived_draft · unverified_draft

### b12-abs-cubam-association-calcium Human renal cubilin and AMN remained associated during coelution in EDTA, indicating that their mutual association did not require calcium under these conditions. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Calcium dependence concerns ligand binding, not every receptor interaction. organism: Homo sapiens tissue_or_cell_type: Renal epithelial receptor complex experimental_model: Human kidney cubilin-AMN purification with chelation limitations: Chelation result concerns CUBN-AMN association, not IF-cobalamin docking or whole-body calcium deficiency. exposure: EDTA present during coelution cross_nutrient: true [fyfe-2004-cubam] The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless. (2004). https://pubmed.ncbi.nlm.nih.gov/14576052/ DOI: 10.1182/blood-2003-08-2852

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

17 Finnish MGA1 families; linkage and molecular analysis

exposure

Inherited biallelic CUBN disease genotypes

limitations

Family-genetic evidence; allele-specific biochemical steps require separate functional experiments.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Inherited cubilin defects can block B12 absorption.

primary_references

[aminoff-1999-cubn] Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1. (1999). https://pubmed.ncbi.nlm.nih.gov/10080186/ DOI: 10.1038/6831

tissue_or_cell_type

Small-intestinal absorption

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 283–294

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 17 Finnish MGA1 families; linkage and molecular analysis · source_derived_draft · unverified_draft

### b12-abs-cubn-genetic-malabsorption Mapping and sequencing identified two independent disease-specific CUBN mutations across 17 Finnish families with selective intestinal cobalamin malabsorption. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Inherited cubilin defects can block B12 absorption. organism: Homo sapiens tissue_or_cell_type: Small-intestinal absorption experimental_model: 17 Finnish MGA1 families; linkage and molecular analysis limitations: Family-genetic evidence; allele-specific biochemical steps require separate functional experiments. exposure: Inherited biallelic CUBN disease genotypes cross_nutrient: false [aminoff-1999-cubn] Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1. (1999). https://pubmed.ncbi.nlm.nih.gov/10080186/ DOI: 10.1038/6831

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Human wild-type/P1297L fragments expressed in CHO cells; SPR

exposure

Site-directed P1297L substitution

limitations

Fragment binding assay; not every CUBN variant shares this mechanism.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

This cubilin variant binds its B12 carrier less efficiently.

primary_references

[kristiansen-2000-p1297l] Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor-vitamin B(12) by cubilin. (2000). https://pubmed.ncbi.nlm.nih.gov/10887099/ DOI: 10.1182/blood.v96.2.405

tissue_or_cell_type

Ileal receptor ligand-binding model

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 270–281

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human wild-type/P1297L fragments expressed in CHO cells; SPR · source_derived_draft · unverified_draft

### b12-abs-cubn-p1297l-affinity The human cubilin P1297L CUB5-8 fragment showed severalfold higher dissociation constant for IF-cobalamin than wild type, mainly from a lower association rate. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This cubilin variant binds its B12 carrier less efficiently. organism: Homo sapiens tissue_or_cell_type: Ileal receptor ligand-binding model experimental_model: Human wild-type/P1297L fragments expressed in CHO cells; SPR limitations: Fragment binding assay; not every CUBN variant shares this mechanism. exposure: Site-directed P1297L substitution cross_nutrient: false [kristiansen-2000-p1297l] Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor-vitamin B(12) by cubilin. (2000). https://pubmed.ncbi.nlm.nih.gov/10887099/ DOI: 10.1182/blood.v96.2.405

cross_nutrient

true

experimental_model

Recombinant human proteins; X-ray crystallography, PDB 3KQ4

exposure

Purified IF-cobalamin plus CUB5-8 fragment

limitations

Partial receptor crystal structure; recognition does not by itself establish endocytosis kinetics.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Cubilin recognizes B12 carried by intrinsic factor.

primary_references

[andersen-2010-if-cubn] Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes. (2010). https://pubmed.ncbi.nlm.nih.gov/20237569/ DOI: 10.1038/nature08874

tissue_or_cell_type

Extracellular ileal receptor recognition model

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 244–255

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human proteins; X-ray crystallography, PDB 3KQ4 · source_derived_draft · unverified_draft

### b12-abs-cubn-recognition The 3.3-angstrom human IF-cobalamin/CUB5-8 structure showed two separated cubilin CUB domains engaging the two intrinsic factor domains. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Cubilin recognizes B12 carried by intrinsic factor. organism: Homo sapiens tissue_or_cell_type: Extracellular ileal receptor recognition model experimental_model: Recombinant human proteins; X-ray crystallography, PDB 3KQ4 limitations: Partial receptor crystal structure; recognition does not by itself establish endocytosis kinetics. exposure: Purified IF-cobalamin plus CUB5-8 fragment cross_nutrient: true [andersen-2010-if-cubn] Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes. (2010). https://pubmed.ncbi.nlm.nih.gov/20237569/ DOI: 10.1038/nature08874

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Reconstruction of human deletion-bearing CD320 followed by codon repair

exposure

Insertion of the missing Glu88 codon

limitations

Laboratory functional rescue, not a tested treatment in newborns; exact host cell is not specified in the inspected abstract.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Repairing the missing receptor codon restored function in the assay.

primary_references

[quadros-2010-e88del] Positive newborn screen for methylmalonic aciduria identifies the first mutation in TCblR/CD320, the gene for cellular uptake of transcobalamin-bound vitamin B(12). (2010). https://pubmed.ncbi.nlm.nih.gov/20524213/ DOI: 10.1002/humu.21297

tissue_or_cell_type

Recombinant cellular receptor assay

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 400–411

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reconstruction of human deletion-bearing CD320 followed by codon repair · source_derived_draft · unverified_draft

### b12-abs-e88del-repair Replacing the missing Glu88 codon by site-directed mutagenesis restored receptor function in the CD320 reconstruction experiments. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Repairing the missing receptor codon restored function in the assay. organism: Homo sapiens tissue_or_cell_type: Recombinant cellular receptor assay experimental_model: Reconstruction of human deletion-bearing CD320 followed by codon repair limitations: Laboratory functional rescue, not a tested treatment in newborns; exact host cell is not specified in the inspected abstract. exposure: Insertion of the missing Glu88 codon cross_nutrient: false [quadros-2010-e88del] Positive newborn screen for methylmalonic aciduria identifies the first mutation in TCblR/CD320, the gene for cellular uptake of transcobalamin-bound vitamin B(12). (2010). https://pubmed.ncbi.nlm.nih.gov/20524213/ DOI: 10.1002/humu.21297

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Five newborn-derived fibroblast lines with homozygous CD320 deletion

exposure

Homozygous c.262_264delGAG / p.Glu88del

limitations

Asymptomatic neonatal ascertainment does not establish later clinical severity. Cellular uptake does not isolate binding from receptor expression or trafficking.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

A receptor deletion reduced B12 delivery in patient cells.

primary_references

[quadros-2010-e88del] Positive newborn screen for methylmalonic aciduria identifies the first mutation in TCblR/CD320, the gene for cellular uptake of transcobalamin-bound vitamin B(12). (2010). https://pubmed.ncbi.nlm.nih.gov/20524213/ DOI: 10.1002/humu.21297

tissue_or_cell_type

Human cultured fibroblasts

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 387–398

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Five newborn-derived fibroblast lines with homozygous CD320 deletion · source_derived_draft · unverified_draft

### b12-abs-e88del-uptake Fibroblasts from five asymptomatic newborns with elevated methylmalonic acid and homozygous CD320 p.Glu88del showed reduced uptake of holo-transcobalamin. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A receptor deletion reduced B12 delivery in patient cells. organism: Homo sapiens tissue_or_cell_type: Human cultured fibroblasts experimental_model: Five newborn-derived fibroblast lines with homozygous CD320 deletion limitations: Asymptomatic neonatal ascertainment does not establish later clinical severity. Cellular uptake does not isolate binding from receptor expression or trafficking. exposure: Homozygous c.262_264delGAG / p.Glu88del cross_nutrient: false [quadros-2010-e88del] Positive newborn screen for methylmalonic aciduria identifies the first mutation in TCblR/CD320, the gene for cellular uptake of transcobalamin-bound vitamin B(12). (2010). https://pubmed.ncbi.nlm.nih.gov/20524213/ DOI: 10.1002/humu.21297

cross_nutrient

false

experimental_model

In vitro egg-yolk cobalamin-binding protein mixed with human saliva/gastric juice

exposure

In vitro pH manipulation

limitations

Food-specific biochemical model; this pH threshold is not a clinical blood threshold or proof that all foods behave identically. Pepsin preparation species was not specified in the inspected abstract.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Acid enabled release and capture of B12 from this food model.

primary_references

[carmel-1990-food-transfer] Transfer of cobalamin from the cobalamin-binding protein of egg yolk to R binder of human saliva and gastric juice. (1990). https://pubmed.ncbi.nlm.nih.gov/2110915/ DOI: 10.1016/0016-5085(90)91076-i

tissue_or_cell_type

Gastric luminal digestion model

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 88–99

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · In vitro egg-yolk cobalamin-binding protein mixed with human saliva/gastric juice · source_derived_draft · unverified_draft

### b12-abs-food-acid In the egg-yolk/human saliva model, acidification to pH 1.5 permitted limited cobalamin transfer to R binder; virtually none occurred above pH 2 despite pepsin. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Acid enabled release and capture of B12 from this food model. organism: Homo sapiens tissue_or_cell_type: Gastric luminal digestion model experimental_model: In vitro egg-yolk cobalamin-binding protein mixed with human saliva/gastric juice limitations: Food-specific biochemical model; this pH threshold is not a clinical blood threshold or proof that all foods behave identically. Pepsin preparation species was not specified in the inspected abstract. exposure: In vitro pH manipulation cross_nutrient: false [carmel-1990-food-transfer] Transfer of cobalamin from the cobalamin-binding protein of egg yolk to R binder of human saliva and gastric juice. (1990). https://pubmed.ncbi.nlm.nih.gov/2110915/ DOI: 10.1016/0016-5085(90)91076-i

cross_nutrient

false

experimental_model

In vitro egg-yolk cobalamin-binding protein mixed with human saliva/gastric juice

exposure

Pepsin supplementation at acidic pH

limitations

Food-specific biochemical model; this pH threshold is not a clinical blood threshold or proof that all foods behave identically. Pepsin preparation species was not specified in the inspected abstract.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Pepsin helped haptocorrin capture food-bound B12.

primary_references

[carmel-1990-food-transfer] Transfer of cobalamin from the cobalamin-binding protein of egg yolk to R binder of human saliva and gastric juice. (1990). https://pubmed.ncbi.nlm.nih.gov/2110915/ DOI: 10.1016/0016-5085(90)91076-i

tissue_or_cell_type

Gastric luminal digestion model

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 101–112

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · In vitro egg-yolk cobalamin-binding protein mixed with human saliva/gastric juice · source_derived_draft · unverified_draft

### b12-abs-food-pepsin Adding pepsin at 1,200 U/mL under acidic conditions increased egg-yolk cobalamin transfer to human salivary or gastric R binders to 39-58%. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Pepsin helped haptocorrin capture food-bound B12. organism: Homo sapiens tissue_or_cell_type: Gastric luminal digestion model experimental_model: In vitro egg-yolk cobalamin-binding protein mixed with human saliva/gastric juice limitations: Food-specific biochemical model; this pH threshold is not a clinical blood threshold or proof that all foods behave identically. Pepsin preparation species was not specified in the inspected abstract. exposure: Pepsin supplementation at acidic pH cross_nutrient: false [carmel-1990-food-transfer] Transfer of cobalamin from the cobalamin-binding protein of egg yolk to R binder of human saliva and gastric juice. (1990). https://pubmed.ncbi.nlm.nih.gov/2110915/ DOI: 10.1016/0016-5085(90)91076-i

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Human family linkage and sequencing study

exposure

Inherited GIF variants

limitations

Genetic classification; not evidence that all variants or all malabsorption have the same cause. Earlier absorption tests were inconclusive.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Some inherited absorption failures originate in intrinsic factor.

primary_references

[tanner-2005-gif] Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene. (2005). https://pubmed.ncbi.nlm.nih.gov/15738392/ DOI: 10.1073/pnas.0500517102

tissue_or_cell_type

Gastric intrinsic factor/intestinal absorption pathway

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 309–320

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human family linkage and sequencing study · source_derived_draft · unverified_draft

### b12-abs-gif-genetic-malabsorption Biallelic GIF mutations in seven families with juvenile cobalamin deficiency identified inherited intrinsic-factor deficiency in cases initially suspected to have receptor-mediated IGS. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Some inherited absorption failures originate in intrinsic factor. organism: Homo sapiens tissue_or_cell_type: Gastric intrinsic factor/intestinal absorption pathway experimental_model: Human family linkage and sequencing study limitations: Genetic classification; not evidence that all variants or all malabsorption have the same cause. Earlier absorption tests were inconclusive. exposure: Inherited GIF variants cross_nutrient: false [tanner-2005-gif] Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene. (2005). https://pubmed.ncbi.nlm.nih.gov/15738392/ DOI: 10.1073/pnas.0500517102

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Rat mini-cubilin 4567ND versus wild type in HEK293T cells coexpressing human AMN

exposure

Four Asn-to-Asp substitutions; Figure 6 and Supplementary Figure 11

limitations

Engineered combined construct; does not show that every single site is individually indispensable. B12 absorption itself was not measured.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Rattus norvegicus construct; Homo sapiens AMN and host cells

plain_language

Several glycosylation sites jointly support receptor maturation.

primary_references

[udagawa-2018-glycosylation] Amnionless-mediated glycosylation is crucial for cell surface targeting of cubilin in renal and intestinal cells. (2018). https://pubmed.ncbi.nlm.nih.gov/29402915/ DOI: 10.1038/s41598-018-20731-4

tissue_or_cell_type

HEK293T biosynthetic trafficking

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 335–346

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat mini-cubilin 4567ND versus wild type in HEK293T cells coexpressing human AMN · source_derived_draft · unverified_draft

### b12-abs-glycosylation-quadruple-mutant Combined N711D/N749D/N781D/N857D substitutions in rat mini-cubilin abolished mature glycosylation and surface targeting with human AMN; the tested smaller combinations did not. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Several glycosylation sites jointly support receptor maturation. organism: Rattus norvegicus construct; Homo sapiens AMN and host cells tissue_or_cell_type: HEK293T biosynthetic trafficking experimental_model: Rat mini-cubilin 4567ND versus wild type in HEK293T cells coexpressing human AMN limitations: Engineered combined construct; does not show that every single site is individually indispensable. B12 absorption itself was not measured. exposure: Four Asn-to-Asp substitutions; Figure 6 and Supplementary Figure 11 cross_nutrient: false [udagawa-2018-glycosylation] Amnionless-mediated glycosylation is crucial for cell surface targeting of cubilin in renal and intestinal cells. (2018). https://pubmed.ncbi.nlm.nih.gov/29402915/ DOI: 10.1038/s41598-018-20731-4

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

One IGS patient renal biopsy compared with a control biopsy

exposure

Patient CUBN G653R; co-occurring AMN P295S also reported

limitations

One patient; AMN P295S contribution was inconclusive. This tissue observation alone cannot assign all disease causality to G653R.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

The patient receptor proteins accumulated inside kidney cells.

primary_references

[udagawa-2018-glycosylation] Amnionless-mediated glycosylation is crucial for cell surface targeting of cubilin in renal and intestinal cells. (2018). https://pubmed.ncbi.nlm.nih.gov/29402915/ DOI: 10.1038/s41598-018-20731-4

tissue_or_cell_type

Human renal proximal tubular epithelium

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 348–359

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · One IGS patient renal biopsy compared with a control biopsy · source_derived_draft · unverified_draft

### b12-abs-human-g653r-er In the renal biopsy of the studied patient carrying CUBN G653R, cubilin and AMN localized with the ER marker instead of normal brush-border localization. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The patient receptor proteins accumulated inside kidney cells. organism: Homo sapiens tissue_or_cell_type: Human renal proximal tubular epithelium experimental_model: One IGS patient renal biopsy compared with a control biopsy limitations: One patient; AMN P295S contribution was inconclusive. This tissue observation alone cannot assign all disease causality to G653R. exposure: Patient CUBN G653R; co-occurring AMN P295S also reported cross_nutrient: false [udagawa-2018-glycosylation] Amnionless-mediated glycosylation is crucial for cell surface targeting of cubilin in renal and intestinal cells. (2018). https://pubmed.ncbi.nlm.nih.gov/29402915/ DOI: 10.1038/s41598-018-20731-4

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Human pernicious-anemia sera; ordered-addition binding assays

exposure

IF plus type I antibody followed by radioactive B12 versus IF-B12 formed first

limitations

Sera cohort contained 79 patients; the abstract does not give functional-assay subset size. This is not every mechanism of autoimmune gastritis.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Some antibodies stop intrinsic factor from loading B12.

primary_references

[schade-1967-if-antibody] Studies on antibody to intrinsic factor. (1967). https://pubmed.ncbi.nlm.nih.gov/6021209/ DOI: 10.1172/jci105563

tissue_or_cell_type

Human gastric intrinsic factor binding system

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 504–515

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human pernicious-anemia sera; ordered-addition binding assays · source_derived_draft · unverified_draft

### b12-abs-if-antibody-blocking Type I antibodies from pernicious-anemia sera blocked radiocobalamin binding when mixed with intrinsic factor before the vitamin, whereas prior IF-B12 formation prevented this blocking effect. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Some antibodies stop intrinsic factor from loading B12. organism: Homo sapiens tissue_or_cell_type: Human gastric intrinsic factor binding system experimental_model: Human pernicious-anemia sera; ordered-addition binding assays limitations: Sera cohort contained 79 patients; the abstract does not give functional-assay subset size. This is not every mechanism of autoimmune gastritis. exposure: IF plus type I antibody followed by radioactive B12 versus IF-B12 formed first cross_nutrient: false [schade-1967-if-antibody] Studies on antibody to intrinsic factor. (1967). https://pubmed.ncbi.nlm.nih.gov/6021209/ DOI: 10.1172/jci105563

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Human absorption experiments with preassembled IF-B12

exposure

IF plus B12 followed by type II antibody

limitations

Demonstrates impaired absorption; does not identify an epitope or directly prove contact competition at cubilin.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Other antibodies interfered even after B12 had bound its carrier.

primary_references

[schade-1967-if-antibody] Studies on antibody to intrinsic factor. (1967). https://pubmed.ncbi.nlm.nih.gov/6021209/ DOI: 10.1172/jci105563

tissue_or_cell_type

Intestinal intrinsic-factor-dependent absorption

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 517–528

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human absorption experiments with preassembled IF-B12 · source_derived_draft · unverified_draft

### b12-abs-if-antibody-preformed-complex Type II antibodies prevented absorption in pernicious-anemia patients when added to a preformed intrinsic-factor-B12 complex. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Other antibodies interfered even after B12 had bound its carrier. organism: Homo sapiens tissue_or_cell_type: Intestinal intrinsic-factor-dependent absorption experimental_model: Human absorption experiments with preassembled IF-B12 limitations: Demonstrates impaired absorption; does not identify an epitope or directly prove contact competition at cubilin. exposure: IF plus B12 followed by type II antibody cross_nutrient: false [schade-1967-if-antibody] Studies on antibody to intrinsic factor. (1967). https://pubmed.ncbi.nlm.nih.gov/6021209/ DOI: 10.1172/jci105563

cross_nutrient

false

experimental_model

Purified human salivary R protein and gastric intrinsic factor in vitro

exposure

Parallel purified binding-protein protease incubations

limitations

Reconstituted binding/protease conditions; measured competition does not quantify absorption in an intact person. Individual protease isoforms and reagent species not resolved in abstract.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Intrinsic factor retained its binding function in these assays.

primary_references

[allen-1978-proteases] Effect of proteolytic enzymes on the binding of cobalamin to R protein and intrinsic factor. In vitro evidence that a failure to partially degrade R protein is responsible for cobalamin malabsorption in pancreatic insufficiency. (1978). https://pubmed.ncbi.nlm.nih.gov/22556/ DOI: 10.1172/jci108924

tissue_or_cell_type

Duodenal luminal model

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 192–203

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human salivary R protein and gastric intrinsic factor in vitro · source_derived_draft · unverified_draft

### b12-abs-if-resistance The pancreatic protease incubations that altered R protein did not alter the tested human intrinsic factor binding parameters. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Intrinsic factor retained its binding function in these assays. organism: Homo sapiens tissue_or_cell_type: Duodenal luminal model experimental_model: Purified human salivary R protein and gastric intrinsic factor in vitro limitations: Reconstituted binding/protease conditions; measured competition does not quantify absorption in an intact person. Individual protease isoforms and reagent species not resolved in abstract. exposure: Parallel purified binding-protein protease incubations cross_nutrient: false [allen-1978-proteases] Effect of proteolytic enzymes on the binding of cobalamin to R protein and intrinsic factor. In vitro evidence that a failure to partially degrade R protein is responsible for cobalamin malabsorption in pancreatic insufficiency. (1978). https://pubmed.ncbi.nlm.nih.gov/22556/ DOI: 10.1172/jci108924

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Megalin-deficient versus control mice

exposure

Genetic megalin deficiency

limitations

Renal content is not a universal marker of whole-body or neural B12 sufficiency; reserve function remains an interpretation.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Mus musculus

plain_language

Impaired renal uptake depleted the kidney B12 pool in mice.

primary_references

[birn-2002-megalin] Megalin is essential for renal proximal tubule reabsorption and accumulation of transcobalamin-B(12). (2002). https://pubmed.ncbi.nlm.nih.gov/11832420/ DOI: 10.1152/ajprenal.00206.2000

tissue_or_cell_type

Kidney cortex

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 426–437

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Megalin-deficient versus control mice · source_derived_draft · unverified_draft

### b12-abs-megalin-kidney-store Kidney cortex B12 content in megalin-deficient mice was approximately fourfold lower than in controls. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Impaired renal uptake depleted the kidney B12 pool in mice. organism: Mus musculus tissue_or_cell_type: Kidney cortex experimental_model: Megalin-deficient versus control mice limitations: Renal content is not a universal marker of whole-body or neural B12 sufficiency; reserve function remains an interpretation. exposure: Genetic megalin deficiency cross_nutrient: false [birn-2002-megalin] Megalin is essential for renal proximal tubule reabsorption and accumulation of transcobalamin-B(12). (2002). https://pubmed.ncbi.nlm.nih.gov/11832420/ DOI: 10.1152/ajprenal.00206.2000

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Megalin-deficient versus control mice

exposure

Genetic megalin deficiency

limitations

Mouse renal evidence; the fourfold urinary amount differs from the separately reported 28-fold clearance increase.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Mus musculus

plain_language

Without megalin, mice lost more B12 in urine.

primary_references

[birn-2002-megalin] Megalin is essential for renal proximal tubule reabsorption and accumulation of transcobalamin-B(12). (2002). https://pubmed.ncbi.nlm.nih.gov/11832420/ DOI: 10.1152/ajprenal.00206.2000

tissue_or_cell_type

Kidney proximal tubule/urine

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 413–424

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Megalin-deficient versus control mice · source_derived_draft · unverified_draft

### b12-abs-megalin-urinary-loss Megalin-deficient mice excreted approximately fourfold more urinary B12 than controls, consistent with defective renal recovery of transcobalamin-B12. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Without megalin, mice lost more B12 in urine. organism: Mus musculus tissue_or_cell_type: Kidney proximal tubule/urine experimental_model: Megalin-deficient versus control mice limitations: Mouse renal evidence; the fourfold urinary amount differs from the separately reported 28-fold clearance increase. exposure: Genetic megalin deficiency cross_nutrient: false [birn-2002-megalin] Megalin is essential for renal proximal tubule reabsorption and accumulation of transcobalamin-B(12). (2002). https://pubmed.ncbi.nlm.nih.gov/11832420/ DOI: 10.1152/ajprenal.00206.2000

cross_nutrient

false

experimental_model

Seven healthy adult completers; three experimental days separated by one-month washouts

exposure

Oral carbon-13 cyanocobalamin with metformin 850 mg versus tracer alone

limitations

Small acute tracer pilot in healthy adults; cannot establish prevention of chronic deficiency or identify the exact molecular metformin target. Doses describe the experiment, not advice.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

A single metformin exposure lowered measured B12 tracer availability.

primary_references

[muralidharan-2024-calcium] Effect of calcium supplementation on reversing metformin-based inhibition of vitamin B12 bioavailability in healthy adults using a [13C] cyanocobalamin tracer - A pilot study. (2024). https://pubmed.ncbi.nlm.nih.gov/38901951/ DOI: 10.1016/j.clnesp.2024.04.024

tissue_or_cell_type

Intestinal absorption assessed from serial venous tracer measurements

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 452–463

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Seven healthy adult completers; three experimental days separated by one-month washouts · source_derived_draft · unverified_draft

### b12-abs-metformin-tracer In seven healthy completers, tracer bioavailability averaged 30.8% with metformin 850 mg versus 42.6% on the control day (paired comparison p=0.010). Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A single metformin exposure lowered measured B12 tracer availability. organism: Homo sapiens tissue_or_cell_type: Intestinal absorption assessed from serial venous tracer measurements experimental_model: Seven healthy adult completers; three experimental days separated by one-month washouts limitations: Small acute tracer pilot in healthy adults; cannot establish prevention of chronic deficiency or identify the exact molecular metformin target. Doses describe the experiment, not advice. exposure: Oral carbon-13 cyanocobalamin with metformin 850 mg versus tracer alone cross_nutrient: false [muralidharan-2024-calcium] Effect of calcium supplementation on reversing metformin-based inhibition of vitamin B12 bioavailability in healthy adults using a [13C] cyanocobalamin tracer - A pilot study. (2024). https://pubmed.ncbi.nlm.nih.gov/38901951/ DOI: 10.1016/j.clnesp.2024.04.024

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Three human pancreatic-insufficiency patients and parallel human binding assays

exposure

Cobinamide competitor during Schilling test

limitations

Small physiological intervention; cobinamide is an experimental analogue, not B12 nutrition. The absorption defect was pancreatic machinery impairment.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Blocking haptocorrin competition restored tracer absorption in three patients.

primary_references

[allen-1978-cobinamide] Correction of cobalamin malabsorption in pancreatic insufficiency with a cobalamin analogue that binds with high affinity to R protein but not to intrinsic factor. In vivo evidence that a failure to partially degrade R protein is responsible for cobalamin malabsorption in pancreatic insufficiency. (1978). https://pubmed.ncbi.nlm.nih.gov/659618/ DOI: 10.1172/jci109083

tissue_or_cell_type

Intestinal absorption and urinary radiotracer recovery

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 205–216

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Three human pancreatic-insufficiency patients and parallel human binding assays · source_derived_draft · unverified_draft

### b12-abs-pancreatic-competitor-rescue In three patients with pancreatic insufficiency, oral cobinamide 100 nmol corrected malabsorption of 0.4 nmol radiocobalamin in Schilling tests, comparably to trypsin. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Blocking haptocorrin competition restored tracer absorption in three patients. organism: Homo sapiens tissue_or_cell_type: Intestinal absorption and urinary radiotracer recovery experimental_model: Three human pancreatic-insufficiency patients and parallel human binding assays limitations: Small physiological intervention; cobinamide is an experimental analogue, not B12 nutrition. The absorption defect was pancreatic machinery impairment. exposure: Cobinamide competitor during Schilling test cross_nutrient: false [allen-1978-cobinamide] Correction of cobalamin malabsorption in pancreatic insufficiency with a cobalamin analogue that binds with high affinity to R protein but not to intrinsic factor. In vivo evidence that a failure to partially degrade R protein is responsible for cobalamin malabsorption in pancreatic insufficiency. (1978). https://pubmed.ncbi.nlm.nih.gov/659618/ DOI: 10.1172/jci109083

cross_nutrient

false

experimental_model

Purified human salivary R protein and gastric intrinsic factor in vitro

exposure

Pancreatic proteases at pH 8

limitations

Reconstituted binding/protease conditions; measured competition does not quantify absorption in an intact person. Individual protease isoforms and reagent species not resolved in abstract.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Digestive proteases loosened haptocorrin binding.

primary_references

[allen-1978-proteases] Effect of proteolytic enzymes on the binding of cobalamin to R protein and intrinsic factor. In vitro evidence that a failure to partially degrade R protein is responsible for cobalamin malabsorption in pancreatic insufficiency. (1978). https://pubmed.ncbi.nlm.nih.gov/22556/ DOI: 10.1172/jci108924

tissue_or_cell_type

Duodenal luminal model

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 166–177

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human salivary R protein and gastric intrinsic factor in vitro · source_derived_draft · unverified_draft

### b12-abs-proteolysis-affinity Pancreatic protease incubation at pH 8 partially degraded human R protein and lowered its cobalamin affinity approximately 150-fold. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Digestive proteases loosened haptocorrin binding. organism: Homo sapiens tissue_or_cell_type: Duodenal luminal model experimental_model: Purified human salivary R protein and gastric intrinsic factor in vitro limitations: Reconstituted binding/protease conditions; measured competition does not quantify absorption in an intact person. Individual protease isoforms and reagent species not resolved in abstract. exposure: Pancreatic proteases at pH 8 cross_nutrient: false [allen-1978-proteases] Effect of proteolytic enzymes on the binding of cobalamin to R protein and intrinsic factor. In vitro evidence that a failure to partially degrade R protein is responsible for cobalamin malabsorption in pancreatic insufficiency. (1978). https://pubmed.ncbi.nlm.nih.gov/22556/ DOI: 10.1172/jci108924

cross_nutrient

false

experimental_model

Purified human salivary R protein and gastric intrinsic factor in vitro

exposure

R protein-Cbl plus pancreatic proteases and IF

limitations

Reconstituted binding/protease conditions; measured competition does not quantify absorption in an intact person. Individual protease isoforms and reagent species not resolved in abstract.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Proteolysis enabled B12 to switch carriers.

primary_references

[allen-1978-proteases] Effect of proteolytic enzymes on the binding of cobalamin to R protein and intrinsic factor. In vitro evidence that a failure to partially degrade R protein is responsible for cobalamin malabsorption in pancreatic insufficiency. (1978). https://pubmed.ncbi.nlm.nih.gov/22556/ DOI: 10.1172/jci108924

tissue_or_cell_type

Duodenal luminal model

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 179–190

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human salivary R protein and gastric intrinsic factor in vitro · source_derived_draft · unverified_draft

### b12-abs-proteolysis-transfer Protease treatment of R-protein-bound cobalamin enabled complete transfer to human intrinsic factor within ten minutes; without proteases, transfer was not observed at pH 2 or 8. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Proteolysis enabled B12 to switch carriers. organism: Homo sapiens tissue_or_cell_type: Duodenal luminal model experimental_model: Purified human salivary R protein and gastric intrinsic factor in vitro limitations: Reconstituted binding/protease conditions; measured competition does not quantify absorption in an intact person. Individual protease isoforms and reagent species not resolved in abstract. exposure: R protein-Cbl plus pancreatic proteases and IF cross_nutrient: false [allen-1978-proteases] Effect of proteolytic enzymes on the binding of cobalamin to R protein and intrinsic factor. In vitro evidence that a failure to partially degrade R protein is responsible for cobalamin malabsorption in pancreatic insufficiency. (1978). https://pubmed.ncbi.nlm.nih.gov/22556/ DOI: 10.1172/jci108924

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

experimental_model

Two infant siblings; chromatography/electrophoresis and family binding-capacity studies

exposure

Inherited TCII deficiency; carrier pattern supported recessive inheritance

limitations

Two-case family report; DNA variants were not identified and total serum B12 did not measure intracellular delivery.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Normal total B12 did not exclude a serious carrier deficiency.

primary_references

[hakami-1971-tcn2] Neonatal megaloblastic anemia due to inherited transcobalamin II deficiency in two siblings. (1971). https://pubmed.ncbi.nlm.nih.gov/5096637/ DOI: 10.1056/nejm197111182852103

tissue_or_cell_type

Systemic B12 delivery/hematopoiesis

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 530–541

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Two infant siblings; chromatography/electrophoresis and family binding-capacity studies · source_derived_draft · unverified_draft

### b12-abs-tcn2-inherited-functional-deficiency Two infant siblings with demonstrated transcobalamin II deficiency developed megaloblastic anemia and systemic B12-deficiency manifestations at three and five weeks despite normal total serum B12. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Normal total B12 did not exclude a serious carrier deficiency. organism: Homo sapiens tissue_or_cell_type: Systemic B12 delivery/hematopoiesis experimental_model: Two infant siblings; chromatography/electrophoresis and family binding-capacity studies limitations: Two-case family report; DNA variants were not identified and total serum B12 did not measure intracellular delivery. exposure: Inherited TCII deficiency; carrier pattern supported recessive inheritance cross_nutrient: false [hakami-1971-tcn2] Neonatal megaloblastic anemia due to inherited transcobalamin II deficiency in two siblings. (1971). https://pubmed.ncbi.nlm.nih.gov/5096637/ DOI: 10.1056/nejm197111182852103

experimental_model

Case-control study: 25956 incident B12-deficiency diagnoses and 184199 controls in Kaiser Permanente Northern California.

exposure

Prescription records for at least two years of PPI or H2-antagonist exposure; no randomized acid suppression.

limitations

Not an independent cohort or a randomized comparison between drug classes; diagnosis is not the same endpoint as measured mean serum concentration.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

A second acid-suppressing drug class showed an association in the same study.

primary_references

[b12-lam2013] Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency (2013). https://pubmed.ncbi.nlm.nih.gov/24327038/ DOI: 10.1001/jama.2013.280490

tissue_or_cell_type

Human blood or whole-person endpoints

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1673–1683

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Case-control study: 25956 incident B12-deficiency diagnoses and 184199 controls in Kaiser Permanente Northern California. · source_derived_draft · unverified_draft

### b12-acid-suppression-h2-association At least two years of H2-antagonist supply without PPI exposure was associated with a B12-deficiency diagnosis (OR 1.25; 95% CI 1.17–1.34). Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A second acid-suppressing drug class showed an association in the same study. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Case-control study: 25956 incident B12-deficiency diagnoses and 184199 controls in Kaiser Permanente Northern California. limitations: Not an independent cohort or a randomized comparison between drug classes; diagnosis is not the same endpoint as measured mean serum concentration. exposure: Prescription records for at least two years of PPI or H2-antagonist exposure; no randomized acid suppression. [b12-lam2013] Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency (2013). https://pubmed.ncbi.nlm.nih.gov/24327038/ DOI: 10.1001/jama.2013.280490

experimental_model

Case-control study: 25956 incident B12-deficiency diagnoses and 184199 controls in Kaiser Permanente Northern California.

exposure

Prescription records for at least two years of PPI or H2-antagonist exposure; no randomized acid suppression.

limitations

Prescription/diagnosis case-control data; no direct gastric pH or absorption measurement, and residual confounding remains.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Long-term acid-suppressing prescriptions were associated with more diagnosed B12 deficiency.

primary_references

[b12-lam2013] Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency (2013). https://pubmed.ncbi.nlm.nih.gov/24327038/ DOI: 10.1001/jama.2013.280490

tissue_or_cell_type

Human blood or whole-person endpoints

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1661–1671

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Case-control study: 25956 incident B12-deficiency diagnoses and 184199 controls in Kaiser Permanente Northern California. · source_derived_draft · unverified_draft

### b12-acid-suppression-ppi-association At least two years of PPI supply was associated with a B12-deficiency diagnosis (OR 1.65; 95% CI 1.58–1.73). Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Long-term acid-suppressing prescriptions were associated with more diagnosed B12 deficiency. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Case-control study: 25956 incident B12-deficiency diagnoses and 184199 controls in Kaiser Permanente Northern California. limitations: Prescription/diagnosis case-control data; no direct gastric pH or absorption measurement, and residual confounding remains. exposure: Prescription records for at least two years of PPI or H2-antagonist exposure; no randomized acid suppression. [b12-lam2013] Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency (2013). https://pubmed.ncbi.nlm.nih.gov/24327038/ DOI: 10.1001/jama.2013.280490

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

evidence_location

Results: Figures 1, 6, 7; Methods: cell lines and CRISPR

experimental_model

HEK293 experimental sorting-motif mutagenesis

exposure

Human LMBD1-GFP 233YERL/AAAA plus ABCD4-HA

limitations

Experimental four-residue substitution; microscopy does not establish direct vitamin transport.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Changing the escort’s sorting sequence sent the transporter to the wrong location.

primary_references

[kawaguchi-2016-lmbd1-escort] Translocation of the ABC transporter ABCD4 from the endoplasmic reticulum to lysosomes requires the escort protein LMBD1 (2016). https://pubmed.ncbi.nlm.nih.gov/27456980/ DOI: 10.1038/srep30183

tissue_or_cell_type

Embryonic kidney-derived cell line

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 599–611

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HEK293 experimental sorting-motif mutagenesis · source_derived_draft · unverified_draft

### b12-lmbd1-sorting-mutant In transfected HEK293 cells, LMBD1 carrying 233YERL-to-AAAA mislocalized partly to the cell surface; coexpressed ABCD4 followed its distribution instead of normal lysosomal targeting. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Changing the escort’s sorting sequence sent the transporter to the wrong location. organism: Homo sapiens tissue_or_cell_type: Embryonic kidney-derived cell line experimental_model: HEK293 experimental sorting-motif mutagenesis limitations: Experimental four-residue substitution; microscopy does not establish direct vitamin transport. exposure: Human LMBD1-GFP 233YERL/AAAA plus ABCD4-HA cross_nutrient: false evidence_location: Results: Figures 1, 6, 7; Methods: cell lines and CRISPR [kawaguchi-2016-lmbd1-escort] Translocation of the ABC transporter ABCD4 from the endoplasmic reticulum to lysosomes requires the escort protein LMBD1 (2016). https://pubmed.ncbi.nlm.nih.gov/27456980/ DOI: 10.1038/srep30183

cross_nutrient

false

evidence_location

Results: Figures 1, 6, 7; Methods: cell lines and CRISPR

experimental_model

Human HuH7 tagged-protein localization

exposure

ABCD4-HA stable expression and transient LMBD1-GFP

limitations

Tagged overexpression; colocalization does not measure cobalamin flux.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

LMBD1 helped the B12 transporter reach lysosomes.

primary_references

[kawaguchi-2016-lmbd1-escort] Translocation of the ABC transporter ABCD4 from the endoplasmic reticulum to lysosomes requires the escort protein LMBD1 (2016). https://pubmed.ncbi.nlm.nih.gov/27456980/ DOI: 10.1038/srep30183

tissue_or_cell_type

Hepatoma cell line

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 571–583

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human HuH7 tagged-protein localization · source_derived_draft · unverified_draft

### b12-lmbrd1-escort-huh7 In HuH7 cells expressing human ABCD4-HA, adding LMBD1-GFP shifted ABCD4 from an ER-like distribution toward LAMP1-positive lysosomes. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: LMBD1 helped the B12 transporter reach lysosomes. organism: Homo sapiens tissue_or_cell_type: Hepatoma cell line experimental_model: Human HuH7 tagged-protein localization limitations: Tagged overexpression; colocalization does not measure cobalamin flux. exposure: ABCD4-HA stable expression and transient LMBD1-GFP cross_nutrient: false evidence_location: Results: Figures 1, 6, 7; Methods: cell lines and CRISPR [kawaguchi-2016-lmbd1-escort] Translocation of the ABC transporter ABCD4 from the endoplasmic reticulum to lysosomes requires the escort protein LMBD1 (2016). https://pubmed.ncbi.nlm.nih.gov/27456980/ DOI: 10.1038/srep30183

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

evidence_location

Results: Figures 1, 6, 7; Methods: cell lines and CRISPR

experimental_model

HEK293 CRISPR knockout and density-gradient immunoblotting

exposure

LMBRD1 knockout versus wild type

limitations

Fractionation-based localization; residual lysosomal signal remains and is not 40% residual transport activity.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Deleting the escort changed where the transporter was located.

primary_references

[kawaguchi-2016-lmbd1-escort] Translocation of the ABC transporter ABCD4 from the endoplasmic reticulum to lysosomes requires the escort protein LMBD1 (2016). https://pubmed.ncbi.nlm.nih.gov/27456980/ DOI: 10.1038/srep30183

tissue_or_cell_type

Human embryonic kidney-derived cell line

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 585–597

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HEK293 CRISPR knockout and density-gradient immunoblotting · source_derived_draft · unverified_draft

### b12-lmbrd1-ko-localization CRISPR LMBRD1 knockout in HEK293 cells reduced the ABCD4 signal overlapping lysosomal fractions to about 40% of control, while total ABCD4 was similar. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Deleting the escort changed where the transporter was located. organism: Homo sapiens tissue_or_cell_type: Human embryonic kidney-derived cell line experimental_model: HEK293 CRISPR knockout and density-gradient immunoblotting limitations: Fractionation-based localization; residual lysosomal signal remains and is not 40% residual transport activity. exposure: LMBRD1 knockout versus wild type cross_nutrient: false evidence_location: Results: Figures 1, 6, 7; Methods: cell lines and CRISPR [kawaguchi-2016-lmbd1-escort] Translocation of the ABC transporter ABCD4 from the endoplasmic reticulum to lysosomes requires the escort protein LMBD1 (2016). https://pubmed.ncbi.nlm.nih.gov/27456980/ DOI: 10.1038/srep30183

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

false

evidence_location

Abstract; Figure 4 caption

experimental_model

Human cblF patient fibroblast complementation

exposure

Wild-type LMBD1 expression construct

limitations

Cultured-cell experiment; not dietary deficiency, a serum B12 threshold, or a human treatment effect.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Restoring the missing lysosomal protein let patient cells make usable B12 cofactors.

primary_references

[rutsch-2009-lmbrd1] Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism (2009). https://pubmed.ncbi.nlm.nih.gov/19136951/ DOI: 10.1038/ng.294

tissue_or_cell_type

Skin-derived fibroblasts

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 543–555

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human cblF patient fibroblast complementation · source_derived_draft · unverified_draft

### b12-lmbrd1-rescue Transfection with wild-type LMBD1 restored cobalamin coenzyme synthesis and function in cultured fibroblasts from individuals with the cblF defect. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Restoring the missing lysosomal protein let patient cells make usable B12 cofactors. organism: Homo sapiens tissue_or_cell_type: Skin-derived fibroblasts experimental_model: Human cblF patient fibroblast complementation limitations: Cultured-cell experiment; not dietary deficiency, a serum B12 threshold, or a human treatment effect. exposure: Wild-type LMBD1 expression construct cross_nutrient: false evidence_location: Abstract; Figure 4 caption [rutsch-2009-lmbrd1] Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism (2009). https://pubmed.ncbi.nlm.nih.gov/19136951/ DOI: 10.1038/ng.294

experimental_model

DPP/DPPOS secondary analysis: initial randomized metformin/placebo period followed by open-label follow-up. Stored-sample analytic groups: year 5 placebo 857/metformin 858; year 13 placebo 756/metformin 764.

exposure

Metformin 850 mg twice daily initially; B12 assessed at approximately 5 and 13 years. Long-term exposure is not continuously blinded randomized treatment.

limitations

Stored-sample subsets and open-label exposure after the initial trial limit continuous randomized interpretation.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

The long-term follow-up supports a status association, with different results for different thresholds and visits.

primary_references

[b12-aroda2016] Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study (2016). https://pubmed.ncbi.nlm.nih.gov/26900641/ DOI: 10.1210/jc.2015-3754

tissue_or_cell_type

Human blood or whole-person endpoints

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1649–1659

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · DPP/DPPOS secondary analysis: initial randomized metformin/placebo period followed by open-label follow-up. Stored-sample analytic groups: year 5 placebo 857/metformin 858; year 13 placebo 756/metformin 764. · source_derived_draft · unverified_draft

### b12-metformin-dppos-longitudinal Low B12 (at most 203 pg/mL) was more frequent with metformin at year 5 (4.3% versus 2.3%) but not significantly at year 13 (7.4% versus 5.4%); low-or-borderline B12 (at most 298 pg/mL) remained more frequent at both assessments. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The long-term follow-up supports a status association, with different results for different thresholds and visits. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: DPP/DPPOS secondary analysis: initial randomized metformin/placebo period followed by open-label follow-up. Stored-sample analytic groups: year 5 placebo 857/metformin 858; year 13 placebo 756/metformin 764. limitations: Stored-sample subsets and open-label exposure after the initial trial limit continuous randomized interpretation. exposure: Metformin 850 mg twice daily initially; B12 assessed at approximately 5 and 13 years. Long-term exposure is not continuously blinded randomized treatment. [b12-aroda2016] Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study (2016). https://pubmed.ncbi.nlm.nih.gov/26900641/ DOI: 10.1210/jc.2015-3754

cross_nutrient

Preserves the B12/folate/homocysteine measurements without a universal depletion cascade.

experimental_model

Multicenter randomized placebo-controlled trial: 390 insulin-treated patients with type 2 diabetes.

exposure

Metformin 850 mg three times daily versus placebo for 4.3 years; historical experimental exposure.

limitations

End-study B12 strata are not randomized mediators. The folate decrease lost significance after adjustment for BMI and smoking.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

A B12 effect did not make the overall homocysteine trial result statistically significant.

primary_references

[b12-dejager2010] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181

tissue_or_cell_type

Human blood or whole-person endpoints

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1636–1647

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Multicenter randomized placebo-controlled trial: 390 insulin-treated patients with type 2 diabetes. · source_derived_draft · unverified_draft

### b12-metformin-homocysteine-boundary The overall metformin-versus-placebo homocysteine change was +5% (95% CI -1% to 11%; P=0.091), although participants with low end-study B12 had higher homocysteine. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A B12 effect did not make the overall homocysteine trial result statistically significant. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Multicenter randomized placebo-controlled trial: 390 insulin-treated patients with type 2 diabetes. limitations: End-study B12 strata are not randomized mediators. The folate decrease lost significance after adjustment for BMI and smoking. exposure: Metformin 850 mg three times daily versus placebo for 4.3 years; historical experimental exposure. cross_nutrient: Preserves the B12/folate/homocysteine measurements without a universal depletion cascade. [b12-dejager2010] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181

experimental_model

Multicenter randomized placebo-controlled trial: 390 insulin-treated patients with type 2 diabetes.

exposure

Metformin 850 mg three times daily versus placebo for 4.3 years; historical experimental exposure.

limitations

Insulin-treated type 2 diabetes; does not directly establish the absorption mechanism or a neurologic outcome.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

Long-term metformin exposure increased biochemical B12 deficiency in this trial.

primary_references

[b12-dejager2010] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181

tissue_or_cell_type

Human blood or whole-person endpoints

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1624–1634

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Multicenter randomized placebo-controlled trial: 390 insulin-treated patients with type 2 diabetes. · source_derived_draft · unverified_draft

### b12-metformin-randomized-status Over 4.3 years, metformin lowered B12 concentration by 19% relative to placebo and increased the absolute risk of B12 below 150 pmol/L by 7.2 percentage points (95% CI 2.3–12.1). Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Long-term metformin exposure increased biochemical B12 deficiency in this trial. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Multicenter randomized placebo-controlled trial: 390 insulin-treated patients with type 2 diabetes. limitations: Insulin-treated type 2 diabetes; does not directly establish the absorption mechanism or a neurologic outcome. exposure: Metformin 850 mg three times daily versus placebo for 4.3 years; historical experimental exposure. [b12-dejager2010] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

B12-dependent folate handling connects to DNA synthesis; linked existing MTR evidence supplies the molecular context.

experimental_model

Prospective perioperative study in 22 patients undergoing cardiac bypass surgery.

exposure

Nitrous oxide/oxygen for 24 hours, during surgery only, or no nitrous oxide; marrow morphology and deoxyuridine suppression assays.

limitations

The clinical experiment did not directly measure intracellular cobalamin oxidation state or prove that serum B12 stores were depleted.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

The exposed marrow behaved as though a B12-linked DNA-synthesis step was impaired.

primary_references

[b12-amess1978] Megaloblastic haemopoiesis in patients receiving nitrous oxide (1978). https://pubmed.ncbi.nlm.nih.gov/79709/ DOI: 10.1016/s0140-6736(78)92941-0

tissue_or_cell_type

Human bone marrow

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1709–1720

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Prospective perioperative study in 22 patients undergoing cardiac bypass surgery. · source_derived_draft · unverified_draft

### b12-nitrous-oxide-marrow All eight patients receiving nitrous oxide/oxygen for 24 hours had megaloblastic marrow and abnormal dU suppression; five unexposed patients had normoblastic marrow and normal assays. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The exposed marrow behaved as though a B12-linked DNA-synthesis step was impaired. organism: Homo sapiens tissue_or_cell_type: Human bone marrow experimental_model: Prospective perioperative study in 22 patients undergoing cardiac bypass surgery. limitations: The clinical experiment did not directly measure intracellular cobalamin oxidation state or prove that serum B12 stores were depleted. exposure: Nitrous oxide/oxygen for 24 hours, during surgery only, or no nitrous oxide; marrow morphology and deoxyuridine suppression assays. cross_nutrient: B12-dependent folate handling connects to DNA synthesis; linked existing MTR evidence supplies the molecular context. [b12-amess1978] Megaloblastic haemopoiesis in patients receiving nitrous oxide (1978). https://pubmed.ncbi.nlm.nih.gov/79709/ DOI: 10.1016/s0140-6736(78)92941-0

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/metformin-research/20488910.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922", "start_char": 0, "end_char": 2518, "text_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922"}

experimental_model

Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin

exposure

850 mg metformin three times daily for 4.3 years versus placebo

limitations

The strongest available human causal evidence for the B12 effect. It measured concentrations and deficiency incidence, not clinical deficiency syndromes.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Human

plain_language

Years of the drug lower the vitamin in blood.

primary_references

[metformin-p20488910] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181

tissue_or_cell_type

Whole body

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1035–1046

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin · source_derived_draft · unverified_draft

### metformin-b12-decrease Compared with placebo, metformin treatment was associated with a mean decrease in vitamin B-12 concentration of 19% over 4.3 years. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Years of the drug lower the vitamin in blood. organism: Human tissue_or_cell_type: Whole body experimental_model: Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin limitations: The strongest available human causal evidence for the B12 effect. It measured concentrations and deficiency incidence, not clinical deficiency syndromes. exposure: 850 mg metformin three times daily for 4.3 years versus placebo evidence_span: {"source_cache": "artifacts/metformin-research/20488910.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922", "start_char": 0, "end_char": 2518, "text_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922"} [metformin-p20488910] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/metformin-research/10977010.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b", "start_char": 0, "end_char": 1267, "text_sha256": "7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b"}

experimental_model

Comparative study in 21 people with type 2 diabetes, 14 switched to metformin, with oral calcium supplementation

exposure

Metformin for three months, then oral calcium supplementation

limitations

A small, non-randomised comparative study. The calcium-dependent ileal mechanism is the authors’ interpretation of the reversal, not a direct measurement of receptor binding.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Human

plain_language

The carrier-bound fraction that reaches cells fell alongside the total.

primary_references

[metformin-p10977010] Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. (2000). https://pubmed.ncbi.nlm.nih.gov/10977010/ DOI: 10.2337/diacare.23.9.1227

tissue_or_cell_type

Ileal absorption

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1126–1137

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Comparative study in 21 people with type 2 diabetes, 14 switched to metformin, with oral calcium supplementation · source_derived_draft · unverified_draft

### metformin-b12-holotc-decline Serial measurements showed a similar decline in serum total vitamin B12 and in holotranscobalamin during metformin therapy. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The carrier-bound fraction that reaches cells fell alongside the total. organism: Human tissue_or_cell_type: Ileal absorption experimental_model: Comparative study in 21 people with type 2 diabetes, 14 switched to metformin, with oral calcium supplementation limitations: A small, non-randomised comparative study. The calcium-dependent ileal mechanism is the authors’ interpretation of the reversal, not a direct measurement of receptor binding. exposure: Metformin for three months, then oral calcium supplementation evidence_span: {"source_cache": "artifacts/metformin-research/10977010.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b", "start_char": 0, "end_char": 1267, "text_sha256": "7aed1bfb7ee680b248e083db467fd4a8199ac933e8a12b4c6ba08f9931a7794b"} [metformin-p10977010] Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. (2000). https://pubmed.ncbi.nlm.nih.gov/10977010/ DOI: 10.2337/diacare.23.9.1227

availability_state

biomarker_context Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/metformin-research/26900641.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09cb74c29fe2d647d668d912a9a01962384e38bcc309a29c429d2caaed3048f1", "start_char": 0, "end_char": 1842, "text_sha256": "09cb74c29fe2d647d668d912a9a01962384e38bcc309a29c429d2caaed3048f1"}

experimental_model

Secondary analysis of the Diabetes Prevention Program Outcomes Study over 13 years

exposure

Metformin 850 mg twice daily versus placebo, then open-label metformin

limitations

Long-duration data. Neuropathy and anaemia were measured as prevalence, and the design cannot separate duration from cumulative dose.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Human

plain_language

The people with both the drug and a low vitamin had more nerve disease.

primary_references

[metformin-p26900641] Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. (2016). https://pubmed.ncbi.nlm.nih.gov/26900641/ DOI: 10.1210/jc.2015-3754

tissue_or_cell_type

Whole body

trigger_kind

biomarker_context Imported condition classification; unverified.

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1100–1111

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Secondary analysis of the Diabetes Prevention Program Outcomes Study over 13 years · source_derived_draft · unverified_draft

### metformin-b12-neuropathy-prevalence Neuropathy prevalence was higher in the metformin group among those with low B12 levels, and anaemia prevalence was higher in the metformin group though it did not differ by B12 status. Condition category: biomarker_context nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The people with both the drug and a low vitamin had more nerve disease. organism: Human tissue_or_cell_type: Whole body experimental_model: Secondary analysis of the Diabetes Prevention Program Outcomes Study over 13 years limitations: Long-duration data. Neuropathy and anaemia were measured as prevalence, and the design cannot separate duration from cumulative dose. exposure: Metformin 850 mg twice daily versus placebo, then open-label metformin evidence_span: {"source_cache": "artifacts/metformin-research/26900641.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "09cb74c29fe2d647d668d912a9a01962384e38bcc309a29c429d2caaed3048f1", "start_char": 0, "end_char": 1842, "text_sha256": "09cb74c29fe2d647d668d912a9a01962384e38bcc309a29c429d2caaed3048f1"} [metformin-p26900641] Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. (2016). https://pubmed.ncbi.nlm.nih.gov/26900641/ DOI: 10.1210/jc.2015-3754

availability_state

biomarker_context Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/metformin-research/19846797.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "801079bb07e94e223a1d7bd7fc99c9f229320aa56b6afa11700765f481558b33", "start_char": 0, "end_char": 1789, "text_sha256": "801079bb07e94e223a1d7bd7fc99c9f229320aa56b6afa11700765f481558b33"}

experimental_model

Prospective case-control study of 122 people with type 2 diabetes and symptomatic neuropathy

exposure

More than six months of metformin versus no metformin exposure

limitations

Case-control design with nerve conduction studies. Cumulative dose correlated with severity, but the design cannot establish that the drug caused the neuropathy.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Human

plain_language

The marker that rises specifically when B12 is short also rose.

primary_references

[metformin-p19846797] Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. (2010). https://pubmed.ncbi.nlm.nih.gov/19846797/ DOI: 10.2337/dc09-0606

tissue_or_cell_type

Peripheral nerve

trigger_kind

biomarker_context Imported condition classification; unverified.

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1204–1215

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Prospective case-control study of 122 people with type 2 diabetes and symptomatic neuropathy · source_derived_draft · unverified_draft

### metformin-mma-elevation Metformin-treated patients had depressed cobalamin levels and elevated fasting methylmalonic acid and homocysteine levels. Condition category: biomarker_context nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The marker that rises specifically when B12 is short also rose. organism: Human tissue_or_cell_type: Peripheral nerve experimental_model: Prospective case-control study of 122 people with type 2 diabetes and symptomatic neuropathy limitations: Case-control design with nerve conduction studies. Cumulative dose correlated with severity, but the design cannot establish that the drug caused the neuropathy. exposure: More than six months of metformin versus no metformin exposure evidence_span: {"source_cache": "artifacts/metformin-research/19846797.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "801079bb07e94e223a1d7bd7fc99c9f229320aa56b6afa11700765f481558b33", "start_char": 0, "end_char": 1789, "text_sha256": "801079bb07e94e223a1d7bd7fc99c9f229320aa56b6afa11700765f481558b33"} [metformin-p19846797] Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. (2010). https://pubmed.ncbi.nlm.nih.gov/19846797/ DOI: 10.2337/dc09-0606

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/metformin-research/14535967.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a", "start_char": 0, "end_char": 1640, "text_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a"}

experimental_model

Placebo-controlled randomised trial of 390 people with type 2 diabetes over 16 weeks

exposure

Metformin added to insulin for 16 weeks versus placebo

limitations

Short-duration randomised evidence that the folate and B12 changes precede a measurable homocysteine change.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Human

plain_language

Both vitamins fall within months, not only after years.

primary_references

[metformin-p14535967] Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. (2003). https://pubmed.ncbi.nlm.nih.gov/14535967/ DOI: 10.1046/j.1365-2796.2003.01213.x

tissue_or_cell_type

Whole body

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1178–1189

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Placebo-controlled randomised trial of 390 people with type 2 diabetes over 16 weeks · source_derived_draft · unverified_draft

### metformin-short-term-b12-folate Sixteen weeks of metformin reduced folate by 7% and vitamin B12 by 14% compared with placebo. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Both vitamins fall within months, not only after years. organism: Human tissue_or_cell_type: Whole body experimental_model: Placebo-controlled randomised trial of 390 people with type 2 diabetes over 16 weeks limitations: Short-duration randomised evidence that the folate and B12 changes precede a measurable homocysteine change. exposure: Metformin added to insulin for 16 weeks versus placebo evidence_span: {"source_cache": "artifacts/metformin-research/14535967.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a", "start_char": 0, "end_char": 1640, "text_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a"} [metformin-p14535967] Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. (2003). https://pubmed.ncbi.nlm.nih.gov/14535967/ DOI: 10.1046/j.1365-2796.2003.01213.x

availability_state

biomarker_context Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/metformin-research/14535967.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a", "start_char": 0, "end_char": 1640, "text_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a"}

experimental_model

Placebo-controlled randomised trial of 390 people with type 2 diabetes over 16 weeks

exposure

Metformin added to insulin for 16 weeks versus placebo

limitations

Short-duration randomised evidence that the folate and B12 changes precede a measurable homocysteine change.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Human

plain_language

The rise in that metabolite was accounted for by the two vitamins falling.

primary_references

[metformin-p14535967] Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. (2003). https://pubmed.ncbi.nlm.nih.gov/14535967/ DOI: 10.1046/j.1365-2796.2003.01213.x

tissue_or_cell_type

Whole body

trigger_kind

biomarker_context Imported condition classification; unverified.

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1191–1202

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Placebo-controlled randomised trial of 390 people with type 2 diabetes over 16 weeks · source_derived_draft · unverified_draft

### metformin-short-term-homocysteine Metformin use was associated with a 4% increase in homocysteine, and the increase could be explained by the decreases in folate and vitamin B12. Condition category: biomarker_context nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The rise in that metabolite was accounted for by the two vitamins falling. organism: Human tissue_or_cell_type: Whole body experimental_model: Placebo-controlled randomised trial of 390 people with type 2 diabetes over 16 weeks limitations: Short-duration randomised evidence that the folate and B12 changes precede a measurable homocysteine change. exposure: Metformin added to insulin for 16 weeks versus placebo evidence_span: {"source_cache": "artifacts/metformin-research/14535967.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a", "start_char": 0, "end_char": 1640, "text_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a"} [metformin-p14535967] Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. (2003). https://pubmed.ncbi.nlm.nih.gov/14535967/ DOI: 10.1046/j.1365-2796.2003.01213.x

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

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

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

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

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

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

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

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

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