Nutrient chapter

Vitamin B12 (cobalamins)

Nutrient family, distinct from individual cobalamin forms. Cobalamin nutrient family; distinct from individual coenzyme forms.

126 recorded mechanisms · 60 availability situations · 1 preserved sources. Draft and verified records are labeled separately.

Read recorded mechanisms Open recursive mind map

The mechanisms

What the sources say this nutrient does, one relationship at a time. Plain wording comes first; the technical statement follows.

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.
Hydrogen ion → Egg-yolk cobalamin transfer to human haptocorrin source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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%.
Pepsin A enzyme family → Egg-yolk cobalamin transfer to human haptocorrin source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Human haptocorrin / TCN1 → Vitamin B12 (cobalamins) source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Omeprazole → Gastric release of food-bound cobalamin source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
In the same crossover experiment, jejunal release of labeled liver cobalamins was near 90% after either omeprazole or placebo, despite earlier gastric effects.
Omeprazole → Jejunal release of food-bound cobalamin source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Human haptocorrin / TCN1 → Vitamin B12 (cobalamins) source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Pancreatic protease incubation at pH 8 partially degraded human R protein and lowered its cobalamin affinity approximately 150-fold.
Pancreatic serine protease family → Human haptocorrin affinity for cobalamin source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Pancreatic serine protease family → Cobalamin transfer from haptocorrin to human intrinsic factor source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The pancreatic protease incubations that altered R protein did not alter the tested human intrinsic factor binding parameters.
Pancreatic serine protease family → Human intrinsic factor cobalamin-binding function source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
In three patients with pancreatic insufficiency, oral cobinamide 100 nmol corrected malabsorption of 0.4 nmol radiocobalamin in Schilling tests, comparably to trypsin.
Cobinamide → Intestinal cobalamin absorption source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human renal cubilin and AMN copurified and coeluted as a tightly associated complex that required denaturing conditions for separation.
Human amnionless / AMN → Human cubilin / CUBN source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human renal cubilin and AMN remained associated during coelution in EDTA, indicating that their mutual association did not require calcium under these conditions.
Calcium ion → Human cubilin-amnionless complex source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The 3.3-angstrom human IF-cobalamin/CUB5-8 structure showed two separated cubilin CUB domains engaging the two intrinsic factor domains.
Human cubilin / CUBN → Human intrinsic factor-cobalamin complex source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Calcium ion → Human cubilin binding of intrinsic factor-cobalamin source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The human cubilin P1297L CUB5-8 fragment showed severalfold higher dissociation constant for IF-cobalamin than wild type, mainly from a lower association rate.
Human cubilin P1297L variant → Human intrinsic factor-cobalamin complex source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Mapping and sequencing identified two independent disease-specific CUBN mutations across 17 Finnish families with selective intestinal cobalamin malabsorption.
Human biallelic CUBN disease genotypes in Aminoff 1999 → Intestinal cobalamin absorption source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Human AMN p.Gln248Ter / c.208-2A>G compound genotype → Urinary cubilin intrinsic factor-binding activity source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Biallelic GIF mutations in seven families with juvenile cobalamin deficiency identified inherited intrinsic-factor deficiency in cases initially suspected to have receptor-mediated IGS.
Human biallelic GIF disease genotypes in Tanner 2005 → Intestinal cobalamin absorption source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Human amnionless / AMN → Rat N-terminal mini-cubilin construct source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Rat mini-cubilin N711D/N749D/N781D/N857D construct → Surface expression of rat mini-cubilin source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Human cubilin G653R variant → Human cubilin-amnionless retention in endoplasmic reticulum source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Purified human placental receptor and recombinant CD320 extracellular domain bound transcobalamin-cobalamin; high-affinity binding did not require the cytoplasmic domain or membrane orientation.
Human transcobalamin receptor / CD320 → Human transcobalamin-cobalamin complex source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The human receptor identified as CD320 binds transcobalamin-cobalamin at the plasma membrane and internalizes the carrier-vitamin complex by endocytosis.
Human transcobalamin receptor / CD320 → Cellular uptake of transcobalamin-bound cobalamin source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Fibroblasts from five asymptomatic newborns with elevated methylmalonic acid and homozygous CD320 p.Glu88del showed reduced uptake of holo-transcobalamin.
Human CD320 p.Glu88del variant → Cellular uptake of transcobalamin-bound cobalamin source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Replacing the missing Glu88 codon by site-directed mutagenesis restored receptor function in the CD320 reconstruction experiments.
Human transcobalamin receptor / CD320 → Cellular uptake of transcobalamin-bound cobalamin source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Megalin-deficient mice excreted approximately fourfold more urinary B12 than controls, consistent with defective renal recovery of transcobalamin-B12.
Mouse Lrp2-null genotype → Urinary cobalamin excretion source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Kidney cortex B12 content in megalin-deficient mice was approximately fourfold lower than in controls.
Mouse Lrp2-null genotype → Kidney cortex cobalamin content source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
In the comparative diabetes study, adding oral calcium after three months of metformin reversed the decline in serum holo-transcobalamin.
Calcium → Serum holotranscobalamin concentration source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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).
Metformin → Oral carbon-13 cyanocobalamin tracer bioavailability source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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).
Calcium → Oral carbon-13 cyanocobalamin tracer bioavailability source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human AMN coexpressed with rat cubilin 1-1389 enabled IF-B12 internalization in CHO-K1 cells; either intact FXNPXF cytoplasmic motif supported uptake.
Human amnionless / AMN → Cubam-mediated IF-cobalamin endocytosis source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Disruption of both human AMN FXNPXF motifs impaired IF-B12 internalization and degradation in CHO-K1 cells despite preserved cubam surface expression.
Human AMN double FXNPXF-signal mutant → Cubam-mediated IF-cobalamin endocytosis source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Human type I intrinsic-factor blocking autoantibodies → Human intrinsic factor cobalamin-binding function source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Type II antibodies prevented absorption in pernicious-anemia patients when added to a preformed intrinsic-factor-B12 complex.
Human type II intrinsic-factor binding autoantibodies → Intestinal cobalamin absorption source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Human inherited transcobalamin II deficiency → Megaloblastic anemia source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Transfection with wild-type LMBD1 restored cobalamin coenzyme synthesis and function in cultured fibroblasts from individuals with the cblF defect.
Human LMBD1 lysosomal membrane protein → Cellular cobalamin coenzyme synthesis source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The human disorder assigned to pathogenic ABCD4 mutations showed failure of lysosomal vitamin B12 release, resembling the cblF cellular defect.
Human ABCD4 gene → Cobalamin release from lysosomal lumen to cytosol source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
In HuH7 cells expressing human ABCD4-HA, adding LMBD1-GFP shifted ABCD4 from an ER-like distribution toward LAMP1-positive lysosomes.
Human LMBD1 lysosomal membrane protein → Human ABCD4 lysosomal cobalamin transporter source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
CRISPR LMBRD1 knockout in HEK293 cells reduced the ABCD4 signal overlapping lysosomal fractions to about 40% of control, while total ABCD4 was similar.
Human LMBRD1 gene → ABCD4 localization to lysosomes source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Human LMBD1 233YERL-to-AAAA → Human ABCD4 lysosomal cobalamin transporter source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Reconstituted human ABCD4 moved cobalamin from liposome interior to exterior with external ATP; the ATPase-defective K427A control lacked this activity.
Human ABCD4 lysosomal cobalamin transporter → Vitamin B12 (cobalamins) source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
LMBD1-only proteoliposomes had no detectable cobalamin transport in the same reconstitution system in which ABCD4 transported cobalamin.
Human LMBD1 lysosomal membrane protein → Vitamin B12 (cobalamins) source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Purified human ABCD4 N141K lost detectable cobalamin transport in liposomes, despite ATPase activity comparable with wild type.
Human ABCD4 N141K → Vitamin B12 (cobalamins) source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Purified human ABCD4 Y319C lost detectable cobalamin transport in liposomes, together with loss of ATPase activity.
Human ABCD4 Y319C → Vitamin B12 (cobalamins) source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human MMACHC converted bound cyanocobalamin to cob(II)alamin during NADPH-supported reductive decyanation; EPR identified the product in a base-off coordination state.
Human MMACHC / cobalamin-processing protein CblC → Cyanocobalamin source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Results: Figure 4; Materials and Methods: Decyanation of CNCbl
experimental_model
Purified human MMACHC with human flavoprotein donor
exposure
Anaerobic CNCbl/MMACHC, NADPH and MTRR or NDOR1
limitations
Reconstituted biochemical system; establishes reaction capability rather than the quantitatively dominant pathway in living humans.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Processing removes the cyano group and leaves a reduced B12 intermediate.
primary_references
[kim-2008-decyanation] Decyanation of vitamin B12 by a trafficking chaperone (2008). https://pubmed.ncbi.nlm.nih.gov/18779575/ DOI: 10.1073/pnas.0805989105
tissue_or_cell_type
Cell-free assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 669–681
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human MMACHC with human flavoprotein donor · source_derived_draft · unverified_draft
### b12-mmachc-decyanation Human MMACHC converted bound cyanocobalamin to cob(II)alamin during NADPH-supported reductive decyanation; EPR identified the product in a base-off coordination state. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Processing removes the cyano group and leaves a reduced B12 intermediate. organism: Homo sapiens tissue_or_cell_type: Cell-free assay experimental_model: Purified human MMACHC with human flavoprotein donor limitations: Reconstituted biochemical system; establishes reaction capability rather than the quantitatively dominant pathway in living humans. exposure: Anaerobic CNCbl/MMACHC, NADPH and MTRR or NDOR1 cross_nutrient: true evidence_location: Results: Figure 4; Materials and Methods: Decyanation of CNCbl [kim-2008-decyanation] Decyanation of vitamin B12 by a trafficking chaperone (2008). https://pubmed.ncbi.nlm.nih.gov/18779575/ DOI: 10.1073/pnas.0805989105
Complete structured claim and evidence
Recombinant human MTRR with NADPH supported MMACHC-bound cyanocobalamin conversion to cob(II)alamin; free cyanocobalamin was not detectably reduced without MMACHC.
Methionine synthase reductase / MTRR → Human MMACHC / cobalamin-processing protein CblC source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Results: Figure 4; Materials and Methods: Decyanation of CNCbl
experimental_model
Human purified-protein anaerobic reconstitution
exposure
4 micromolar reductase, 20 micromolar MMACHC/CNCbl, 200 micromolar NADPH
limitations
Reconstituted biochemical system; establishes reaction capability rather than the quantitatively dominant pathway in living humans.
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 flavoprotein can pass reducing power into B12 processing.
primary_references
[kim-2008-decyanation] Decyanation of vitamin B12 by a trafficking chaperone (2008). https://pubmed.ncbi.nlm.nih.gov/18779575/ DOI: 10.1073/pnas.0805989105
tissue_or_cell_type
Cell-free assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 683–695
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human purified-protein anaerobic reconstitution · source_derived_draft · unverified_draft
### b12-mtrr-mmachc-electrons Recombinant human MTRR with NADPH supported MMACHC-bound cyanocobalamin conversion to cob(II)alamin; free cyanocobalamin was not detectably reduced without MMACHC. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This flavoprotein can pass reducing power into B12 processing. organism: Homo sapiens tissue_or_cell_type: Cell-free assay experimental_model: Human purified-protein anaerobic reconstitution limitations: Reconstituted biochemical system; establishes reaction capability rather than the quantitatively dominant pathway in living humans. exposure: 4 micromolar reductase, 20 micromolar MMACHC/CNCbl, 200 micromolar NADPH cross_nutrient: true evidence_location: Results: Figure 4; Materials and Methods: Decyanation of CNCbl [kim-2008-decyanation] Decyanation of vitamin B12 by a trafficking chaperone (2008). https://pubmed.ncbi.nlm.nih.gov/18779575/ DOI: 10.1073/pnas.0805989105
Complete structured claim and evidence
Recombinant human NDOR1/NR1 with NADPH supported MMACHC-bound cyanocobalamin conversion to cob(II)alamin; free cyanocobalamin was not detectably reduced without MMACHC.
Human NADPH-dependent diflavin oxidoreductase 1 → Human MMACHC / cobalamin-processing protein CblC source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Results: Figure 4; Materials and Methods: Decyanation of CNCbl
experimental_model
Human purified-protein anaerobic reconstitution
exposure
4 micromolar reductase, 20 micromolar MMACHC/CNCbl, 200 micromolar NADPH
limitations
Reconstituted biochemical system; establishes reaction capability rather than the quantitatively dominant pathway in living humans.
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 flavoprotein can pass reducing power into B12 processing.
primary_references
[kim-2008-decyanation] Decyanation of vitamin B12 by a trafficking chaperone (2008). https://pubmed.ncbi.nlm.nih.gov/18779575/ DOI: 10.1073/pnas.0805989105
tissue_or_cell_type
Cell-free assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 697–709
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human purified-protein anaerobic reconstitution · source_derived_draft · unverified_draft
### b12-ndor1-mmachc-electrons Recombinant human NDOR1/NR1 with NADPH supported MMACHC-bound cyanocobalamin conversion to cob(II)alamin; free cyanocobalamin was not detectably reduced without MMACHC. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This flavoprotein can pass reducing power into B12 processing. organism: Homo sapiens tissue_or_cell_type: Cell-free assay experimental_model: Human purified-protein anaerobic reconstitution limitations: Reconstituted biochemical system; establishes reaction capability rather than the quantitatively dominant pathway in living humans. exposure: 4 micromolar reductase, 20 micromolar MMACHC/CNCbl, 200 micromolar NADPH cross_nutrient: true evidence_location: Results: Figure 4; Materials and Methods: Decyanation of CNCbl [kim-2008-decyanation] Decyanation of vitamin B12 by a trafficking chaperone (2008). https://pubmed.ncbi.nlm.nih.gov/18779575/ DOI: 10.1073/pnas.0805989105
Complete structured claim and evidence
Human MMACHC transfers the methyl group from methylcobalamin to glutathione, yielding cob(I)alamin and the corresponding glutathione thioether; reported turnover was 11.7 +/- 0.2 per hour at 20 C.
Human MMACHC / cobalamin-processing protein CblC → Methylcobalamin source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Primary abstract; indexed article Introduction/Figure 1
experimental_model
Purified human MMACHC substrate chemistry
exposure
Specified alkylcobalamin plus GSH; kinetic temperature 20 C
limitations
Reconstituted biochemical system; establishes reaction capability rather than the quantitatively dominant pathway in living humans.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Glutathione receives the side group removed from this B12 form.
primary_references
[kim-2009-gsh-dealkylation] A human vitamin B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins (2009). https://pubmed.ncbi.nlm.nih.gov/19801555/ DOI: 10.1074/jbc.M109.057877
tissue_or_cell_type
Cell-free assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 711–723
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human MMACHC substrate chemistry · source_derived_draft · unverified_draft
### b12-mmachc-methyl-dealkylation Human MMACHC transfers the methyl group from methylcobalamin to glutathione, yielding cob(I)alamin and the corresponding glutathione thioether; reported turnover was 11.7 +/- 0.2 per hour at 20 C. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Glutathione receives the side group removed from this B12 form. organism: Homo sapiens tissue_or_cell_type: Cell-free assay experimental_model: Purified human MMACHC substrate chemistry limitations: Reconstituted biochemical system; establishes reaction capability rather than the quantitatively dominant pathway in living humans. exposure: Specified alkylcobalamin plus GSH; kinetic temperature 20 C cross_nutrient: true evidence_location: Primary abstract; indexed article Introduction/Figure 1 [kim-2009-gsh-dealkylation] A human vitamin B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins (2009). https://pubmed.ncbi.nlm.nih.gov/19801555/ DOI: 10.1074/jbc.M109.057877
Complete structured claim and evidence
Human MMACHC transfers the 5′-deoxyadenosyl group from adenosylcobalamin to glutathione, yielding cob(I)alamin and the corresponding glutathione thioether; reported turnover was 0.174 +/- 0.006 per hour at 20 C.
Human MMACHC / cobalamin-processing protein CblC → 5'-Deoxyadenosylcobalamin source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Primary abstract; indexed article Introduction/Figure 1
experimental_model
Purified human MMACHC substrate chemistry
exposure
Specified alkylcobalamin plus GSH; kinetic temperature 20 C
limitations
Reconstituted biochemical system; establishes reaction capability rather than the quantitatively dominant pathway in living humans.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Glutathione receives the side group removed from this B12 form.
primary_references
[kim-2009-gsh-dealkylation] A human vitamin B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins (2009). https://pubmed.ncbi.nlm.nih.gov/19801555/ DOI: 10.1074/jbc.M109.057877
tissue_or_cell_type
Cell-free assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 725–737
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human MMACHC substrate chemistry · source_derived_draft · unverified_draft
### b12-mmachc-adenosyl-dealkylation Human MMACHC transfers the 5′-deoxyadenosyl group from adenosylcobalamin to glutathione, yielding cob(I)alamin and the corresponding glutathione thioether; reported turnover was 0.174 +/- 0.006 per hour at 20 C. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Glutathione receives the side group removed from this B12 form. organism: Homo sapiens tissue_or_cell_type: Cell-free assay experimental_model: Purified human MMACHC substrate chemistry limitations: Reconstituted biochemical system; establishes reaction capability rather than the quantitatively dominant pathway in living humans. exposure: Specified alkylcobalamin plus GSH; kinetic temperature 20 C cross_nutrient: true evidence_location: Primary abstract; indexed article Introduction/Figure 1 [kim-2009-gsh-dealkylation] A human vitamin B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins (2009). https://pubmed.ncbi.nlm.nih.gov/19801555/ DOI: 10.1074/jbc.M109.057877
Complete structured claim and evidence
In the human MMACHC dealkylation study, cysteine and homocysteine did not substitute for glutathione as the thiol co-substrate.
GSH → MMACHC-catalyzed alkylcobalamin dealkylation source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Primary abstract; indexed article Introduction/Figure 1
experimental_model
Purified human MMACHC thiol substitution assays
exposure
GSH versus cysteine or homocysteine
limitations
No implication that cysteine availability is irrelevant to cellular GSH synthesis; that upstream pathway was not tested here.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Having a thiol group was not enough; the enzyme required glutathione in these assays.
primary_references
[kim-2009-gsh-dealkylation] A human vitamin B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins (2009). https://pubmed.ncbi.nlm.nih.gov/19801555/ DOI: 10.1074/jbc.M109.057877
tissue_or_cell_type
Cell-free assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 739–751
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human MMACHC thiol substitution assays · source_derived_draft · unverified_draft
### b12-mmachc-thiol-specificity In the human MMACHC dealkylation study, cysteine and homocysteine did not substitute for glutathione as the thiol co-substrate. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Having a thiol group was not enough; the enzyme required glutathione in these assays. organism: Homo sapiens tissue_or_cell_type: Cell-free assay experimental_model: Purified human MMACHC thiol substitution assays limitations: No implication that cysteine availability is irrelevant to cellular GSH synthesis; that upstream pathway was not tested here. exposure: GSH versus cysteine or homocysteine cross_nutrient: true evidence_location: Primary abstract; indexed article Introduction/Figure 1 [kim-2009-gsh-dealkylation] A human vitamin B12 trafficking protein uses glutathione transferase activity for processing alkylcobalamins (2009). https://pubmed.ncbi.nlm.nih.gov/19801555/ DOI: 10.1074/jbc.M109.057877
Complete structured claim and evidence
Human MMACHC residues 1–244 supported cyanocobalamin decyanation with FMN or FAD plus NADPH, without a separately supplied flavoprotein reductase; reduced FMN also supported the reaction.
Human MMACHC deltaC38 → Cyanocobalamin source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
true
evidence_location
Experimental procedures and Results: CblC Has a Flavin Reductase Fold; Figure 1c
experimental_model
Recombinant human MMACHC deltaC38 biochemical assay
exposure
30–40 micromolar FMN/FAD with 200 micromolar NADPH, or photoreduced FMN
limitations
Engineered truncation and reconstitution; does not establish that riboflavin supplementation rescues MMACHC defects.
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 truncated B12-processing protein could use supplied flavins to carry out this reaction.
primary_references
[koutmos-2011-flavin] Structural Basis of Multifunctionality in a Vitamin B12-processing Enzyme (2011). https://pubmed.ncbi.nlm.nih.gov/21697092/ DOI: 10.1074/jbc.M111.261370
tissue_or_cell_type
Cell-free assay
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 753–765
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MMACHC deltaC38 biochemical assay · source_derived_draft · unverified_draft
### b12-mmachc-free-flavin-decyanation Human MMACHC residues 1–244 supported cyanocobalamin decyanation with FMN or FAD plus NADPH, without a separately supplied flavoprotein reductase; reduced FMN also supported the reaction. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A truncated B12-processing protein could use supplied flavins to carry out this reaction. organism: Homo sapiens tissue_or_cell_type: Cell-free assay experimental_model: Recombinant human MMACHC deltaC38 biochemical assay limitations: Engineered truncation and reconstitution; does not establish that riboflavin supplementation rescues MMACHC defects. exposure: 30–40 micromolar FMN/FAD with 200 micromolar NADPH, or photoreduced FMN cross_nutrient: true evidence_location: Experimental procedures and Results: CblC Has a Flavin Reductase Fold; Figure 1c [koutmos-2011-flavin] Structural Basis of Multifunctionality in a Vitamin B12-processing Enzyme (2011). https://pubmed.ncbi.nlm.nih.gov/21697092/ DOI: 10.1074/jbc.M111.261370
Complete structured claim and evidence
Purified human CblC/MMACHC supported GSH-dependent decyanation of cyanocobalamin to cob(II)alamin efficiently under anaerobic conditions; the human reaction was oxygen-sensitive.
Human MMACHC / cobalamin-processing protein CblC → Cyanocobalamin source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Abstract; indexed primary Results summary
experimental_model
Purified human MMACHC; oxygen-controlled biochemical assay
exposure
GSH and specified B12 form under anaerobic versus aerobic conditions
limitations
Abstract-level extraction; stronger aerobic activity of the C. elegans enzyme must not be attributed to human MMACHC.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Glutathione could supply reducing power, but oxygen strongly affected this human-protein reaction.
primary_references
[li-2014-gsh-electron] Glutathione-dependent one-electron transfer reactions catalyzed by a B12 trafficking protein (2014). https://pubmed.ncbi.nlm.nih.gov/24742678/ DOI: 10.1074/jbc.M114.567339
tissue_or_cell_type
Cell-free assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 767–779
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human MMACHC; oxygen-controlled biochemical assay · source_derived_draft · unverified_draft
### b12-human-gsh-decyanation Purified human CblC/MMACHC supported GSH-dependent decyanation of cyanocobalamin to cob(II)alamin efficiently under anaerobic conditions; the human reaction was oxygen-sensitive. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Glutathione could supply reducing power, but oxygen strongly affected this human-protein reaction. organism: Homo sapiens tissue_or_cell_type: Cell-free assay experimental_model: Purified human MMACHC; oxygen-controlled biochemical assay limitations: Abstract-level extraction; stronger aerobic activity of the C. elegans enzyme must not be attributed to human MMACHC. exposure: GSH and specified B12 form under anaerobic versus aerobic conditions cross_nutrient: true evidence_location: Abstract; indexed primary Results summary [li-2014-gsh-electron] Glutathione-dependent one-electron transfer reactions catalyzed by a B12 trafficking protein (2014). https://pubmed.ncbi.nlm.nih.gov/24742678/ DOI: 10.1074/jbc.M114.567339
Complete structured claim and evidence
Purified human CblC/MMACHC supported GSH-dependent reduction of aquocobalamin to cob(II)alamin efficiently under anaerobic conditions; the human reaction was oxygen-sensitive.
Human MMACHC / cobalamin-processing protein CblC → Aquocobalamin source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Abstract; indexed primary Results summary
experimental_model
Purified human MMACHC; oxygen-controlled biochemical assay
exposure
GSH and specified B12 form under anaerobic versus aerobic conditions
limitations
Abstract-level extraction; stronger aerobic activity of the C. elegans enzyme must not be attributed to human MMACHC.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Glutathione could supply reducing power, but oxygen strongly affected this human-protein reaction.
primary_references
[li-2014-gsh-electron] Glutathione-dependent one-electron transfer reactions catalyzed by a B12 trafficking protein (2014). https://pubmed.ncbi.nlm.nih.gov/24742678/ DOI: 10.1074/jbc.M114.567339
tissue_or_cell_type
Cell-free assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 781–793
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human MMACHC; oxygen-controlled biochemical assay · source_derived_draft · unverified_draft
### b12-human-gsh-reduction Purified human CblC/MMACHC supported GSH-dependent reduction of aquocobalamin to cob(II)alamin efficiently under anaerobic conditions; the human reaction was oxygen-sensitive. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Glutathione could supply reducing power, but oxygen strongly affected this human-protein reaction. organism: Homo sapiens tissue_or_cell_type: Cell-free assay experimental_model: Purified human MMACHC; oxygen-controlled biochemical assay limitations: Abstract-level extraction; stronger aerobic activity of the C. elegans enzyme must not be attributed to human MMACHC. exposure: GSH and specified B12 form under anaerobic versus aerobic conditions cross_nutrient: true evidence_location: Abstract; indexed primary Results summary [li-2014-gsh-electron] Glutathione-dependent one-electron transfer reactions catalyzed by a B12 trafficking protein (2014). https://pubmed.ncbi.nlm.nih.gov/24742678/ DOI: 10.1074/jbc.M114.567339
Complete structured claim and evidence
Bovine aortic endothelial cells converted cobalt-57-labeled adenosylcobalamin into labeled methylcobalamin during metabolic labeling.
5'-Deoxyadenosylcobalamin → Methylcobalamin source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Abstract; indexed Methods: Assessment of dealkylation; Discussion
experimental_model
Bovine aortic endothelial cell metabolic labeling
exposure
0.125 nM labeled alkylcobalamin; 48-hour processing assay protected from light
limitations
Cellular conversion supports processing but does not by itself identify every enzyme or establish a human supplement hierarchy.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Bos taurus
plain_language
These bovine cells could rework one active B12 form into the other.
primary_references
[hannibal-2009-cell-processing] Processing of alkylcobalamins in mammalian cells: A role for the MMACHC (cblC) gene product (2009). https://pubmed.ncbi.nlm.nih.gov/19447654/ DOI: 10.1016/j.ymgme.2009.04.005
tissue_or_cell_type
Aortic endothelium
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 795–807
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Bovine aortic endothelial cell metabolic labeling · source_derived_draft · unverified_draft
### b12-bovine-ado-to-methyl Bovine aortic endothelial cells converted cobalt-57-labeled adenosylcobalamin into labeled methylcobalamin during metabolic labeling. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: These bovine cells could rework one active B12 form into the other. organism: Bos taurus tissue_or_cell_type: Aortic endothelium experimental_model: Bovine aortic endothelial cell metabolic labeling limitations: Cellular conversion supports processing but does not by itself identify every enzyme or establish a human supplement hierarchy. exposure: 0.125 nM labeled alkylcobalamin; 48-hour processing assay protected from light cross_nutrient: false evidence_location: Abstract; indexed Methods: Assessment of dealkylation; Discussion [hannibal-2009-cell-processing] Processing of alkylcobalamins in mammalian cells: A role for the MMACHC (cblC) gene product (2009). https://pubmed.ncbi.nlm.nih.gov/19447654/ DOI: 10.1016/j.ymgme.2009.04.005
Complete structured claim and evidence
Fibroblasts from three cblC patients had little or no conversion of cobalt-57-labeled propylcobalamin into adenosylcobalamin and methylcobalamin, whereas control skin fibroblasts converted the probe.
Human MMACHC gene → Propylcobalamin source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Abstract; indexed Methods: Assessment of dealkylation; Discussion
experimental_model
Human control and cblC patient fibroblast labeling
exposure
0.125 nM cobalt-57 propylcobalamin for 48 hours
limitations
Propylcobalamin is a synthetic C3 probe; patients and genotypes differ and this comparison does not quantify every natural vitamer response.
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 synthetic B12 probe exposed the processing defect in patient cells.
primary_references
[hannibal-2009-cell-processing] Processing of alkylcobalamins in mammalian cells: A role for the MMACHC (cblC) gene product (2009). https://pubmed.ncbi.nlm.nih.gov/19447654/ DOI: 10.1016/j.ymgme.2009.04.005
tissue_or_cell_type
Skin fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 809–821
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human control and cblC patient fibroblast labeling · source_derived_draft · unverified_draft
### b12-cblc-propyl-probe Fibroblasts from three cblC patients had little or no conversion of cobalt-57-labeled propylcobalamin into adenosylcobalamin and methylcobalamin, whereas control skin fibroblasts converted the probe. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A synthetic B12 probe exposed the processing defect in patient cells. organism: Homo sapiens tissue_or_cell_type: Skin fibroblasts experimental_model: Human control and cblC patient fibroblast labeling limitations: Propylcobalamin is a synthetic C3 probe; patients and genotypes differ and this comparison does not quantify every natural vitamer response. exposure: 0.125 nM cobalt-57 propylcobalamin for 48 hours cross_nutrient: false evidence_location: Abstract; indexed Methods: Assessment of dealkylation; Discussion [hannibal-2009-cell-processing] Processing of alkylcobalamins in mammalian cells: A role for the MMACHC (cblC) gene product (2009). https://pubmed.ncbi.nlm.nih.gov/19447654/ DOI: 10.1016/j.ymgme.2009.04.005
Complete structured claim and evidence
In cblD-MMA/HC fibroblasts, an MMADHC construct with improved mitochondrial targeting increased adenosylcobalamin formation relative to the targeting comparator.
MMADHC with enhanced mitochondrial targeting sequence → 5'-Deoxyadenosylcobalamin source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Abstract
experimental_model
Human cblD-MMA/HC fibroblast transfection
exposure
Engineered mitochondrial leader sequence
limitations
Abstract-level construct experiment; effect in isolated cblD-MMA lines depended on mutation and endogenous expression.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Redirecting MMADHC toward mitochondria increased production of this B12 cofactor.
primary_references
[stucki-2012-mmad-routing] Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism (2012). https://pubmed.ncbi.nlm.nih.gov/22156578/ DOI: 10.1093/hmg/ddr579
tissue_or_cell_type
Patient fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 823–835
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human cblD-MMA/HC fibroblast transfection · source_derived_draft · unverified_draft
### b12-mmad-mito-target-adenosylcobalamin In cblD-MMA/HC fibroblasts, an MMADHC construct with improved mitochondrial targeting increased adenosylcobalamin formation relative to the targeting comparator. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Redirecting MMADHC toward mitochondria increased production of this B12 cofactor. organism: Homo sapiens tissue_or_cell_type: Patient fibroblasts experimental_model: Human cblD-MMA/HC fibroblast transfection limitations: Abstract-level construct experiment; effect in isolated cblD-MMA lines depended on mutation and endogenous expression. exposure: Engineered mitochondrial leader sequence cross_nutrient: false evidence_location: Abstract [stucki-2012-mmad-routing] Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism (2012). https://pubmed.ncbi.nlm.nih.gov/22156578/ DOI: 10.1093/hmg/ddr579
Complete structured claim and evidence
In cblD-MMA/HC fibroblasts, an MMADHC construct with improved mitochondrial targeting decreased methylcobalamin formation relative to the targeting comparator.
MMADHC with enhanced mitochondrial targeting sequence → Methylcobalamin source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Abstract
experimental_model
Human cblD-MMA/HC fibroblast transfection
exposure
Engineered mitochondrial leader sequence
limitations
Abstract-level construct experiment; effect in isolated cblD-MMA lines depended on mutation and endogenous expression.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Redirecting MMADHC toward mitochondria decreased production of this B12 cofactor.
primary_references
[stucki-2012-mmad-routing] Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism (2012). https://pubmed.ncbi.nlm.nih.gov/22156578/ DOI: 10.1093/hmg/ddr579
tissue_or_cell_type
Patient fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 837–849
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human cblD-MMA/HC fibroblast transfection · source_derived_draft · unverified_draft
### b12-mmad-mito-target-methylcobalamin In cblD-MMA/HC fibroblasts, an MMADHC construct with improved mitochondrial targeting decreased methylcobalamin formation relative to the targeting comparator. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Redirecting MMADHC toward mitochondria decreased production of this B12 cofactor. organism: Homo sapiens tissue_or_cell_type: Patient fibroblasts experimental_model: Human cblD-MMA/HC fibroblast transfection limitations: Abstract-level construct experiment; effect in isolated cblD-MMA lines depended on mutation and endogenous expression. exposure: Engineered mitochondrial leader sequence cross_nutrient: false evidence_location: Abstract [stucki-2012-mmad-routing] Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism (2012). https://pubmed.ncbi.nlm.nih.gov/22156578/ DOI: 10.1093/hmg/ddr579
Complete structured claim and evidence
MMADHC expression/translation-reinitiation experiments in cblD patient fibroblasts indicated that sequence after Met116 was sufficient to support methylcobalamin synthesis.
Human MMADHC segment after Met116 → Methylcobalamin source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Abstract
experimental_model
Human cblD fibroblast construct-rescue study
exposure
MMADHC constructs changing stop codons or downstream translation starts
limitations
Abstract-level domain inference; no claim of an independently purified physiological isoform.
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 later portion of MMADHC could support the methyl-B12 branch in these cells.
primary_references
[stucki-2012-mmad-routing] Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism (2012). https://pubmed.ncbi.nlm.nih.gov/22156578/ DOI: 10.1093/hmg/ddr579
tissue_or_cell_type
Patient fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 851–863
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human cblD fibroblast construct-rescue study · source_derived_draft · unverified_draft
### b12-mmad-after116-methyl MMADHC expression/translation-reinitiation experiments in cblD patient fibroblasts indicated that sequence after Met116 was sufficient to support methylcobalamin synthesis. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The later portion of MMADHC could support the methyl-B12 branch in these cells. organism: Homo sapiens tissue_or_cell_type: Patient fibroblasts experimental_model: Human cblD fibroblast construct-rescue study limitations: Abstract-level domain inference; no claim of an independently purified physiological isoform. exposure: MMADHC constructs changing stop codons or downstream translation starts cross_nutrient: false evidence_location: Abstract [stucki-2012-mmad-routing] Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism (2012). https://pubmed.ncbi.nlm.nih.gov/22156578/ DOI: 10.1093/hmg/ddr579
Complete structured claim and evidence
Human MMADHC delta123 carrying T182N showed strongly reduced complex formation with full-length human MMACHC after MeCbl/GSH incubation, compared with matched delta123 MMADHC.
Human MMADHC delta123 T182N → Human MMACHC / cobalamin-processing protein CblC source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Results: Figure 5D; Experimental Procedures
experimental_model
Recombinant human proteins; blue-native PAGE
exposure
T182N versus matched delta123 comparator, MMACHC, MeCbl and GSH
limitations
Functional assay used human proteins; mouse MMADHC was used for the separate crystal structure. Truncation may affect full-length behavior.
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 variant disrupted the two processing proteins’ association.
primary_references
[froese-2015-complex] Structural Insights into the MMACHC-MMADHC Protein Complex Involved in Vitamin B12 Trafficking (2015). https://pubmed.ncbi.nlm.nih.gov/26483544/ DOI: 10.1074/jbc.M115.683268
tissue_or_cell_type
Cell-free assay
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 865–877
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human proteins; blue-native PAGE · source_derived_draft · unverified_draft
### b12-mmad-t182n-complex Human MMADHC delta123 carrying T182N showed strongly reduced complex formation with full-length human MMACHC after MeCbl/GSH incubation, compared with matched delta123 MMADHC. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This variant disrupted the two processing proteins’ association. organism: Homo sapiens tissue_or_cell_type: Cell-free assay experimental_model: Recombinant human proteins; blue-native PAGE limitations: Functional assay used human proteins; mouse MMADHC was used for the separate crystal structure. Truncation may affect full-length behavior. exposure: T182N versus matched delta123 comparator, MMACHC, MeCbl and GSH cross_nutrient: false evidence_location: Results: Figure 5D; Experimental Procedures [froese-2015-complex] Structural Insights into the MMACHC-MMADHC Protein Complex Involved in Vitamin B12 Trafficking (2015). https://pubmed.ncbi.nlm.nih.gov/26483544/ DOI: 10.1074/jbc.M115.683268
Complete structured claim and evidence
Human MMADHC donated the Cys261 sulfur ligand to MMACHC-bound cob(II)alamin, forming an interprotein complex that oxidized to thiolato-cob(III)alamin.
Human MMADHC / cobalamin-trafficking protein CblD → Human MMACHC / cobalamin-processing protein CblC source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Abstract; indexed Results: CblD binds H2OCbl and forms a complex with CblC
experimental_model
Human recombinant chaperones; cysteine scanning and EPR/X-ray absorption
exposure
MMACHC-bound cob(II)alamin mixed with MMADHC; oxygen controls
limitations
Chemical complex formation does not alone prove the complete in-cell route from lysosome to either client enzyme.
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 sulfur atom on one chaperone helped hold B12 while it remained bound to the other.
primary_references
[li-2020-co-s] An Interprotein Co-S Coordination Complex in the B12-Trafficking Pathway (2020). https://pubmed.ncbi.nlm.nih.gov/32871076/ DOI: 10.1021/jacs.0c06590
tissue_or_cell_type
Cell-free assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 879–891
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human recombinant chaperones; cysteine scanning and EPR/X-ray absorption · source_derived_draft · unverified_draft
### b12-mmad-cys261-co-s Human MMADHC donated the Cys261 sulfur ligand to MMACHC-bound cob(II)alamin, forming an interprotein complex that oxidized to thiolato-cob(III)alamin. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A sulfur atom on one chaperone helped hold B12 while it remained bound to the other. organism: Homo sapiens tissue_or_cell_type: Cell-free assay experimental_model: Human recombinant chaperones; cysteine scanning and EPR/X-ray absorption limitations: Chemical complex formation does not alone prove the complete in-cell route from lysosome to either client enzyme. exposure: MMACHC-bound cob(II)alamin mixed with MMADHC; oxygen controls cross_nutrient: false evidence_location: Abstract; indexed Results: CblD binds H2OCbl and forms a complex with CblC [li-2020-co-s] An Interprotein Co-S Coordination Complex in the B12-Trafficking Pathway (2020). https://pubmed.ncbi.nlm.nih.gov/32871076/ DOI: 10.1021/jacs.0c06590
Complete structured claim and evidence
Reduced, full-length human MMADHC bound free aquocobalamin in vitro with a reported KD of 1.0 +/- 0.4 micromolar and formed a base-on thiolato-cob(III)alamin species.
Human MMADHC / cobalamin-trafficking protein CblD → Aquocobalamin source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Abstract; indexed Results: CblD binds H2OCbl and forms a complex with CblC
experimental_model
Human full-length recombinant MMADHC binding assay
exposure
Reduction of cysteines followed by removal of excess DTT; free aquocobalamin
limitations
Slow binding and micromolar affinity make free aquocobalamin capture an uncertain physiological route; older no-binding results were condition-sensitive.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
MMADHC could bind this B12 form directly under the preparation conditions.
primary_references
[li-2020-co-s] An Interprotein Co-S Coordination Complex in the B12-Trafficking Pathway (2020). https://pubmed.ncbi.nlm.nih.gov/32871076/ DOI: 10.1021/jacs.0c06590
tissue_or_cell_type
Cell-free assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 893–905
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human full-length recombinant MMADHC binding assay · source_derived_draft · unverified_draft
### b12-mmad-free-aquo-binding Reduced, full-length human MMADHC bound free aquocobalamin in vitro with a reported KD of 1.0 +/- 0.4 micromolar and formed a base-on thiolato-cob(III)alamin species. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: MMADHC could bind this B12 form directly under the preparation conditions. organism: Homo sapiens tissue_or_cell_type: Cell-free assay experimental_model: Human full-length recombinant MMADHC binding assay limitations: Slow binding and micromolar affinity make free aquocobalamin capture an uncertain physiological route; older no-binding results were condition-sensitive. exposure: Reduction of cysteines followed by removal of excess DTT; free aquocobalamin cross_nutrient: false evidence_location: Abstract; indexed Results: CblD binds H2OCbl and forms a complex with CblC [li-2020-co-s] An Interprotein Co-S Coordination Complex in the B12-Trafficking Pathway (2020). https://pubmed.ncbi.nlm.nih.gov/32871076/ DOI: 10.1021/jacs.0c06590
Complete structured claim and evidence
PRDX1 splice-acceptor variants c.515-1G>T or c.515-2A>T were linked to exon-6/termination-signal skipping and antisense readthrough across MMACHC in epi-cblC fibroblasts.
Human PRDX1 gene → PRDX1 readthrough antisense RNA across MMACHC source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Results: Figures 1, 4–6; Methods: PRDX1 silencing
experimental_model
Human epi-cblC fibroblast RNA-seq and RT-PCR
exposure
Inherited PRDX1 splice variants
limitations
Specific cis-acting alleles; does not imply ordinary PRDX1 antioxidant activity suppresses B12 processing.
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 neighboring gene’s splice defect made transcription run through the B12-processing gene.
primary_references
[gueant-2018-epi-cblc] A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients (2018). https://pubmed.ncbi.nlm.nih.gov/29302025/ DOI: 10.1038/s41467-017-02306-5
tissue_or_cell_type
Patient skin fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 907–919
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human epi-cblC fibroblast RNA-seq and RT-PCR · source_derived_draft · unverified_draft
### b12-prdx1-readthrough PRDX1 splice-acceptor variants c.515-1G>T or c.515-2A>T were linked to exon-6/termination-signal skipping and antisense readthrough across MMACHC in epi-cblC fibroblasts. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A neighboring gene’s splice defect made transcription run through the B12-processing gene. organism: Homo sapiens tissue_or_cell_type: Patient skin fibroblasts experimental_model: Human epi-cblC fibroblast RNA-seq and RT-PCR limitations: Specific cis-acting alleles; does not imply ordinary PRDX1 antioxidant activity suppresses B12 processing. exposure: Inherited PRDX1 splice variants cross_nutrient: false evidence_location: Results: Figures 1, 4–6; Methods: PRDX1 silencing [gueant-2018-epi-cblc] A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients (2018). https://pubmed.ncbi.nlm.nih.gov/29302025/ DOI: 10.1038/s41467-017-02306-5
Complete structured claim and evidence
In CHU-12122 epi-cblC fibroblasts, the promoter-hypermethylated paternal MMACHC allele was transcriptionally silent; only the maternal coding-mutant allele was detected in transcripts.
MMACHC promoter CpG methylation → MMACHC gene transcription source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Results: Figures 1, 4–6; Methods: PRDX1 silencing
experimental_model
Allele-specific human epi-cblC expression and bisulfite analysis
exposure
Paternal secondary epimutation plus maternal c.270_271insA coding variant
limitations
Family-specific compound genetic/epigenetic machinery defect; not a nutritional methylation intervention.
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 intact B12-processing allele was switched off by the inherited epigenetic defect.
primary_references
[gueant-2018-epi-cblc] A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients (2018). https://pubmed.ncbi.nlm.nih.gov/29302025/ DOI: 10.1038/s41467-017-02306-5
tissue_or_cell_type
CHU-12122 fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 921–933
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Allele-specific human epi-cblC expression and bisulfite analysis · source_derived_draft · unverified_draft
### b12-mmachc-epi-silencing In CHU-12122 epi-cblC fibroblasts, the promoter-hypermethylated paternal MMACHC allele was transcriptionally silent; only the maternal coding-mutant allele was detected in transcripts. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The intact B12-processing allele was switched off by the inherited epigenetic defect. organism: Homo sapiens tissue_or_cell_type: CHU-12122 fibroblasts experimental_model: Allele-specific human epi-cblC expression and bisulfite analysis limitations: Family-specific compound genetic/epigenetic machinery defect; not a nutritional methylation intervention. exposure: Paternal secondary epimutation plus maternal c.270_271insA coding variant cross_nutrient: false evidence_location: Results: Figures 1, 4–6; Methods: PRDX1 silencing [gueant-2018-epi-cblc] A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients (2018). https://pubmed.ncbi.nlm.nih.gov/29302025/ DOI: 10.1038/s41467-017-02306-5
Complete structured claim and evidence
PRDX1-targeting siRNA restored detectable MMACHC expression in WG3838 epi-cblC fibroblasts, unlike control siRNA.
Human PRDX1 gene → MMACHC gene transcription source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Results: Figures 1, 4–6; Methods: PRDX1 silencing
experimental_model
Human WG3838 fibroblast siRNA and quantitative RT-PCR
exposure
PRDX1-targeting versus control siRNA
limitations
Expression rescue is not demonstrated clinical treatment or proof of complete metabolic correction; MeWo-LC1 methylation endpoint is a different 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
Reducing the abnormal neighboring transcript allowed the processing gene to be expressed again.
primary_references
[gueant-2018-epi-cblc] A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients (2018). https://pubmed.ncbi.nlm.nih.gov/29302025/ DOI: 10.1038/s41467-017-02306-5
tissue_or_cell_type
Patient fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 935–947
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human WG3838 fibroblast siRNA and quantitative RT-PCR · source_derived_draft · unverified_draft
### b12-prdx1-sirna-restores-mmachc PRDX1-targeting siRNA restored detectable MMACHC expression in WG3838 epi-cblC fibroblasts, unlike control siRNA. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Reducing the abnormal neighboring transcript allowed the processing gene to be expressed again. organism: Homo sapiens tissue_or_cell_type: Patient fibroblasts experimental_model: Human WG3838 fibroblast siRNA and quantitative RT-PCR limitations: Expression rescue is not demonstrated clinical treatment or proof of complete metabolic correction; MeWo-LC1 methylation endpoint is a different experiment. exposure: PRDX1-targeting versus control siRNA cross_nutrient: false evidence_location: Results: Figures 1, 4–6; Methods: PRDX1 silencing [gueant-2018-epi-cblc] A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients (2018). https://pubmed.ncbi.nlm.nih.gov/29302025/ DOI: 10.1038/s41467-017-02306-5
Complete structured claim and evidence
Human ABCD4 Y482A showed markedly impaired association with LMBD1 in HEK293T co-immunoprecipitation compared with wild-type ABCD4.
Human ABCD4 Y482A → Human LMBD1 lysosomal membrane protein source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Human ABCD4 Y482A coexpressed with LMBD1 in HEK293T cells showed a reticular distribution without normal LAMP1 overlap.
Human ABCD4 Y482A → ABCD4 localization to lysosomes source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Purified human MMAB uses ATP to adenosylate cob(I)alamin to adenosylcobalamin.
Human ATP:cob(I)alamin adenosyltransferase / MMAB → Cob(I)alamin source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Indexed primary abstract
experimental_model
Purified human proteins
exposure
Cob(I)alamin and ATP
limitations
Biochemical reconstitution; does not determine cellular rate or dietary requirement.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
In a purified human-protein assay, MMAB made the B12 cofactor used by MMUT.
primary_references
[leal-2004-human-mmab] Human ATP:Cob(I)alamin adenosyltransferase and its interaction with methionine synthase reductase. (2004). https://pubmed.ncbi.nlm.nih.gov/15347655/ DOI: 10.1074/jbc.m405449200
tissue_or_cell_type
Purified protein assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 977–989
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human proteins · source_derived_draft · unverified_draft
### mmab-adenosylates-cob-i Purified human MMAB uses ATP to adenosylate cob(I)alamin to adenosylcobalamin. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: In a purified human-protein assay, MMAB made the B12 cofactor used by MMUT. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human proteins limitations: Biochemical reconstitution; does not determine cellular rate or dietary requirement. exposure: Cob(I)alamin and ATP cross_nutrient: false evidence_location: Indexed primary abstract [leal-2004-human-mmab] Human ATP:Cob(I)alamin adenosyltransferase and its interaction with methionine synthase reductase. (2004). https://pubmed.ncbi.nlm.nih.gov/15347655/ DOI: 10.1074/jbc.m405449200
Complete structured claim and evidence
Purified human MTRR coupled cob(II)alamin reduction to MMAB-dependent adenosylcobalamin synthesis in vitro.
Methionine synthase reductase / MTRR → Human ATP:cob(I)alamin adenosyltransferase / MMAB source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Indexed primary abstract
experimental_model
Purified human proteins
exposure
Purified MTRR plus MMAB and reductants
limitations
MTRR coupling in vitro does not identify the physiological mitochondrial electron donor.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Human MTRR supported B12 activation in a test-tube system; this does not establish its mitochondrial role.
primary_references
[leal-2004-human-mmab] Human ATP:Cob(I)alamin adenosyltransferase and its interaction with methionine synthase reductase. (2004). https://pubmed.ncbi.nlm.nih.gov/15347655/ DOI: 10.1074/jbc.m405449200
tissue_or_cell_type
Purified protein assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 991–1003
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human proteins · source_derived_draft · unverified_draft
### mtrr-supports-mmab-in-vitro Purified human MTRR coupled cob(II)alamin reduction to MMAB-dependent adenosylcobalamin synthesis in vitro. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Human MTRR supported B12 activation in a test-tube system; this does not establish its mitochondrial role. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human proteins limitations: MTRR coupling in vitro does not identify the physiological mitochondrial electron donor. exposure: Purified MTRR plus MMAB and reductants cross_nutrient: true evidence_location: Indexed primary abstract [leal-2004-human-mmab] Human ATP:Cob(I)alamin adenosyltransferase and its interaction with methionine synthase reductase. (2004). https://pubmed.ncbi.nlm.nih.gov/15347655/ DOI: 10.1074/jbc.m405449200
Complete structured claim and evidence
Human [2Fe-2S] ferredoxin FDX1 supplied electrons for MMAB-dependent adenosylcobalamin synthesis in the FDXR/NADPH reconstitution.
Human adrenodoxin / FDX1 → Human ATP:cob(I)alamin adenosyltransferase / MMAB source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Abstract and indexed primary Results, Figure 3
experimental_model
Purified human proteins
exposure
FDX1, FDXR and NADPH with MMAB, cob(II)alamin and ATP
limitations
Biochemically competent donor; exclusivity or necessity in living humans was not tested.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
In the purified human system, an iron-sulfur electron carrier supported B12 activation.
primary_references
[gouda-2023-mmab-redox] Coordination Chemistry Controls Coenzyme B12 Synthesis by Human Adenosine Triphosphate:Cob(I)alamin Adenosyltransferase. (2023). https://pubmed.ncbi.nlm.nih.gov/37526260/ DOI: 10.1021/acs.inorgchem.3c02163
tissue_or_cell_type
Purified protein assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1005–1017
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human proteins · source_derived_draft · unverified_draft
### fdx1-supports-mmab Human [2Fe-2S] ferredoxin FDX1 supplied electrons for MMAB-dependent adenosylcobalamin synthesis in the FDXR/NADPH reconstitution. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: In the purified human system, an iron-sulfur electron carrier supported B12 activation. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human proteins limitations: Biochemically competent donor; exclusivity or necessity in living humans was not tested. exposure: FDX1, FDXR and NADPH with MMAB, cob(II)alamin and ATP cross_nutrient: true evidence_location: Abstract and indexed primary Results, Figure 3 [gouda-2023-mmab-redox] Coordination Chemistry Controls Coenzyme B12 Synthesis by Human Adenosine Triphosphate:Cob(I)alamin Adenosyltransferase. (2023). https://pubmed.ncbi.nlm.nih.gov/37526260/ DOI: 10.1021/acs.inorgchem.3c02163
Complete structured claim and evidence
R186Q human MMAB showed no detectable adenosylcobalamin synthesis with FDX1/FDXR/NADPH, although a strong chemical reductant supported activity.
Human MMAB p.Arg186Gln → Human MMAB adenosylcobalamin synthesis source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
true
evidence_location
Abstract and indexed primary Results, Figure 3
experimental_model
Purified human MMAB R186Q
exposure
R186Q variant; FDX1/FDXR/NADPH versus titanium(III)citrate
limitations
Detection-limited in-vitro activity; not proof of zero activity in every tissue.
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 MMAB variant failed in the ferredoxin assay; the result depended on the electron donor.
primary_references
[gouda-2023-mmab-redox] Coordination Chemistry Controls Coenzyme B12 Synthesis by Human Adenosine Triphosphate:Cob(I)alamin Adenosyltransferase. (2023). https://pubmed.ncbi.nlm.nih.gov/37526260/ DOI: 10.1021/acs.inorgchem.3c02163
tissue_or_cell_type
Purified protein assay
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1019–1031
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human MMAB R186Q · source_derived_draft · unverified_draft
### mmab-r186q-fdx-system-fails R186Q human MMAB showed no detectable adenosylcobalamin synthesis with FDX1/FDXR/NADPH, although a strong chemical reductant supported activity. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This MMAB variant failed in the ferredoxin assay; the result depended on the electron donor. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human MMAB R186Q limitations: Detection-limited in-vitro activity; not proof of zero activity in every tissue. exposure: R186Q variant; FDX1/FDXR/NADPH versus titanium(III)citrate cross_nutrient: true evidence_location: Abstract and indexed primary Results, Figure 3 [gouda-2023-mmab-redox] Coordination Chemistry Controls Coenzyme B12 Synthesis by Human Adenosine Triphosphate:Cob(I)alamin Adenosyltransferase. (2023). https://pubmed.ncbi.nlm.nih.gov/37526260/ DOI: 10.1021/acs.inorgchem.3c02163
Complete structured claim and evidence
Purified human MMAA displayed intrinsic GTPase activity modulated by human MMUT.
Human MMAA GTPase → Guanosine triphosphate source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Indexed primary abstract; indexed Results
experimental_model
Purified human proteins
exposure
GTP hydrolysis assay
limitations
Biochemical reconstitution; does not determine cellular rate or dietary requirement.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Human MMAA consumed GTP in the protein assay, linking energy use to B12 handling.
primary_references
[froese-2010-human-mmaa] Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation. (2010). https://pubmed.ncbi.nlm.nih.gov/20876572/ DOI: 10.1074/jbc.m110.177717
tissue_or_cell_type
Purified protein assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1033–1045
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human proteins · source_derived_draft · unverified_draft
### mmaa-hydrolyzes-gtp Purified human MMAA displayed intrinsic GTPase activity modulated by human MMUT. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Human MMAA consumed GTP in the protein assay, linking energy use to B12 handling. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human proteins limitations: Biochemical reconstitution; does not determine cellular rate or dietary requirement. exposure: GTP hydrolysis assay cross_nutrient: false evidence_location: Indexed primary abstract; indexed Results [froese-2010-human-mmaa] Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation. (2010). https://pubmed.ncbi.nlm.nih.gov/20876572/ DOI: 10.1074/jbc.m110.177717
Complete structured claim and evidence
Human MMAA formed a stable complex preferentially with apo-MMUT and with GMPPNP rather than GDP.
Human MMAA GTPase → Human methylmalonyl-CoA mutase / MMUT source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Indexed primary abstract; indexed Results
experimental_model
Purified human proteins
exposure
Apo versus holo-MMUT; GMPPNP versus GDP
limitations
GMPPNP is a GTP analogue; stable-complex abundance is not cofactor transfer rate.
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 purified human proteins assembled differently depending on MMUT cofactor occupancy and nucleotide state.
primary_references
[froese-2010-human-mmaa] Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation. (2010). https://pubmed.ncbi.nlm.nih.gov/20876572/ DOI: 10.1074/jbc.m110.177717
tissue_or_cell_type
Purified protein assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1047–1059
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human proteins · source_derived_draft · unverified_draft
### mmaa-prefers-apo-mmut-complex Human MMAA formed a stable complex preferentially with apo-MMUT and with GMPPNP rather than GDP. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The purified human proteins assembled differently depending on MMUT cofactor occupancy and nucleotide state. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human proteins limitations: GMPPNP is a GTP analogue; stable-complex abundance is not cofactor transfer rate. exposure: Apo versus holo-MMUT; GMPPNP versus GDP cross_nutrient: false evidence_location: Indexed primary abstract; indexed Results [froese-2010-human-mmaa] Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation. (2010). https://pubmed.ncbi.nlm.nih.gov/20876572/ DOI: 10.1074/jbc.m110.177717
Complete structured claim and evidence
Human MMAA G188R retained basal GTPase activity but lost the detected MMUT interaction.
Human MMAA p.Gly188Arg → Human methylmalonyl-CoA mutase / MMUT source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Indexed primary abstract; indexed Results
experimental_model
Human MMAA G188R functional assays
exposure
G188R patient variant versus wild type
limitations
Interaction defect in experimental assays; residual tissue-specific function was not quantified.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
In the human-protein experiment, this MMAA variant still hydrolyzed GTP but failed to bind MMUT normally.
primary_references
[froese-2010-human-mmaa] Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation. (2010). https://pubmed.ncbi.nlm.nih.gov/20876572/ DOI: 10.1074/jbc.m110.177717
tissue_or_cell_type
Purified protein assay
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1061–1073
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human MMAA G188R functional assays · source_derived_draft · unverified_draft
### mmaa-g188r-loses-mmut-interaction Human MMAA G188R retained basal GTPase activity but lost the detected MMUT interaction. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: In the human-protein experiment, this MMAA variant still hydrolyzed GTP but failed to bind MMUT normally. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Human MMAA G188R functional assays limitations: Interaction defect in experimental assays; residual tissue-specific function was not quantified. exposure: G188R patient variant versus wild type cross_nutrient: false evidence_location: Indexed primary abstract; indexed Results [froese-2010-human-mmaa] Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation. (2010). https://pubmed.ncbi.nlm.nih.gov/20876572/ DOI: 10.1074/jbc.m110.177717
Complete structured claim and evidence
Adding human MMAA at reaction initiation protected recombinant human MMUT against catalytic inactivation.
Human MMAA GTPase → Human methylmalonyl-CoA mutase / MMUT source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Indexed primary abstract
experimental_model
Purified human proteins
exposure
MMAA added at reaction initiation
limitations
Biochemical reconstitution; does not determine cellular rate or dietary requirement.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
MMAA helped purified human MMUT remain active during the tested reaction.
primary_references
[takahashi-2010-mmaa-repair] Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein. (2011). https://pubmed.ncbi.nlm.nih.gov/21138732/ DOI: 10.1016/j.bbrc.2010.11.141
tissue_or_cell_type
Purified protein assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1075–1087
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human proteins · source_derived_draft · unverified_draft
### mmaa-protects-mmut-activity Adding human MMAA at reaction initiation protected recombinant human MMUT against catalytic inactivation. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: MMAA helped purified human MMUT remain active during the tested reaction. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human proteins limitations: Biochemical reconstitution; does not determine cellular rate or dietary requirement. exposure: MMAA added at reaction initiation cross_nutrient: false evidence_location: Indexed primary abstract [takahashi-2010-mmaa-repair] Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein. (2011). https://pubmed.ncbi.nlm.nih.gov/21138732/ DOI: 10.1016/j.bbrc.2010.11.141
Complete structured claim and evidence
Adding MMAA after 60 minutes restored activity in an inactivated human MMUT reaction through GTP hydrolysis.
Human MMAA GTPase → Human methylmalonyl-CoA mutase / MMUT source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Indexed primary abstract
experimental_model
Purified human proteins
exposure
MMAA added after 60-minute catalytic inactivation
limitations
In-vitro reactivation; abstract interprets damaged-cofactor exchange rather than measuring every intermediate.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
MMAA restarted an inactive purified human MMUT reaction in a GTP-dependent assay.
primary_references
[takahashi-2010-mmaa-repair] Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein. (2011). https://pubmed.ncbi.nlm.nih.gov/21138732/ DOI: 10.1016/j.bbrc.2010.11.141
tissue_or_cell_type
Purified protein assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1089–1101
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human proteins · source_derived_draft · unverified_draft
### mmaa-reactivates-mmut Adding MMAA after 60 minutes restored activity in an inactivated human MMUT reaction through GTP hydrolysis. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: MMAA restarted an inactive purified human MMUT reaction in a GTP-dependent assay. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human proteins limitations: In-vitro reactivation; abstract interprets damaged-cofactor exchange rather than measuring every intermediate. exposure: MMAA added after 60-minute catalytic inactivation cross_nutrient: false evidence_location: Indexed primary abstract [takahashi-2010-mmaa-repair] Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein. (2011). https://pubmed.ncbi.nlm.nih.gov/21138732/ DOI: 10.1016/j.bbrc.2010.11.141
Complete structured claim and evidence
Adenosylcobalamin-loaded human MMUT converts (R)-methylmalonyl-CoA to succinyl-CoA in the coupled enzyme assay.
Human methylmalonyl-CoA mutase / MMUT → (R)-Methylmalonyl-CoA source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Full text Results; Figures 2-4; cofactor off-loading and MMUT activity Methods
experimental_model
Purified human proteins
exposure
AdoCbl-loaded MMUT and methylmalonyl-CoA; thiokinase-coupled readout
limitations
Product formation is a coupled assay; cellular net flux was not measured.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Purified human MMUT used activated B12 to make succinyl-CoA from the matching methylmalonyl-CoA epimer.
primary_references
[mascarenhas-2023-nanoassembly] Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B12 delivery and repair. (2023). https://pubmed.ncbi.nlm.nih.gov/37468522/ DOI: 10.1038/s41467-023-40077-4
tissue_or_cell_type
Purified protein assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1103–1115
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human proteins · source_derived_draft · unverified_draft
### mmut-isomerizes-r-methylmalonyl-coa Adenosylcobalamin-loaded human MMUT converts (R)-methylmalonyl-CoA to succinyl-CoA in the coupled enzyme assay. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Purified human MMUT used activated B12 to make succinyl-CoA from the matching methylmalonyl-CoA epimer. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human proteins limitations: Product formation is a coupled assay; cellular net flux was not measured. exposure: AdoCbl-loaded MMUT and methylmalonyl-CoA; thiokinase-coupled readout cross_nutrient: false evidence_location: Full text Results; Figures 2-4; cofactor off-loading and MMUT activity Methods [mascarenhas-2023-nanoassembly] Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B12 delivery and repair. (2023). https://pubmed.ncbi.nlm.nih.gov/37468522/ DOI: 10.1038/s41467-023-40077-4
Complete structured claim and evidence
The human MMUT-MMAA structure showed MMAA stabilizing a roughly 180-degree rotation that exposed the MMUT B12-binding domain.
Human MMAA GTPase → Exposure of the human MMUT cobalamin-binding domain source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Full text Results; Figures 2-4; cofactor off-loading and MMUT activity Methods
experimental_model
Purified human proteins
exposure
Crystallized complex with CoA, GDP and Mg2+
limitations
Static structure; does not directly measure the complete loading trajectory.
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 human-protein structure showed how MMAA opens access to MMUT-bound B12.
primary_references
[mascarenhas-2023-nanoassembly] Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B12 delivery and repair. (2023). https://pubmed.ncbi.nlm.nih.gov/37468522/ DOI: 10.1038/s41467-023-40077-4
tissue_or_cell_type
Purified protein assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1117–1129
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human proteins · source_derived_draft · unverified_draft
### mmaa-exposes-mmut-cobalamin-domain The human MMUT-MMAA structure showed MMAA stabilizing a roughly 180-degree rotation that exposed the MMUT B12-binding domain. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The human-protein structure showed how MMAA opens access to MMUT-bound B12. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human proteins limitations: Static structure; does not directly measure the complete loading trajectory. exposure: Crystallized complex with CoA, GDP and Mg2+ cross_nutrient: false evidence_location: Full text Results; Figures 2-4; cofactor off-loading and MMUT activity Methods [mascarenhas-2023-nanoassembly] Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B12 delivery and repair. (2023). https://pubmed.ncbi.nlm.nih.gov/37468522/ DOI: 10.1038/s41467-023-40077-4
Complete structured claim and evidence
A human MMAA/MMAB repair mixture with GTP and ATP transferred cob(II)alamin from MMUT to MMAB in anaerobic spectroscopy.
Human MMAA GTPase → Cob(II)alamin off-loading from human MMUT source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Full text Results; Figures 2-4; cofactor off-loading and MMUT activity Methods
experimental_model
Purified human proteins
exposure
Anaerobic assay; MMAB, MMAA, GTP and ATP
limitations
Reconstituted transfer; spectroscopy reports cofactor environment, not cellular turnover.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
In the purified repair assay, inactive B12 moved from MMUT back to MMAB.
primary_references
[mascarenhas-2023-nanoassembly] Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B12 delivery and repair. (2023). https://pubmed.ncbi.nlm.nih.gov/37468522/ DOI: 10.1038/s41467-023-40077-4
tissue_or_cell_type
Purified protein assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1131–1143
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human proteins · source_derived_draft · unverified_draft
### mmaa-mmab-offload-cob-ii A human MMAA/MMAB repair mixture with GTP and ATP transferred cob(II)alamin from MMUT to MMAB in anaerobic spectroscopy. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: In the purified repair assay, inactive B12 moved from MMUT back to MMAB. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human proteins limitations: Reconstituted transfer; spectroscopy reports cofactor environment, not cellular turnover. exposure: Anaerobic assay; MMAB, MMAA, GTP and ATP cross_nutrient: false evidence_location: Full text Results; Figures 2-4; cofactor off-loading and MMUT activity Methods [mascarenhas-2023-nanoassembly] Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B12 delivery and repair. (2023). https://pubmed.ncbi.nlm.nih.gov/37468522/ DOI: 10.1038/s41467-023-40077-4
Complete structured claim and evidence
PCC partially purified from control human fibroblasts contained biotin.
Human propionyl-CoA carboxylase / PCC → Biotin source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Indexed primary abstract
experimental_model
Partially purified human fibroblast PCC
exposure
Control fibroblast enzyme fraction
limitations
Biotin content in an enzyme preparation; does not establish whole-body biotin thresholds.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Human fibroblast PCC carried biotin, a different vitamin required upstream of the B12-dependent step.
primary_references
[hsia-1979-pcc] Human propionyl CoA carboxylase: some properties of the partially purified enzyme in fibroblasts from controls and patients with propionic acidemia. (1979). https://pubmed.ncbi.nlm.nih.gov/481943/ DOI: 10.1203/00006450-197906000-00005
tissue_or_cell_type
Fibroblasts
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1145–1157
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Partially purified human fibroblast PCC · source_derived_draft · unverified_draft
### human-pcc-biotin PCC partially purified from control human fibroblasts contained biotin. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Human fibroblast PCC carried biotin, a different vitamin required upstream of the B12-dependent step. organism: Homo sapiens tissue_or_cell_type: Fibroblasts experimental_model: Partially purified human fibroblast PCC limitations: Biotin content in an enzyme preparation; does not establish whole-body biotin thresholds. exposure: Control fibroblast enzyme fraction cross_nutrient: true evidence_location: Indexed primary abstract [hsia-1979-pcc] Human propionyl CoA carboxylase: some properties of the partially purified enzyme in fibroblasts from controls and patients with propionic acidemia. (1979). https://pubmed.ncbi.nlm.nih.gov/481943/ DOI: 10.1203/00006450-197906000-00005
Complete structured claim and evidence
Human PCC supplies (S)-methylmalonyl-CoA by propionyl-CoA carboxylation upstream of the MCEE-MMUT sequence examined in fibroblast assays.
Human propionyl-CoA carboxylase / PCC → Propionyl-CoA source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Indexed primary abstract; Full text Methods 2.6 and Results 3.6; Figure 5
experimental_model
Human fibroblast PCC and coupled-pathway assays
exposure
Propionyl-CoA, ATP and bicarbonate in enzyme pathway
limitations
Pathway assignment combines human PCC characterization with coupled assays; it is not a simultaneous dietary biotin/B12 intervention.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Biotin-dependent PCC makes the precursor that must be rearranged before human MMUT can use B12 on it.
primary_references
[hsia-1979-pcc] Human propionyl CoA carboxylase: some properties of the partially purified enzyme in fibroblasts from controls and patients with propionic acidemia. (1979). https://pubmed.ncbi.nlm.nih.gov/481943/ DOI: 10.1203/00006450-197906000-00005 [heuberger-2019-mcee] Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency. (2019). https://pubmed.ncbi.nlm.nih.gov/30682498/ DOI: 10.1016/j.bbadis.2019.01.021
tissue_or_cell_type
Fibroblasts
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1159–1172
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human fibroblast PCC and coupled-pathway assays · source_derived_draft · unverified_draft
### pcc-carboxylation-upstream-b12 Human PCC supplies (S)-methylmalonyl-CoA by propionyl-CoA carboxylation upstream of the MCEE-MMUT sequence examined in fibroblast assays. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Biotin-dependent PCC makes the precursor that must be rearranged before human MMUT can use B12 on it. organism: Homo sapiens tissue_or_cell_type: Fibroblasts experimental_model: Human fibroblast PCC and coupled-pathway assays limitations: Pathway assignment combines human PCC characterization with coupled assays; it is not a simultaneous dietary biotin/B12 intervention. exposure: Propionyl-CoA, ATP and bicarbonate in enzyme pathway cross_nutrient: true evidence_location: Indexed primary abstract; Full text Methods 2.6 and Results 3.6; Figure 5 [hsia-1979-pcc] Human propionyl CoA carboxylase: some properties of the partially purified enzyme in fibroblasts from controls and patients with propionic acidemia. (1979). https://pubmed.ncbi.nlm.nih.gov/481943/ DOI: 10.1203/00006450-197906000-00005 [heuberger-2019-mcee] Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency. (2019). https://pubmed.ncbi.nlm.nih.gov/30682498/ DOI: 10.1016/j.bbadis.2019.01.021
Complete structured claim and evidence
Human MCEE interconverts methylmalonyl-CoA epimers, supplying the (R) form for MMUT; MCEE expression increased coupled succinate production.
Human methylmalonyl-CoA epimerase / MCEE → (S)-Methylmalonyl-CoA source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Full text Methods 2.6 and Results 3.6; Figure 5
experimental_model
Human fibroblast lysates overexpressing MCEE and/or MMUT
exposure
Radiolabeled propionyl-CoA; MCEE/MMUT expression and AdoCbl
limitations
Coupled labeled hydrolysis-product assay; MCEE being limiting here is not a universal in-vivo rate limitation.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Human fibroblast assays showed why the epimerase step matters before the B12 enzyme.
primary_references
[heuberger-2019-mcee] Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency. (2019). https://pubmed.ncbi.nlm.nih.gov/30682498/ DOI: 10.1016/j.bbadis.2019.01.021
tissue_or_cell_type
Fibroblasts
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1174–1186
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human fibroblast lysates overexpressing MCEE and/or MMUT · source_derived_draft · unverified_draft
### mcee-epimerizes-methylmalonyl-coa Human MCEE interconverts methylmalonyl-CoA epimers, supplying the (R) form for MMUT; MCEE expression increased coupled succinate production. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Human fibroblast assays showed why the epimerase step matters before the B12 enzyme. organism: Homo sapiens tissue_or_cell_type: Fibroblasts experimental_model: Human fibroblast lysates overexpressing MCEE and/or MMUT limitations: Coupled labeled hydrolysis-product assay; MCEE being limiting here is not a universal in-vivo rate limitation. exposure: Radiolabeled propionyl-CoA; MCEE/MMUT expression and AdoCbl cross_nutrient: false evidence_location: Full text Methods 2.6 and Results 3.6; Figure 5 [heuberger-2019-mcee] Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency. (2019). https://pubmed.ncbi.nlm.nih.gov/30682498/ DOI: 10.1016/j.bbadis.2019.01.021
Complete structured claim and evidence
Human MCEE I53R lacked measured activity in the coupled patient-fibroblast assay with overexpressed MMUT and added adenosylcobalamin.
Human MCEE p.Ile53Arg → Human MCEE-dependent coupled propionyl-CoA pathway activity source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Full text Methods 2.6 and Results 3.6; Figure 5
experimental_model
MCEE-null human fibroblasts expressing MCEE I53R
exposure
I53R expression; MMUT coexpression; 50 micromolar AdoCbl
limitations
Overexpression assay; not a clinical test of B12 treatment.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Adding activated B12 did not make this defective epimerase work in the human-cell assay.
primary_references
[heuberger-2019-mcee] Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency. (2019). https://pubmed.ncbi.nlm.nih.gov/30682498/ DOI: 10.1016/j.bbadis.2019.01.021
tissue_or_cell_type
Fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1188–1200
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · MCEE-null human fibroblasts expressing MCEE I53R · source_derived_draft · unverified_draft
### mcee-i53r-reduces-coupled-activity Human MCEE I53R lacked measured activity in the coupled patient-fibroblast assay with overexpressed MMUT and added adenosylcobalamin. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding activated B12 did not make this defective epimerase work in the human-cell assay. organism: Homo sapiens tissue_or_cell_type: Fibroblasts experimental_model: MCEE-null human fibroblasts expressing MCEE I53R limitations: Overexpression assay; not a clinical test of B12 treatment. exposure: I53R expression; MMUT coexpression; 50 micromolar AdoCbl cross_nutrient: false evidence_location: Full text Methods 2.6 and Results 3.6; Figure 5 [heuberger-2019-mcee] Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency. (2019). https://pubmed.ncbi.nlm.nih.gov/30682498/ DOI: 10.1016/j.bbadis.2019.01.021
Complete structured claim and evidence
In seven adults, 28-day egg-white-induced biotin depletion reduced mean lymphocyte PCC activity to 23% of baseline.
Biotin → Human lymphocyte propionyl-CoA carboxylase activity source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
cross_nutrient
true
evidence_location
Primary abstract and indexed Results: PCC activity
experimental_model
Seven healthy adults
exposure
28-day egg-white-rich biotin-depletion diet
limitations
Lymphocyte enzyme activity; no concurrent B12 intervention or systemic pathway 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
In this small depletion study, low biotin weakened a human enzyme upstream of B12-dependent metabolism.
primary_references
[stratton-2006-biotin] Lymphocyte propionyl-CoA carboxylase and its activation by biotin are sensitive indicators of marginal biotin deficiency in humans. (2006). https://pubmed.ncbi.nlm.nih.gov/16895887/ DOI: 10.1093/ajcn/84.1.384
tissue_or_cell_type
Peripheral blood lymphocytes
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1202–1214
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Seven healthy adults · source_derived_draft · unverified_draft
### biotin-depletion-lowers-pcc In seven adults, 28-day egg-white-induced biotin depletion reduced mean lymphocyte PCC activity to 23% of baseline. Condition category: nutrient_deficiency nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: In this small depletion study, low biotin weakened a human enzyme upstream of B12-dependent metabolism. organism: Homo sapiens tissue_or_cell_type: Peripheral blood lymphocytes experimental_model: Seven healthy adults limitations: Lymphocyte enzyme activity; no concurrent B12 intervention or systemic pathway flux measurement. exposure: 28-day egg-white-rich biotin-depletion diet cross_nutrient: true evidence_location: Primary abstract and indexed Results: PCC activity [stratton-2006-biotin] Lymphocyte propionyl-CoA carboxylase and its activation by biotin are sensitive indicators of marginal biotin deficiency in humans. (2006). https://pubmed.ncbi.nlm.nih.gov/16895887/ DOI: 10.1093/ajcn/84.1.384
Complete structured claim and evidence
Carbon-13 valine supplied the lipogenic propionyl-CoA precursor in cultured 3T3-L1 adipocytes.
L-Valine → Propionyl-CoA source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Full text Results; Figures 6-8 and isotope model
experimental_model
Differentiated mouse 3T3-L1 adipocytes
exposure
24-hour [U-13C]valine tracing
limitations
Mouse cell culture; isotope labeling and model assumptions do not establish human dietary carbon fractions.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Mus musculus
plain_language
Mouse fat-cell tracing placed valine carbon into the precursor that can enter B12-dependent metabolism or odd-chain fat synthesis.
primary_references
[crown-2015-bcaa-fatty-acids] Catabolism of Branched Chain Amino Acids Contributes Significantly to Synthesis of Odd-Chain and Even-Chain Fatty Acids in 3T3-L1 Adipocytes. (2015). https://pubmed.ncbi.nlm.nih.gov/26710334/ DOI: 10.1371/journal.pone.0145850
tissue_or_cell_type
Adipocytes
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1216–1228
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Differentiated mouse 3T3-L1 adipocytes · source_derived_draft · unverified_draft
### valine-propionyl-coa-lipogenesis Carbon-13 valine supplied the lipogenic propionyl-CoA precursor in cultured 3T3-L1 adipocytes. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Mouse fat-cell tracing placed valine carbon into the precursor that can enter B12-dependent metabolism or odd-chain fat synthesis. organism: Mus musculus tissue_or_cell_type: Adipocytes experimental_model: Differentiated mouse 3T3-L1 adipocytes limitations: Mouse cell culture; isotope labeling and model assumptions do not establish human dietary carbon fractions. exposure: 24-hour [U-13C]valine tracing cross_nutrient: true evidence_location: Full text Results; Figures 6-8 and isotope model [crown-2015-bcaa-fatty-acids] Catabolism of Branched Chain Amino Acids Contributes Significantly to Synthesis of Odd-Chain and Even-Chain Fatty Acids in 3T3-L1 Adipocytes. (2015). https://pubmed.ncbi.nlm.nih.gov/26710334/ DOI: 10.1371/journal.pone.0145850
Complete structured claim and evidence
Carbon-13 isoleucine supplied lipogenic propionyl-CoA in cultured 3T3-L1 adipocytes.
L-Isoleucine → Propionyl-CoA source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
true
evidence_location
Full text Results; Figures 6-8 and isotope model
experimental_model
Differentiated mouse 3T3-L1 adipocytes
exposure
24-hour [U-13C]isoleucine tracing
limitations
Mouse cell culture; isotope labeling and model assumptions do not establish human dietary carbon fractions.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Mus musculus
plain_language
Mouse fat-cell tracing identified isoleucine as another source of the B12-pathway precursor.
primary_references
[crown-2015-bcaa-fatty-acids] Catabolism of Branched Chain Amino Acids Contributes Significantly to Synthesis of Odd-Chain and Even-Chain Fatty Acids in 3T3-L1 Adipocytes. (2015). https://pubmed.ncbi.nlm.nih.gov/26710334/ DOI: 10.1371/journal.pone.0145850
tissue_or_cell_type
Adipocytes
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1230–1242
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Differentiated mouse 3T3-L1 adipocytes · source_derived_draft · unverified_draft
### isoleucine-propionyl-coa-lipogenesis Carbon-13 isoleucine supplied lipogenic propionyl-CoA in cultured 3T3-L1 adipocytes. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Mouse fat-cell tracing identified isoleucine as another source of the B12-pathway precursor. organism: Mus musculus tissue_or_cell_type: Adipocytes experimental_model: Differentiated mouse 3T3-L1 adipocytes limitations: Mouse cell culture; isotope labeling and model assumptions do not establish human dietary carbon fractions. exposure: 24-hour [U-13C]isoleucine tracing cross_nutrient: true evidence_location: Full text Results; Figures 6-8 and isotope model [crown-2015-bcaa-fatty-acids] Catabolism of Branched Chain Amino Acids Contributes Significantly to Synthesis of Odd-Chain and Even-Chain Fatty Acids in 3T3-L1 Adipocytes. (2015). https://pubmed.ncbi.nlm.nih.gov/26710334/ DOI: 10.1371/journal.pone.0145850
Complete structured claim and evidence
Fatty-acid fragment labeling identified propionyl-CoA as the primer for odd-chain fatty-acid synthesis in 3T3-L1 adipocytes.
Propionyl-CoA → Odd-chain fatty acid synthesis source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Full text Results; Figures 6-8 and isotope model
experimental_model
Differentiated mouse 3T3-L1 adipocytes
exposure
Parallel carbon-13 tracer and GC-MS fragment analysis
limitations
Mouse cell culture; isotope labeling and model assumptions do not establish human dietary carbon fractions.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Mus musculus
plain_language
These mouse fat cells could divert the B12-pathway precursor into odd-chain fats.
primary_references
[crown-2015-bcaa-fatty-acids] Catabolism of Branched Chain Amino Acids Contributes Significantly to Synthesis of Odd-Chain and Even-Chain Fatty Acids in 3T3-L1 Adipocytes. (2015). https://pubmed.ncbi.nlm.nih.gov/26710334/ DOI: 10.1371/journal.pone.0145850
tissue_or_cell_type
Adipocytes
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1244–1256
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Differentiated mouse 3T3-L1 adipocytes · source_derived_draft · unverified_draft
### propionyl-primes-odd-chain-fatty-acids Fatty-acid fragment labeling identified propionyl-CoA as the primer for odd-chain fatty-acid synthesis in 3T3-L1 adipocytes. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: These mouse fat cells could divert the B12-pathway precursor into odd-chain fats. organism: Mus musculus tissue_or_cell_type: Adipocytes experimental_model: Differentiated mouse 3T3-L1 adipocytes limitations: Mouse cell culture; isotope labeling and model assumptions do not establish human dietary carbon fractions. exposure: Parallel carbon-13 tracer and GC-MS fragment analysis cross_nutrient: false evidence_location: Full text Results; Figures 6-8 and isotope model [crown-2015-bcaa-fatty-acids] Catabolism of Branched Chain Amino Acids Contributes Significantly to Synthesis of Odd-Chain and Even-Chain Fatty Acids in 3T3-L1 Adipocytes. (2015). https://pubmed.ncbi.nlm.nih.gov/26710334/ DOI: 10.1371/journal.pone.0145850
Complete structured claim and evidence
Adding 2.5 micromolar B12 during ECHDC1-knockout L929 adipocyte differentiation lowered whole-cell methylmalonyl-CoA approximately 20-fold.
Vitamin B12 (cobalamins) → Whole-cell methylmalonyl-CoA pool source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
B12 supplementation lowered the measured propionyl-CoA pool approximately fourfold in differentiating ECHDC1-knockout L929 adipocytes.
Vitamin B12 (cobalamins) → Propionyl-CoA source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Despite lower acyl-CoA pools, B12 supplementation barely changed measured methyl-branched fatty acids in ECHDC1-knockout L929 adipocytes.
Vitamin B12 (cobalamins) → Methyl-branched fatty acid abundance source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
MMUT knockout reduced propionate-derived protein labeling about sixfold in HFF1 human fibroblasts.
MMUT gene (Homo sapiens) → Propionate-derived carbon incorporation into cellular protein source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Full text Results; Figure 2C,E
experimental_model
HFF1 human fibroblasts with two CRISPR guides
exposure
MMUT CRISPR knockout versus OR7G3 guide control; [14C]propionate
limitations
Protein labeling integrates metabolism and protein synthesis; not direct MMUT 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
These human fibroblasts relied strongly on MMUT for the measured use of propionate carbon.
primary_references
[2024-propionate-cell-dependence] Differential utilization of vitamin B12-dependent and independent pathways for propionate metabolism across human cells. (2024). https://pubmed.ncbi.nlm.nih.gov/39128713/ DOI: 10.1016/j.jbc.2024.107662
tissue_or_cell_type
Foreskin fibroblasts
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1300–1312
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HFF1 human fibroblasts with two CRISPR guides · source_derived_draft · unverified_draft
### hff1-mmut-ko-lowers-propionate-label MMUT knockout reduced propionate-derived protein labeling about sixfold in HFF1 human fibroblasts. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: These human fibroblasts relied strongly on MMUT for the measured use of propionate carbon. organism: Homo sapiens tissue_or_cell_type: Foreskin fibroblasts experimental_model: HFF1 human fibroblasts with two CRISPR guides limitations: Protein labeling integrates metabolism and protein synthesis; not direct MMUT flux. exposure: MMUT CRISPR knockout versus OR7G3 guide control; [14C]propionate cross_nutrient: false evidence_location: Full text Results; Figure 2C,E [2024-propionate-cell-dependence] Differential utilization of vitamin B12-dependent and independent pathways for propionate metabolism across human cells. (2024). https://pubmed.ncbi.nlm.nih.gov/39128713/ DOI: 10.1016/j.jbc.2024.107662
Complete structured claim and evidence
MMUT knockout did not reduce propionate-derived protein labeling in HT-29 colorectal cancer cells.
MMUT gene (Homo sapiens) → Propionate-derived carbon incorporation into cellular protein source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Full text Results; Figure 2C,E
experimental_model
HT-29 human colorectal adenocarcinoma cells
exposure
MMUT CRISPR knockout versus OR7G3 guide control; [14C]propionate
limitations
Transformed cell line; does not establish pathway proportions in normal human colon.
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 human cancer cell line retained propionate use without MMUT, unlike the tested fibroblasts.
primary_references
[2024-propionate-cell-dependence] Differential utilization of vitamin B12-dependent and independent pathways for propionate metabolism across human cells. (2024). https://pubmed.ncbi.nlm.nih.gov/39128713/ DOI: 10.1016/j.jbc.2024.107662
tissue_or_cell_type
Colorectal adenocarcinoma cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1314–1326
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HT-29 human colorectal adenocarcinoma cells · source_derived_draft · unverified_draft
### ht29-mmut-ko-preserves-propionate-label MMUT knockout did not reduce propionate-derived protein labeling in HT-29 colorectal cancer cells. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This human cancer cell line retained propionate use without MMUT, unlike the tested fibroblasts. organism: Homo sapiens tissue_or_cell_type: Colorectal adenocarcinoma cells experimental_model: HT-29 human colorectal adenocarcinoma cells limitations: Transformed cell line; does not establish pathway proportions in normal human colon. exposure: MMUT CRISPR knockout versus OR7G3 guide control; [14C]propionate cross_nutrient: false evidence_location: Full text Results; Figure 2C,E [2024-propionate-cell-dependence] Differential utilization of vitamin B12-dependent and independent pathways for propionate metabolism across human cells. (2024). https://pubmed.ncbi.nlm.nih.gov/39128713/ DOI: 10.1016/j.jbc.2024.107662
Complete structured claim and evidence
Human mut0 MMA kidney tubular cells had lower basal oxygen consumption than control cells.
MMUT gene (Homo sapiens) → Basal mitochondrial oxygen consumption source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Full text Results; Figures 2f,5c-f,6c-d
experimental_model
Urine-derived human mut0 MMA kidney tubular cells
exposure
Patient MMUT-inactivating genotypes versus controls
limitations
Inherited MMUT machinery defect; cannot be generalized to nutritional B12 deficiency or neurons.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Kidney cells from these patients with MMUT defects consumed less oxygen in the basal assay.
primary_references
[luciani-2020-mmut-mitophagy] Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency. (2020). https://pubmed.ncbi.nlm.nih.gov/32080200/ DOI: 10.1038/s41467-020-14729-8
tissue_or_cell_type
Kidney tubular cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1328–1340
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Urine-derived human mut0 MMA kidney tubular cells · source_derived_draft · unverified_draft
### mut0-kidney-reduced-respiration Human mut0 MMA kidney tubular cells had lower basal oxygen consumption than control cells. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Kidney cells from these patients with MMUT defects consumed less oxygen in the basal assay. organism: Homo sapiens tissue_or_cell_type: Kidney tubular cells experimental_model: Urine-derived human mut0 MMA kidney tubular cells limitations: Inherited MMUT machinery defect; cannot be generalized to nutritional B12 deficiency or neurons. exposure: Patient MMUT-inactivating genotypes versus controls cross_nutrient: false evidence_location: Full text Results; Figures 2f,5c-f,6c-d [luciani-2020-mmut-mitophagy] Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency. (2020). https://pubmed.ncbi.nlm.nih.gov/32080200/ DOI: 10.1038/s41467-020-14729-8
Complete structured claim and evidence
MMUT-deficient human kidney cells failed to show the control mt-Keima lysosomal shift after 24 hours of 5 micromolar rotenone.
MMUT gene (Homo sapiens) → Mitochondrial delivery to lysosomes source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Full text Results; Figures 2f,5c-f,6c-d
experimental_model
Urine-derived human mut0 MMA kidney tubular cells
exposure
MMUT-inactivating genotypes plus 5 micromolar rotenone for 24 hours
limitations
Inherited MMUT machinery defect; cannot be generalized to nutritional B12 deficiency or neurons. mt-Keima is a delivery reporter.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
After experimental mitochondrial damage, these patient kidney cells delivered fewer mitochondria to lysosomes.
primary_references
[luciani-2020-mmut-mitophagy] Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency. (2020). https://pubmed.ncbi.nlm.nih.gov/32080200/ DOI: 10.1038/s41467-020-14729-8
tissue_or_cell_type
Kidney tubular cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1342–1354
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Urine-derived human mut0 MMA kidney tubular cells · source_derived_draft · unverified_draft
### mut0-kidney-impaired-mito-delivery MMUT-deficient human kidney cells failed to show the control mt-Keima lysosomal shift after 24 hours of 5 micromolar rotenone. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: After experimental mitochondrial damage, these patient kidney cells delivered fewer mitochondria to lysosomes. organism: Homo sapiens tissue_or_cell_type: Kidney tubular cells experimental_model: Urine-derived human mut0 MMA kidney tubular cells limitations: Inherited MMUT machinery defect; cannot be generalized to nutritional B12 deficiency or neurons. mt-Keima is a delivery reporter. exposure: MMUT-inactivating genotypes plus 5 micromolar rotenone for 24 hours cross_nutrient: false evidence_location: Full text Results; Figures 2f,5c-f,6c-d [luciani-2020-mmut-mitophagy] Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency. (2020). https://pubmed.ncbi.nlm.nih.gov/32080200/ DOI: 10.1038/s41467-020-14729-8
Complete structured claim and evidence
MMUT-deficient human kidney cells showed reduced Parkin recruitment after 5 micromolar rotenone for four hours.
MMUT gene (Homo sapiens) → Parkin recruitment to mitochondria source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Full text Results; Figures 2f,5c-f,6c-d
experimental_model
Urine-derived human mut0 MMA kidney tubular cells
exposure
MMUT-inactivating genotypes plus 5 micromolar rotenone for four hours
limitations
Inherited MMUT machinery defect; cannot be generalized to nutritional B12 deficiency or neurons. Endogenous PINK1 was not directly quantified.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
In this damage assay, patient kidney cells marked fewer mitochondria with Parkin.
primary_references
[luciani-2020-mmut-mitophagy] Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency. (2020). https://pubmed.ncbi.nlm.nih.gov/32080200/ DOI: 10.1038/s41467-020-14729-8
tissue_or_cell_type
Kidney tubular cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1356–1368
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Urine-derived human mut0 MMA kidney tubular cells · source_derived_draft · unverified_draft
### mut0-kidney-parkin-recruitment MMUT-deficient human kidney cells showed reduced Parkin recruitment after 5 micromolar rotenone for four hours. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: In this damage assay, patient kidney cells marked fewer mitochondria with Parkin. organism: Homo sapiens tissue_or_cell_type: Kidney tubular cells experimental_model: Urine-derived human mut0 MMA kidney tubular cells limitations: Inherited MMUT machinery defect; cannot be generalized to nutritional B12 deficiency or neurons. Endogenous PINK1 was not directly quantified. exposure: MMUT-inactivating genotypes plus 5 micromolar rotenone for four hours cross_nutrient: false evidence_location: Full text Results; Figures 2f,5c-f,6c-d [luciani-2020-mmut-mitophagy] Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency. (2020). https://pubmed.ncbi.nlm.nih.gov/32080200/ DOI: 10.1038/s41467-020-14729-8
Complete structured claim and evidence
Adenoviral human PINK1 expression restored Parkin recruitment in MMUT-deficient human kidney tubular cells.
Human PINK1 kinase → Parkin recruitment to mitochondria source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
cross_nutrient
false
evidence_location
Full text Results; Figures 2f,5c-f,6c-d
experimental_model
Urine-derived human mut0 MMA kidney tubular cells
exposure
HA-PINK1 adenovirus versus empty-vector control
limitations
Inherited MMUT machinery defect; cannot be generalized to nutritional B12 deficiency or neurons. Gene-delivery rescue is not an established clinical therapy.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Adding PINK1 restored mitochondrial marking in this patient-cell model.
primary_references
[luciani-2020-mmut-mitophagy] Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency. (2020). https://pubmed.ncbi.nlm.nih.gov/32080200/ DOI: 10.1038/s41467-020-14729-8
tissue_or_cell_type
Kidney tubular cells
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1370–1382
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Urine-derived human mut0 MMA kidney tubular cells · source_derived_draft · unverified_draft
### pink1-restores-parkin-mmut-kidney Adenoviral human PINK1 expression restored Parkin recruitment in MMUT-deficient human kidney tubular cells. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding PINK1 restored mitochondrial marking in this patient-cell model. organism: Homo sapiens tissue_or_cell_type: Kidney tubular cells experimental_model: Urine-derived human mut0 MMA kidney tubular cells limitations: Inherited MMUT machinery defect; cannot be generalized to nutritional B12 deficiency or neurons. Gene-delivery rescue is not an established clinical therapy. exposure: HA-PINK1 adenovirus versus empty-vector control cross_nutrient: false evidence_location: Full text Results; Figures 2f,5c-f,6c-d [luciani-2020-mmut-mitophagy] Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency. (2020). https://pubmed.ncbi.nlm.nih.gov/32080200/ DOI: 10.1038/s41467-020-14729-8
Complete structured claim and evidence
Itaconyl-CoA inactivated purified human MMUT by forming a stable adduct with the B12-derived deoxyadenosyl moiety.
Itaconyl-CoA → Human methylmalonyl-CoA mutase / MMUT source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Primary abstract; indexed Results and Figure 3E
experimental_model
Purified human MMUT; inhibitor-product spectroscopy and analysis
exposure
Itaconyl-CoA exposure in the purified-enzyme assay
limitations
Mechanism-based inhibitor is distinct from physiological methylmalonyl-CoA; no human dietary effect inferred.
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 itaconyl-CoA experiment trapped B12 radical chemistry and stopped the purified human enzyme.
primary_references
[ruetz-2019-itaconyl-radical] Itaconyl-CoA forms a stable biradical in methylmalonyl-CoA mutase and derails its activity and repair. (2019). https://pubmed.ncbi.nlm.nih.gov/31672889/ DOI: 10.1126/science.aay0934
tissue_or_cell_type
Purified protein assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1384–1396
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human MMUT; inhibitor-product spectroscopy and analysis · source_derived_draft · unverified_draft
### itaconyl-coa-inactivates-human-mmut Itaconyl-CoA inactivated purified human MMUT by forming a stable adduct with the B12-derived deoxyadenosyl moiety. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The itaconyl-CoA experiment trapped B12 radical chemistry and stopped the purified human enzyme. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human MMUT; inhibitor-product spectroscopy and analysis limitations: Mechanism-based inhibitor is distinct from physiological methylmalonyl-CoA; no human dietary effect inferred. exposure: Itaconyl-CoA exposure in the purified-enzyme assay cross_nutrient: false evidence_location: Primary abstract; indexed Results and Figure 3E [ruetz-2019-itaconyl-radical] Itaconyl-CoA forms a stable biradical in methylmalonyl-CoA mutase and derails its activity and repair. (2019). https://pubmed.ncbi.nlm.nih.gov/31672889/ DOI: 10.1126/science.aay0934
Complete structured claim and evidence
ADP binding protected cob(II)alamin on human MMUT from air oxidation by stabilizing a solvent-shielded conformation.
Adenosine diphosphate → Overoxidation of human MMUT-bound cob(II)alamin source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Full text Results; Figures 2-3, Table 3
experimental_model
Purified human proteins
exposure
ADP added to MMUT-bound cob(II)alamin under air
limitations
Structural/biochemical protection does not establish regulation by cellular energy charge.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
ADP helped preserve an inactive B12 cofactor for repair in the human-protein assay.
primary_references
[gouda-2023-adp-repair] Bivalent molecular mimicry by ADP protects metal redox state and promotes coenzyme B12 repair. (2023). https://pubmed.ncbi.nlm.nih.gov/36888659/ DOI: 10.1073/pnas.2220677120
tissue_or_cell_type
Purified protein assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1398–1410
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human proteins · source_derived_draft · unverified_draft
### adp-protects-mmut-cofactor-redox ADP binding protected cob(II)alamin on human MMUT from air oxidation by stabilizing a solvent-shielded conformation. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: ADP helped preserve an inactive B12 cofactor for repair in the human-protein assay. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human proteins limitations: Structural/biochemical protection does not establish regulation by cellular energy charge. exposure: ADP added to MMUT-bound cob(II)alamin under air cross_nutrient: false evidence_location: Full text Results; Figures 2-3, Table 3 [gouda-2023-adp-repair] Bivalent molecular mimicry by ADP protects metal redox state and promotes coenzyme B12 repair. (2023). https://pubmed.ncbi.nlm.nih.gov/36888659/ DOI: 10.1073/pnas.2220677120
Complete structured claim and evidence
Under anaerobic conditions, ADP reduced the rate of cob(II)alamin transfer from human MMUT to MMAB in the MMAA repair system.
Adenosine diphosphate → Cob(II)alamin off-loading from human MMUT source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
false
evidence_location
Full text Results; Figures 2-3, Table 3
experimental_model
Purified human proteins
exposure
Anaerobic cofactor-transfer assay with ADP
limitations
Transfer rate differs from oxidation protection; methylmalonyl-CoA reversed ADP inhibition in this assay.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
When oxidation was excluded, ADP slowed transfer of inactive B12 between the purified human proteins.
primary_references
[gouda-2023-adp-repair] Bivalent molecular mimicry by ADP protects metal redox state and promotes coenzyme B12 repair. (2023). https://pubmed.ncbi.nlm.nih.gov/36888659/ DOI: 10.1073/pnas.2220677120
tissue_or_cell_type
Purified protein assay
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1412–1424
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human proteins · source_derived_draft · unverified_draft
### adp-slows-mmut-cob-ii-offloading Under anaerobic conditions, ADP reduced the rate of cob(II)alamin transfer from human MMUT to MMAB in the MMAA repair system. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: When oxidation was excluded, ADP slowed transfer of inactive B12 between the purified human proteins. organism: Homo sapiens tissue_or_cell_type: Purified protein assay experimental_model: Purified human proteins limitations: Transfer rate differs from oxidation protection; methylmalonyl-CoA reversed ADP inhibition in this assay. exposure: Anaerobic cofactor-transfer assay with ADP cross_nutrient: false evidence_location: Full text Results; Figures 2-3, Table 3 [gouda-2023-adp-repair] Bivalent molecular mimicry by ADP protects metal redox state and promotes coenzyme B12 repair. (2023). https://pubmed.ncbi.nlm.nih.gov/36888659/ DOI: 10.1073/pnas.2220677120
Complete structured claim and evidence
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.
Vitamin B12 (cobalamins) → B12-associated neuropsychiatric impairment source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Vitamin B12 (cobalamins) → Neurologic recovery following B12 replacement source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
In 121 adequately followed episodes, all responded and 57 (47.1%) recovered completely; post-treatment involvement was related to pretreatment severity and symptom duration.
Vitamin B12 (cobalamins) → Neurologic recovery following B12 replacement source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
MMA was elevated in 98.4% of 434 clear-cut B12-deficiency episodes in the diagnostic series.
Vitamin B12 (cobalamins) → Methylmalonic acid source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Total homocysteine was elevated in 95.9% of the B12-deficiency episodes; it was also elevated in 91% of the folate-deficiency episodes.
Vitamin B12 (cobalamins) → Homocysteine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
MMA was elevated in 12.2% of the folate-deficient group; all but one were attributed to renal insufficiency or hypovolemia.
Methylmalonic acid → B12 deficiency diagnosis source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
cross_nutrient
Separates a shared diagnostic setting from direct cofactor identity.
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
These are authors’ clinical attributions, not randomized tests of renal causation. Folate does not thereby become the MMUT cofactor.
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 abnormal MMA result needs its clinical and kidney context.
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 1487–1498
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-mma-folate-renal-confounding MMA was elevated in 12.2% of the folate-deficient group; all but one were attributed to renal insufficiency or hypovolemia. Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: An abnormal MMA result needs its clinical and kidney context. 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: These are authors’ clinical attributions, not randomized tests of renal causation. Folate does not thereby become the MMUT cofactor. exposure: Serum MMA and total homocysteine assays; elevation defined above three standard deviations of the reference mean. cross_nutrient: Separates a shared diagnostic setting from direct cofactor identity. [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
Complete structured claim and evidence
Twelve of 419 recognized B12-deficient patients had serum cobalamin above 200 pg/mL; five had prominent neurologic involvement that responded to therapy.
Serum cobalamin concentration → B12-associated neuropsychiatric impairment source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
experimental_model
Maintenance-relapse observations plus a review of 419 recognized B12-deficient patients.
exposure
Serum cobalamin, MMA and total homocysteine measurements; clinical response used in diagnosis.
limitations
Retrospective diagnostic attribution; no estimate of specificity in unselected patients. Potential cohort overlap with related reports.
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 circulating B12 measurement is not a complete picture of function.
primary_references
[b12-lindenbaum1990] Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations (1990). https://pubmed.ncbi.nlm.nih.gov/2339684/ DOI: 10.1002/ajh.2830340205
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 1500–1510
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Maintenance-relapse observations plus a review of 419 recognized B12-deficient patients. · source_derived_draft · unverified_draft
### b12-serum-normal-recognized-cases Twelve of 419 recognized B12-deficient patients had serum cobalamin above 200 pg/mL; five had prominent neurologic involvement that responded to therapy. Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A single circulating B12 measurement is not a complete picture of function. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Maintenance-relapse observations plus a review of 419 recognized B12-deficient patients. limitations: Retrospective diagnostic attribution; no estimate of specificity in unselected patients. Potential cohort overlap with related reports. exposure: Serum cobalamin, MMA and total homocysteine measurements; clinical response used in diagnosis. [b12-lindenbaum1990] Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations (1990). https://pubmed.ncbi.nlm.nih.gov/2339684/ DOI: 10.1002/ajh.2830340205
Complete structured claim and evidence
Cyanocobalamin increased serum B12 and holotranscobalamin and reduced total homocysteine during the 12-month trial.
Cyanocobalamin → Serum cobalamin concentration source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
experimental_model
Double-blind randomized trial: 201 adults aged at least 75 with B12 107–210 pmol/L, without anemia or relevant neurologic/cognitive signs; 191 had outcome assessment.
exposure
Oral cyanocobalamin 1 mg/day versus placebo for 12 months.
limitations
Blood responses do not establish delivery or functional recovery in every tissue.
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 tablets changed the biochemical measurements.
primary_references
[b12-dangour2015] Effects of vitamin B-12 supplementation on neurologic and cognitive function in older people: a randomized controlled trial (2015). https://pubmed.ncbi.nlm.nih.gov/26135351/ DOI: 10.3945/ajcn.115.110775
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 1512–1522
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized trial: 201 adults aged at least 75 with B12 107–210 pmol/L, without anemia or relevant neurologic/cognitive signs; 191 had outcome assessment. · source_derived_draft · unverified_draft
### b12-dangour-status-response Cyanocobalamin increased serum B12 and holotranscobalamin and reduced total homocysteine during the 12-month trial. Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The tablets changed the biochemical measurements. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Double-blind randomized trial: 201 adults aged at least 75 with B12 107–210 pmol/L, without anemia or relevant neurologic/cognitive signs; 191 had outcome assessment. limitations: Blood responses do not establish delivery or functional recovery in every tissue. exposure: Oral cyanocobalamin 1 mg/day versus placebo for 12 months. [b12-dangour2015] Effects of vitamin B-12 supplementation on neurologic and cognitive function in older people: a randomized controlled trial (2015). https://pubmed.ncbi.nlm.nih.gov/26135351/ DOI: 10.3945/ajcn.115.110775
Complete structured claim and evidence
The primary posterior tibial CMAP endpoint showed a mean difference of -0.2 mV (95% CI -0.8 to 0.3); secondary nerve-conduction and cognitive outcomes also showed no significant benefit.
Cyanocobalamin → Posterior tibial compound muscle action potential amplitude source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
experimental_model
Double-blind randomized trial: 201 adults aged at least 75 with B12 107–210 pmol/L, without anemia or relevant neurologic/cognitive signs; 191 had outcome assessment.
exposure
Oral cyanocobalamin 1 mg/day versus placebo for 12 months.
limitations
Null results have confidence limits; do not extrapolate to symptomatic 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
Improved B12-related markers did not translate into measured neurologic or cognitive improvement in this asymptomatic group.
primary_references
[b12-dangour2015] Effects of vitamin B-12 supplementation on neurologic and cognitive function in older people: a randomized controlled trial (2015). https://pubmed.ncbi.nlm.nih.gov/26135351/ DOI: 10.3945/ajcn.115.110775
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 1524–1534
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized trial: 201 adults aged at least 75 with B12 107–210 pmol/L, without anemia or relevant neurologic/cognitive signs; 191 had outcome assessment. · source_derived_draft · unverified_draft
### b12-dangour-neural-null The primary posterior tibial CMAP endpoint showed a mean difference of -0.2 mV (95% CI -0.8 to 0.3); secondary nerve-conduction and cognitive outcomes also showed no significant benefit. Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Improved B12-related markers did not translate into measured neurologic or cognitive improvement in this asymptomatic group. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Double-blind randomized trial: 201 adults aged at least 75 with B12 107–210 pmol/L, without anemia or relevant neurologic/cognitive signs; 191 had outcome assessment. limitations: Null results have confidence limits; do not extrapolate to symptomatic deficiency. exposure: Oral cyanocobalamin 1 mg/day versus placebo for 12 months. [b12-dangour2015] Effects of vitamin B-12 supplementation on neurologic and cognitive function in older people: a randomized controlled trial (2015). https://pubmed.ncbi.nlm.nih.gov/26135351/ DOI: 10.3945/ajcn.115.110775
Complete structured claim and evidence
B12 plus folic acid increased red-cell folate and decreased total homocysteine by 36%; B12 treatment corrected mild biochemical deficiency.
Cyanocobalamin → Homocysteine source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
cross_nutrient
Direct combined B12/folic-acid exposure.
experimental_model
Double-blind randomized trial: 195 adults aged at least 70 with mild B12 deficiency.
exposure
Cyanocobalamin 1000 micrograms/day, cyanocobalamin 1000 micrograms plus folic acid 400 micrograms/day, or placebo for 24 weeks.
limitations
The combined group cannot isolate the contribution of folic acid versus 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
The two connected vitamins changed the shared marker.
primary_references
[b12-eussen2006] Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial (2006). https://pubmed.ncbi.nlm.nih.gov/16895884/ DOI: 10.1093/ajcn/84.2.361
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 1536–1547
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized trial: 195 adults aged at least 70 with mild B12 deficiency. · source_derived_draft · unverified_draft
### b12-eussen-folate-homocysteine B12 plus folic acid increased red-cell folate and decreased total homocysteine by 36%; B12 treatment corrected mild biochemical deficiency. Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The two connected vitamins changed the shared marker. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Double-blind randomized trial: 195 adults aged at least 70 with mild B12 deficiency. limitations: The combined group cannot isolate the contribution of folic acid versus B12. exposure: Cyanocobalamin 1000 micrograms/day, cyanocobalamin 1000 micrograms plus folic acid 400 micrograms/day, or placebo for 24 weeks. cross_nutrient: Direct combined B12/folic-acid exposure. [b12-eussen2006] Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial (2006). https://pubmed.ncbi.nlm.nih.gov/16895884/ DOI: 10.1093/ajcn/84.2.361
Complete structured claim and evidence
No cognitive benefit accompanied B12 alone or B12 plus folic acid over 24 weeks; memory improvement was greater with placebo than B12 alone (P=0.0036).
Cyanocobalamin → Neuropsychological test performance source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
experimental_model
Double-blind randomized trial: 195 adults aged at least 70 with mild B12 deficiency.
exposure
Cyanocobalamin 1000 micrograms/day, cyanocobalamin 1000 micrograms plus folic acid 400 micrograms/day, or placebo for 24 weeks.
limitations
Several tested domains and a short trial; the memory comparison does not prove generalized neurotoxicity.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Correcting the biochemical shortage was not a general cognitive enhancer in this trial.
primary_references
[b12-eussen2006] Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial (2006). https://pubmed.ncbi.nlm.nih.gov/16895884/ DOI: 10.1093/ajcn/84.2.361
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 1549–1559
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized trial: 195 adults aged at least 70 with mild B12 deficiency. · source_derived_draft · unverified_draft
### b12-eussen-cognition-boundary No cognitive benefit accompanied B12 alone or B12 plus folic acid over 24 weeks; memory improvement was greater with placebo than B12 alone (P=0.0036). Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Correcting the biochemical shortage was not a general cognitive enhancer in this trial. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Double-blind randomized trial: 195 adults aged at least 70 with mild B12 deficiency. limitations: Several tested domains and a short trial; the memory comparison does not prove generalized neurotoxicity. exposure: Cyanocobalamin 1000 micrograms/day, cyanocobalamin 1000 micrograms plus folic acid 400 micrograms/day, or placebo for 24 weeks. [b12-eussen2006] Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial (2006). https://pubmed.ncbi.nlm.nih.gov/16895884/ DOI: 10.1093/ajcn/84.2.361
Complete structured claim and evidence
MMA and homocysteine were significantly lower with methylcobalamin than placebo at months 9 and 27.
Methylcobalamin → Methylmalonic acid source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
experimental_model
Randomized placebo-controlled trial: 271 nondemented diabetic outpatients aged at least 70, plasma B12 150–300 pmol/L.
exposure
Oral methylcobalamin 1000 micrograms/day versus placebo for 27 months.
limitations
No direct cellular flux measurement and no head-to-head form comparison.
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 B12 form improved the measured metabolic markers.
primary_references
[b12-kwok2017] A randomized placebo controlled trial of vitamin B12 supplementation to prevent cognitive decline in older diabetic people with borderline low serum vitamin B12 (2017). https://pubmed.ncbi.nlm.nih.gov/27823800/ DOI: 10.1016/j.clnu.2016.10.018
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 1561–1571
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized placebo-controlled trial: 271 nondemented diabetic outpatients aged at least 70, plasma B12 150–300 pmol/L. · source_derived_draft · unverified_draft
### b12-methylcobalamin-diabetes-metabolites MMA and homocysteine were significantly lower with methylcobalamin than placebo at months 9 and 27. Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This B12 form improved the measured metabolic markers. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Randomized placebo-controlled trial: 271 nondemented diabetic outpatients aged at least 70, plasma B12 150–300 pmol/L. limitations: No direct cellular flux measurement and no head-to-head form comparison. exposure: Oral methylcobalamin 1000 micrograms/day versus placebo for 27 months. [b12-kwok2017] A randomized placebo controlled trial of vitamin B12 supplementation to prevent cognitive decline in older diabetic people with borderline low serum vitamin B12 (2017). https://pubmed.ncbi.nlm.nih.gov/27823800/ DOI: 10.1016/j.clnu.2016.10.018
Complete structured claim and evidence
At 27 months, groups did not differ significantly in change in Clinical Dementia Rating or neuropsychological test z-scores.
Methylcobalamin → Clinical Dementia Rating score source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
experimental_model
Randomized placebo-controlled trial: 271 nondemented diabetic outpatients aged at least 70, plasma B12 150–300 pmol/L.
exposure
Oral methylcobalamin 1000 micrograms/day versus placebo for 27 months.
limitations
More smokers were randomized to active treatment; excluding smokers did not change the reported result.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Better markers did not establish protection from cognitive decline in this group.
primary_references
[b12-kwok2017] A randomized placebo controlled trial of vitamin B12 supplementation to prevent cognitive decline in older diabetic people with borderline low serum vitamin B12 (2017). https://pubmed.ncbi.nlm.nih.gov/27823800/ DOI: 10.1016/j.clnu.2016.10.018
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 1573–1583
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized placebo-controlled trial: 271 nondemented diabetic outpatients aged at least 70, plasma B12 150–300 pmol/L. · source_derived_draft · unverified_draft
### b12-methylcobalamin-diabetes-cognition At 27 months, groups did not differ significantly in change in Clinical Dementia Rating or neuropsychological test z-scores. Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Better markers did not establish protection from cognitive decline in this group. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Randomized placebo-controlled trial: 271 nondemented diabetic outpatients aged at least 70, plasma B12 150–300 pmol/L. limitations: More smokers were randomized to active treatment; excluding smokers did not change the reported result. exposure: Oral methylcobalamin 1000 micrograms/day versus placebo for 27 months. [b12-kwok2017] A randomized placebo controlled trial of vitamin B12 supplementation to prevent cognitive decline in older diabetic people with borderline low serum vitamin B12 (2017). https://pubmed.ncbi.nlm.nih.gov/27823800/ DOI: 10.1016/j.clnu.2016.10.018
Complete structured claim and evidence
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%.
Vitamin B12 (cobalamins) → Serum iron concentration source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Iron deficiency was identified in 7 of 75 patients before cobalamin therapy and 37 of 75 afterward.
Vitamin B12 (cobalamins) → Iron deficiency classification source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The authors proposed that ineffective erythropoiesis during cobalamin deficiency reduces iron use by erythroblasts, helping explain the before/after iron results.
Vitamin B12 (cobalamins) → Iron utilization by erythroblasts source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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).
Metformin → Serum cobalamin concentration source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Metformin → Homocysteine source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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.
Metformin → Prevalence of low serum B12 source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
At least two years of PPI supply was associated with a B12-deficiency diagnosis (OR 1.65; 95% CI 1.58–1.73).
Proton pump inhibitor drug class → B12 deficiency diagnosis source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
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).
Histamine H2 receptor antagonist drug class → B12 deficiency diagnosis source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
The oral and IM groups showed prompt, indistinguishable improvement in hematologic and neurologic abnormalities.
Cyanocobalamin → Neurologic recovery following B12 replacement source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Randomized oral-versus-intramuscular study: 38 allocated; five subsequently identified as folate deficient excluded, leaving 18 oral and 15 injection participants.
exposure
Cyanocobalamin 2 mg orally each day for 120 days versus 1 mg IM on days 1, 3, 7, 10, 14, 21, 30, 60 and 90. Unequal cumulative exposures.
limitations
Small evaluable groups do not establish equivalence for every severe presentation or rare processing disorder.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Absorption through the usual food route was not required for every effective replacement regimen in this trial.
primary_references
[b12-kuzminski1998] Effective treatment of cobalamin deficiency with oral cobalamin (1998). https://pubmed.ncbi.nlm.nih.gov/9694707/ DOI: 10.1182/blood.v92.4.1191
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 1685–1695
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized oral-versus-intramuscular study: 38 allocated; five subsequently identified as folate deficient excluded, leaving 18 oral and 15 injection participants. · source_derived_draft · unverified_draft
### b12-oral-im-clinical-response The oral and IM groups showed prompt, indistinguishable improvement in hematologic and neurologic abnormalities. Condition category: nutrient_deficiency nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Absorption through the usual food route was not required for every effective replacement regimen in this trial. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Randomized oral-versus-intramuscular study: 38 allocated; five subsequently identified as folate deficient excluded, leaving 18 oral and 15 injection participants. limitations: Small evaluable groups do not establish equivalence for every severe presentation or rare processing disorder. exposure: Cyanocobalamin 2 mg orally each day for 120 days versus 1 mg IM on days 1, 3, 7, 10, 14, 21, 30, 60 and 90. Unequal cumulative exposures. [b12-kuzminski1998] Effective treatment of cobalamin deficiency with oral cobalamin (1998). https://pubmed.ncbi.nlm.nih.gov/9694707/ DOI: 10.1182/blood.v92.4.1191
Complete structured claim and evidence
At four months, mean MMA was 169 nmol/L with oral versus 265 with IM treatment; homocysteine was 10.6 versus 12.2 micromol/L. Oral-group MMA was significantly lower.
Cyanocobalamin → Methylmalonic acid source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
experimental_model
Randomized oral-versus-intramuscular study: 38 allocated; five subsequently identified as folate deficient excluded, leaving 18 oral and 15 injection participants.
exposure
Cyanocobalamin 2 mg orally each day for 120 days versus 1 mg IM on days 1, 3, 7, 10, 14, 21, 30, 60 and 90. Unequal cumulative exposures.
limitations
Different cumulative exposures prevent interpreting the result as inherent route superiority.
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 biochemical response was recorded separately from the clinical response.
primary_references
[b12-kuzminski1998] Effective treatment of cobalamin deficiency with oral cobalamin (1998). https://pubmed.ncbi.nlm.nih.gov/9694707/ DOI: 10.1182/blood.v92.4.1191
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 1697–1707
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized oral-versus-intramuscular study: 38 allocated; five subsequently identified as folate deficient excluded, leaving 18 oral and 15 injection participants. · source_derived_draft · unverified_draft
### b12-oral-im-metabolic-response At four months, mean MMA was 169 nmol/L with oral versus 265 with IM treatment; homocysteine was 10.6 versus 12.2 micromol/L. Oral-group MMA was significantly lower. Condition category: nutrient_deficiency nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The biochemical response was recorded separately from the clinical response. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Randomized oral-versus-intramuscular study: 38 allocated; five subsequently identified as folate deficient excluded, leaving 18 oral and 15 injection participants. limitations: Different cumulative exposures prevent interpreting the result as inherent route superiority. exposure: Cyanocobalamin 2 mg orally each day for 120 days versus 1 mg IM on days 1, 3, 7, 10, 14, 21, 30, 60 and 90. Unequal cumulative exposures. [b12-kuzminski1998] Effective treatment of cobalamin deficiency with oral cobalamin (1998). https://pubmed.ncbi.nlm.nih.gov/9694707/ DOI: 10.1182/blood.v92.4.1191
Complete structured claim and evidence
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.
Nitrous oxide → Bone marrow megaloblastosis source_derived_draftungraded
Experimental context and source evidence
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
Complete structured claim and evidence
Serum B12 remained normal despite the abnormal marrow dU suppression pattern; three of nine surgery-only nitrous oxide recipients also had abnormal assays at 24 hours.
Serum cobalamin concentration → Deoxyuridine suppression assay source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
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 assay is an indirect functional test, not a direct methionine-synthase rate 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
A normal amount measured in serum did not establish normal intracellular function under this exposure.
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 and serum
trigger_kind
machinery_impairment Imported condition classification; unverified.
Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1722–1732
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-serum-function-discordance Serum B12 remained normal despite the abnormal marrow dU suppression pattern; three of nine surgery-only nitrous oxide recipients also had abnormal assays at 24 hours. Condition category: machinery_impairment nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A normal amount measured in serum did not establish normal intracellular function under this exposure. organism: Homo sapiens tissue_or_cell_type: Human bone marrow and serum experimental_model: Prospective perioperative study in 22 patients undergoing cardiac bypass surgery. limitations: The assay is an indirect functional test, not a direct methionine-synthase rate measurement. exposure: Nitrous oxide/oxygen for 24 hours, during surgery only, or no nitrous oxide; marrow morphology and deoxyuridine suppression assays. [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
Complete structured claim and evidence
After injection, total homocysteine fell 54% and MMA 84%; placebo showed no significant changes.
Hydroxocobalamin → Methylmalonic acid source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
experimental_model
Double-blind randomized trial: 79 referred infants younger than eight months with plasma total homocysteine at least 6.5 micromol/L, from 105 assessed.
exposure
One 400-microgram intramuscular hydroxocobalamin injection (42 infants) versus sham injection (37); one-month follow-up.
limitations
One-month response does not define a treatment regimen for other infants.
nutrient_topic
Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)
organism
Homo sapiens
plain_language
Both connected metabolic markers responded to the intervention.
primary_references
[b12-torsvik2013] Cobalamin supplementation improves motor development and regurgitations in infants: results from a randomized intervention study (2013). https://pubmed.ncbi.nlm.nih.gov/24025626/ DOI: 10.3945/ajcn.113.061549
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 1734–1744
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized trial: 79 referred infants younger than eight months with plasma total homocysteine at least 6.5 micromol/L, from 105 assessed. · source_derived_draft · unverified_draft
### b12-infant-biochemical-response After injection, total homocysteine fell 54% and MMA 84%; placebo showed no significant changes. Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Both connected metabolic markers responded to the intervention. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Double-blind randomized trial: 79 referred infants younger than eight months with plasma total homocysteine at least 6.5 micromol/L, from 105 assessed. limitations: One-month response does not define a treatment regimen for other infants. exposure: One 400-microgram intramuscular hydroxocobalamin injection (42 infants) versus sham injection (37); one-month follow-up. [b12-torsvik2013] Cobalamin supplementation improves motor development and regurgitations in infants: results from a randomized intervention study (2013). https://pubmed.ncbi.nlm.nih.gov/24025626/ DOI: 10.3945/ajcn.113.061549
Complete structured claim and evidence
Median AIMS improvement was 7.0 points with hydroxocobalamin versus 4.5 with sham (P=0.003).
Hydroxocobalamin → Alberta Infant Motor Scale score source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
experimental_model
Double-blind randomized trial: 79 referred infants younger than eight months with plasma total homocysteine at least 6.5 micromol/L, from 105 assessed.
exposure
One 400-microgram intramuscular hydroxocobalamin injection (42 infants) versus sham injection (37); one-month follow-up.
limitations
Different age, symptoms and endpoint from null older-adult cognition trials; no unexplained contradiction.
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 selected infants improved more on the measured motor scale.
primary_references
[b12-torsvik2013] Cobalamin supplementation improves motor development and regurgitations in infants: results from a randomized intervention study (2013). https://pubmed.ncbi.nlm.nih.gov/24025626/ DOI: 10.3945/ajcn.113.061549
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 1746–1756
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized trial: 79 referred infants younger than eight months with plasma total homocysteine at least 6.5 micromol/L, from 105 assessed. · source_derived_draft · unverified_draft
### b12-infant-motor-response Median AIMS improvement was 7.0 points with hydroxocobalamin versus 4.5 with sham (P=0.003). Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The selected infants improved more on the measured motor scale. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Double-blind randomized trial: 79 referred infants younger than eight months with plasma total homocysteine at least 6.5 micromol/L, from 105 assessed. limitations: Different age, symptoms and endpoint from null older-adult cognition trials; no unexplained contradiction. exposure: One 400-microgram intramuscular hydroxocobalamin injection (42 infants) versus sham injection (37); one-month follow-up. [b12-torsvik2013] Cobalamin supplementation improves motor development and regurgitations in infants: results from a randomized intervention study (2013). https://pubmed.ncbi.nlm.nih.gov/24025626/ DOI: 10.3945/ajcn.113.061549
Complete structured claim and evidence
Regurgitation improvement was reported in 69% versus 29% (P=0.003).
Hydroxocobalamin → Reported infant regurgitation improvement source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
experimental_model
Double-blind randomized trial: 79 referred infants younger than eight months with plasma total homocysteine at least 6.5 micromol/L, from 105 assessed.
exposure
One 400-microgram intramuscular hydroxocobalamin injection (42 infants) versus sham injection (37); one-month follow-up.
limitations
Parental symptom report in a selected short trial; does not identify the molecular gut 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
Feeding-related symptoms also improved more often in the intervention group.
primary_references
[b12-torsvik2013] Cobalamin supplementation improves motor development and regurgitations in infants: results from a randomized intervention study (2013). https://pubmed.ncbi.nlm.nih.gov/24025626/ DOI: 10.3945/ajcn.113.061549
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 1758–1768
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind randomized trial: 79 referred infants younger than eight months with plasma total homocysteine at least 6.5 micromol/L, from 105 assessed. · source_derived_draft · unverified_draft
### b12-infant-regurgitation-response Regurgitation improvement was reported in 69% versus 29% (P=0.003). Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Feeding-related symptoms also improved more often in the intervention group. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Double-blind randomized trial: 79 referred infants younger than eight months with plasma total homocysteine at least 6.5 micromol/L, from 105 assessed. limitations: Parental symptom report in a selected short trial; does not identify the molecular gut mechanism. exposure: One 400-microgram intramuscular hydroxocobalamin injection (42 infants) versus sham injection (37); one-month follow-up. [b12-torsvik2013] Cobalamin supplementation improves motor development and regurgitations in infants: results from a randomized intervention study (2013). https://pubmed.ncbi.nlm.nih.gov/24025626/ DOI: 10.3945/ajcn.113.061549
Complete structured claim and evidence

Availability and dependencies

Each situation shows the normal role first, then what the sources report under a specific condition. A shortfall in the diet, a fault in the machinery, and a low blood reading are kept separate because they are not the same thing.

Blocking haptocorrin competition restored tracer absorption in three patients.

Condition: machinery_impairment · Exocrine pancreatic insufficiency with impaired radiocobalamin absorption

Normal role: Intact absorption and delivery machinery makes cobalamin accessible to tissue metabolism.

Recorded consequence: In three patients with pancreatic insufficiency, oral cobinamide 100 nmol corrected malabsorption of 0.4 nmol radiocobalamin in Schilling tests, comparably to trypsin.

Scope: Three human pancreatic-insufficiency patients and parallel human binding assays; Homo sapiens

This cubilin variant binds its B12 carrier less efficiently.

Condition: machinery_impairment · Site-directed P1297L substitution

Normal role: Intact absorption and delivery machinery makes cobalamin accessible to tissue metabolism.

Recorded consequence: The human cubilin P1297L CUB5-8 fragment showed severalfold higher dissociation constant for IF-cobalamin than wild type, mainly from a lower association rate.

Scope: Human wild-type/P1297L fragments expressed in CHO cells; SPR; Homo sapiens

Inherited cubilin defects can block B12 absorption.

Condition: machinery_impairment · Inherited biallelic CUBN disease genotypes

Normal role: Intact absorption and delivery machinery makes cobalamin accessible to tissue metabolism.

Recorded consequence: Mapping and sequencing identified two independent disease-specific CUBN mutations across 17 Finnish families with selective intestinal cobalamin malabsorption.

Scope: 17 Finnish MGA1 families; linkage and molecular analysis; Homo sapiens

Faulty amnionless reduced available receptor without changing its affinity.

Condition: machinery_impairment · Inherited compound AMN nonsense/splice genotype

Normal role: Intact absorption and delivery machinery makes cobalamin accessible to tissue metabolism.

Recorded consequence: 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.

Scope: Two affected siblings and family carriers; urinary receptor characterization; Homo sapiens

Some inherited absorption failures originate in intrinsic factor.

Condition: machinery_impairment · Inherited GIF variants

Normal role: Intact absorption and delivery machinery makes cobalamin accessible to tissue metabolism.

Recorded consequence: Biallelic GIF mutations in seven families with juvenile cobalamin deficiency identified inherited intrinsic-factor deficiency in cases initially suspected to have receptor-mediated IGS.

Scope: Human family linkage and sequencing study; Homo sapiens

Several glycosylation sites jointly support receptor maturation.

Condition: machinery_impairment · Four Asn-to-Asp substitutions; Figure 6 and Supplementary Figure 11

Normal role: Intact absorption and delivery machinery makes cobalamin accessible to tissue metabolism.

Recorded consequence: 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.

Scope: Rat mini-cubilin 4567ND versus wild type in HEK293T cells coexpressing human AMN; Rattus norvegicus construct; Homo sapiens AMN and host cells

The patient receptor proteins accumulated inside kidney cells.

Condition: machinery_impairment · Patient CUBN G653R; co-occurring AMN P295S also reported

Normal role: Intact absorption and delivery machinery makes cobalamin accessible to tissue metabolism.

Recorded consequence: 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.

Scope: One IGS patient renal biopsy compared with a control biopsy; Homo sapiens

A receptor deletion reduced B12 delivery in patient cells.

Condition: machinery_impairment · Homozygous c.262_264delGAG / p.Glu88del

Normal role: Intact absorption and delivery machinery makes cobalamin accessible to tissue metabolism.

Recorded consequence: Fibroblasts from five asymptomatic newborns with elevated methylmalonic acid and homozygous CD320 p.Glu88del showed reduced uptake of holo-transcobalamin.

Scope: Five newborn-derived fibroblast lines with homozygous CD320 deletion; Homo sapiens

Functional B12 impairment in HeLa cells

Condition: machinery_impairment · N2O exposure under B12-depleted culture conditions

Normal role: Cobalamin supports MTR folate recycling.

Recorded consequence: Increased methylfolate fraction of the nuclear folate pool

Scope: HeLa model

Repairing the missing receptor codon restored function in the assay.

Condition: machinery_impairment · Deletion-bearing CD320 construct before site-directed codon repair

Normal role: Intact absorption and delivery machinery makes cobalamin accessible to tissue metabolism.

Recorded consequence: Replacing the missing Glu88 codon by site-directed mutagenesis restored receptor function in the CD320 reconstruction experiments.

Scope: Reconstruction of human deletion-bearing CD320 followed by codon repair; Homo sapiens

Without megalin, mice lost more B12 in urine.

Condition: machinery_impairment · Genetic megalin deficiency

Normal role: Intact absorption and delivery machinery makes cobalamin accessible to tissue metabolism.

Recorded consequence: Megalin-deficient mice excreted approximately fourfold more urinary B12 than controls, consistent with defective renal recovery of transcobalamin-B12.

Scope: Megalin-deficient versus control mice; Mus musculus

When metformin lowers vitamin B12 over years

Condition: nutrient_deficiency · Long-term metformin treatment.

Normal role: Dietary vitamin B12 is absorbed in the ileum as the intrinsic-factor-cobalamin complex and carried in blood on transcobalamin.

Recorded consequence: Serum B12 and holotranscobalamin fall, biochemical deficiency becomes more common, and homocysteine and methylmalonic acid rise.

Scope: Human randomised and observational studies during metformin treatment

Impaired renal uptake depleted the kidney B12 pool in mice.

Condition: machinery_impairment · Genetic megalin deficiency

Normal role: Intact absorption and delivery machinery makes cobalamin accessible to tissue metabolism.

Recorded consequence: Kidney cortex B12 content in megalin-deficient mice was approximately fourfold lower than in controls.

Scope: Megalin-deficient versus control mice; Mus musculus

When metformin lowers vitamin B12 over years

Condition: biomarker_context · Long-term metformin treatment.

Normal role: Dietary vitamin B12 is absorbed in the ileum as the intrinsic-factor-cobalamin complex and carried in blood on transcobalamin.

Recorded consequence: Serum B12 and holotranscobalamin fall, biochemical deficiency becomes more common, and homocysteine and methylmalonic acid rise.

Scope: Human randomised and observational studies during metformin treatment

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

Condition: machinery_impairment · Both cytoplasmic motifs disrupted; wild-type and single-motif mutants as comparators

Normal role: Intact absorption and delivery machinery makes cobalamin accessible to tissue metabolism.

Recorded consequence: Disruption of both human AMN FXNPXF motifs impaired IF-B12 internalization and degradation in CHO-K1 cells despite preserved cubam surface expression.

Scope: Human AMN double-signal mutant plus rat cubilin 1-1389 in CHO-K1 cells; Human AMN; rat cubilin; Chinese hamster host cells; human/porcine IF reagents

Some antibodies stop intrinsic factor from loading B12.

Condition: machinery_impairment · Patient-derived intrinsic-factor blocking antibody activity

Normal role: Intact absorption and delivery machinery makes cobalamin accessible to tissue metabolism.

Recorded consequence: 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.

Scope: Human pernicious-anemia sera; ordered-addition binding assays; Homo sapiens

Other antibodies interfered even after B12 had bound its carrier.

Condition: machinery_impairment · Patient-derived type II intrinsic-factor antibody activity

Normal role: Intact absorption and delivery machinery makes cobalamin accessible to tissue metabolism.

Recorded consequence: Type II antibodies prevented absorption in pernicious-anemia patients when added to a preformed intrinsic-factor-B12 complex.

Scope: Human absorption experiments with preassembled IF-B12; Homo sapiens

Normal total B12 did not exclude a serious carrier deficiency.

Condition: machinery_impairment · Inherited TCII deficiency; carrier pattern supported recessive inheritance

Normal role: Intact absorption and delivery machinery makes cobalamin accessible to tissue metabolism.

Recorded consequence: 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.

Scope: Two infant siblings; chromatography/electrophoresis and family binding-capacity studies; Homo sapiens

cblF fibroblast complementation

Condition: machinery_impairment · Inherited LMBRD1 dysfunction; rescue by wild-type construct

Normal role: LMBD1 supports intracellular cobalamin handling

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

Scope: Patient fibroblasts; abstract-level outcome

Inherited ABCD4 transport defect

Condition: machinery_impairment · Pathogenic ABCD4 mutations

Normal role: ABCD4 enables B12 movement out of lysosomes

Recorded consequence: An inherited transporter defect can trap B12 in lysosomes.

Scope: Human cblJ disorder; not low dietary intake

LMBRD1 knockout localization defect

Condition: machinery_impairment · CRISPR deletion of LMBRD1

Normal role: LMBD1 helps ABCD4 reach lysosomes

Recorded consequence: Deleting the escort changed where the transporter was located.

Scope: HEK293 fractionation experiment

LMBD1 sorting-motif perturbation

Condition: machinery_impairment · 233YERL replaced with AAAA

Normal role: Correctly targeted LMBD1 escorts ABCD4

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

Scope: Tagged human protein experiment

ABCD4 N141K transport defect

Condition: machinery_impairment · Purified ABCD4 N141K substitution

Normal role: Wild-type ABCD4 transports B12 using ATP

Recorded consequence: The variant disrupted B12 movement across the membrane.

Scope: Reconstituted human transporter

ABCD4 Y319C transport defect

Condition: machinery_impairment · Purified ABCD4 Y319C substitution

Normal role: Wild-type ABCD4 transports B12 using ATP

Recorded consequence: The variant disrupted B12 movement across the membrane.

Scope: Reconstituted human transporter

Truncated MMACHC retains flavin-supported chemistry

Condition: machinery_impairment · Experimental deletion of C-terminal 38 residues

Normal role: MMACHC removes the cyano ligand from CNCbl

Recorded consequence: A truncated B12-processing protein could use supplied flavins to carry out this reaction.

Scope: Purified construct; activity retained rather than a deficiency phenotype

cblC fibroblast synthetic-probe processing

Condition: machinery_impairment · Inherited MMACHC mutations in WG1801, WG2176 and WG3354 cells

Normal role: MMACHC enables early cobalamin ligand removal

Recorded consequence: A synthetic B12 probe exposed the processing defect in patient cells.

Scope: Three human patient lines versus controls; synthetic propylcobalamin

MMADHC mitochondrial targeting redistribution

Condition: machinery_impairment · Enhanced mitochondrial leader in deficient patient cells

Normal role: MMADHC supports allocation toward mitochondrial and cytosolic pathways

Recorded consequence: Redirecting MMADHC toward mitochondria increased production of this B12 cofactor.

Scope: Combined cblD-MMA/HC fibroblasts; cofactor allocation

MMADHC mitochondrial targeting redistribution

Condition: machinery_impairment · Enhanced mitochondrial leader in deficient patient cells

Normal role: MMADHC supports allocation toward mitochondrial and cytosolic pathways

Recorded consequence: Redirecting MMADHC toward mitochondria decreased production of this B12 cofactor.

Scope: Combined cblD-MMA/HC fibroblasts; cofactor allocation

MMADHC shortened-sequence rescue

Condition: machinery_impairment · Engineered MMADHC sequence/reinitiation constructs

Normal role: MMADHC supports cellular cofactor synthesis

Recorded consequence: The later portion of MMADHC could support the methyl-B12 branch in these cells.

Scope: Human fibroblast rescue; branch-specific sufficiency

MMADHC T182N complex defect

Condition: machinery_impairment · T182N on delta123 construct

Normal role: MMADHC associates with processed cofactor on MMACHC

Recorded consequence: This variant disrupted the two processing proteins’ association.

Scope: Human purified-protein assay; matched truncation control

PRDX1 splice-related epi-cblC

Condition: machinery_impairment · Specified PRDX1 intron-5 acceptor variants

Normal role: Proper RNA termination prevents aberrant transcription across adjacent loci

Recorded consequence: A neighboring gene’s splice defect made transcription run through the B12-processing gene.

Scope: CHU-12122 and WG3838 fibroblasts; variants specified

A high folate result does not establish B12 sufficiency

Condition: biomarker_context · Low B12 status with high serum folate in NHANES older adults.

Normal role: B12-dependent reactions remain necessary alongside folate.

Recorded consequence: Anemia and cognitive impairment associations differed by B12 status.

Scope: Cross-sectional older-adult analysis with clinical exclusions.

Compound genetic/epigenetic cblC

Condition: machinery_impairment · Paternal methylated MMACHC promoter plus maternal coding mutation

Normal role: MMACHC transcription supplies the B12-processing protein

Recorded consequence: The intact B12-processing allele was switched off by the inherited epigenetic defect.

Scope: CHU-12122 patient allele-specific fibroblast results

Folate and B12 measurements must be interpreted together

Condition: biomarker_context · Low serum B12 in two cross-sectional NHANES datasets.

Normal role: B12 participates in methionine recycling and methylmalonyl-CoA metabolism.

Recorded consequence: Higher folate tracked with higher homocysteine and MMA in low-B12 strata.

Scope: Adult analyses from 1991–1994 and 1999–2002.

PRDX1 knockdown in epi-cblC fibroblasts

Condition: machinery_impairment · PRDX1 siRNA in WG3838 cells carrying c.515-2A>T

Normal role: Correctly regulated MMACHC expression supports B12 processing

Recorded consequence: Reducing the abnormal neighboring transcript allowed the processing gene to be expressed again.

Scope: Human WG3838 fibroblasts only

ABCD4 Y482A interface perturbation

Condition: machinery_impairment · Tyr482 replaced experimentally by alanine

Normal role: ABCD4–LMBD1 association supports lysosomal targeting

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

Scope: HEK293T experimental constructs

ABCD4 Y482A interface perturbation

Condition: machinery_impairment · Tyr482 replaced experimentally by alanine

Normal role: ABCD4–LMBD1 association supports lysosomal targeting

Recorded consequence: The interface variant failed to reach lysosomes normally.

Scope: HEK293T experimental constructs

This MMAB variant failed in the ferredoxin assay; the result depended on the electron donor.

Condition: machinery_impairment · R186Q variant; FDX1/FDXR/NADPH versus titanium(III)citrate

Normal role: Adenosylcobalamin-dependent propionyl-CoA metabolism requires intact upstream enzymes, MMAB, MMAA and MMUT.

Recorded consequence: R186Q human MMAB showed no detectable adenosylcobalamin synthesis with FDX1/FDXR/NADPH, although a strong chemical reductant supported activity.

Scope: Purified protein assay; Homo sapiens

In the human-protein experiment, this MMAA variant still hydrolyzed GTP but failed to bind MMUT normally.

Condition: machinery_impairment · G188R patient variant versus wild type

Normal role: Adenosylcobalamin-dependent propionyl-CoA metabolism requires intact upstream enzymes, MMAB, MMAA and MMUT.

Recorded consequence: Human MMAA G188R retained basal GTPase activity but lost the detected MMUT interaction.

Scope: Purified protein assay; Homo sapiens

Adding activated B12 did not make this defective epimerase work in the human-cell assay.

Condition: machinery_impairment · I53R expression; MMUT coexpression; 50 micromolar AdoCbl

Normal role: Adenosylcobalamin-dependent propionyl-CoA metabolism requires intact upstream enzymes, MMAB, MMAA and MMUT.

Recorded consequence: Human MCEE I53R lacked measured activity in the coupled patient-fibroblast assay with overexpressed MMUT and added adenosylcobalamin.

Scope: Fibroblasts; Homo sapiens

B12 supplementation in ECHDC1-knockout L929 adipocytes

Condition: machinery_impairment · ECHDC1 knockout; 2.5 micromolar supplementary B12 during differentiation

Normal role: MMUT uses adenosylcobalamin to metabolize methylmalonyl-CoA; ECHDC1 separately clears aberrant acyl-CoA metabolites.

Recorded consequence: Adding 2.5 micromolar B12 during ECHDC1-knockout L929 adipocyte differentiation lowered whole-cell methylmalonyl-CoA approximately 20-fold.

Scope: Mouse L929 adipocyte culture

B12 supplementation in ECHDC1-knockout L929 adipocytes

Condition: machinery_impairment · ECHDC1 knockout; 2.5 micromolar supplementary B12 during differentiation

Normal role: MMUT uses adenosylcobalamin to metabolize methylmalonyl-CoA; ECHDC1 separately clears aberrant acyl-CoA metabolites.

Recorded consequence: B12 supplementation lowered the measured propionyl-CoA pool approximately fourfold in differentiating ECHDC1-knockout L929 adipocytes.

Scope: Mouse L929 adipocyte culture

B12 supplementation in ECHDC1-knockout L929 adipocytes

Condition: machinery_impairment · ECHDC1 knockout; 2.5 micromolar supplementary B12 during differentiation

Normal role: MMUT uses adenosylcobalamin to metabolize methylmalonyl-CoA; ECHDC1 separately clears aberrant acyl-CoA metabolites.

Recorded consequence: Despite lower acyl-CoA pools, B12 supplementation barely changed measured methyl-branched fatty acids in ECHDC1-knockout L929 adipocytes.

Scope: Mouse L929 adipocyte culture

These human fibroblasts relied strongly on MMUT for the measured use of propionate carbon.

Condition: machinery_impairment · MMUT CRISPR knockout versus OR7G3 guide control; [14C]propionate

Normal role: Adenosylcobalamin-dependent propionyl-CoA metabolism requires intact upstream enzymes, MMAB, MMAA and MMUT.

Recorded consequence: MMUT knockout reduced propionate-derived protein labeling about sixfold in HFF1 human fibroblasts.

Scope: Foreskin fibroblasts; Homo sapiens

This human cancer cell line retained propionate use without MMUT, unlike the tested fibroblasts.

Condition: machinery_impairment · MMUT CRISPR knockout versus OR7G3 guide control; [14C]propionate

Normal role: Adenosylcobalamin-dependent propionyl-CoA metabolism requires intact upstream enzymes, MMAB, MMAA and MMUT.

Recorded consequence: MMUT knockout did not reduce propionate-derived protein labeling in HT-29 colorectal cancer cells.

Scope: Colorectal adenocarcinoma cells; Homo sapiens

Kidney cells from these patients with MMUT defects consumed less oxygen in the basal assay.

Condition: machinery_impairment · Patient MMUT-inactivating genotypes versus controls

Normal role: Adenosylcobalamin-dependent propionyl-CoA metabolism requires intact upstream enzymes, MMAB, MMAA and MMUT.

Recorded consequence: Human mut0 MMA kidney tubular cells had lower basal oxygen consumption than control cells.

Scope: Kidney tubular cells; Homo sapiens

After experimental mitochondrial damage, these patient kidney cells delivered fewer mitochondria to lysosomes.

Condition: machinery_impairment · MMUT-inactivating genotypes plus 5 micromolar rotenone for 24 hours

Normal role: Adenosylcobalamin-dependent propionyl-CoA metabolism requires intact upstream enzymes, MMAB, MMAA and MMUT.

Recorded consequence: MMUT-deficient human kidney cells failed to show the control mt-Keima lysosomal shift after 24 hours of 5 micromolar rotenone.

Scope: Kidney tubular cells; Homo sapiens

In this damage assay, patient kidney cells marked fewer mitochondria with Parkin.

Condition: machinery_impairment · MMUT-inactivating genotypes plus 5 micromolar rotenone for four hours

Normal role: Adenosylcobalamin-dependent propionyl-CoA metabolism requires intact upstream enzymes, MMAB, MMAA and MMUT.

Recorded consequence: MMUT-deficient human kidney cells showed reduced Parkin recruitment after 5 micromolar rotenone for four hours.

Scope: Kidney tubular cells; Homo sapiens

Adding PINK1 restored mitochondrial marking in this patient-cell model.

Condition: machinery_impairment · HA-PINK1 adenovirus versus empty-vector control

Normal role: Adenosylcobalamin-dependent propionyl-CoA metabolism requires intact upstream enzymes, MMAB, MMAA and MMUT.

Recorded consequence: Adenoviral human PINK1 expression restored Parkin recruitment in MMUT-deficient human kidney tubular cells.

Scope: Kidney tubular cells; Homo sapiens

Neurologic deficiency can occur without the expected blood-count flags

Condition: nutrient_deficiency · Clinically attributed B12 deficiency with neuropsychiatric symptoms.

Normal role: B12 coenzymes support methionine synthase and methylmalonyl-CoA mutase; clinical measurements do not directly quantify every tissue reaction.

Recorded consequence: Blood-count screening did not identify every neurologic presentation.

Scope: Selected clinical series, largely clinical deficiency rather than asymptomatic population screening.

Duration and severity are associated with recovery

Condition: nutrient_deficiency · Clinically established neurologic B12 deficiency before treatment.

Normal role: B12 coenzymes support methionine synthase and methylmalonyl-CoA mutase; clinical measurements do not directly quantify every tissue reaction.

Recorded consequence: Longer and more severe involvement was associated with more residual impairment.

Scope: Retrospective clinical series with adequate follow-up in 121 episodes.

MMA and homocysteine add information to B12 measurements

Condition: biomarker_context · Clear-cut clinical B12 deficiency in a selected diagnostic series.

Normal role: B12 coenzymes support methionine synthase and methylmalonyl-CoA mutase; clinical measurements do not directly quantify every tissue reaction.

Recorded consequence: MMA and total homocysteine were often elevated.

Scope: Study-specific reference range and case ascertainment.

Serum B12 alone can miss some recognized cases

Condition: biomarker_context · Clinically recognized cobalamin deficiency despite serum B12 above the study threshold.

Normal role: B12 coenzymes support methionine synthase and methylmalonyl-CoA mutase; clinical measurements do not directly quantify every tissue reaction.

Recorded consequence: Functional markers and clinical response supplied additional evidence.

Scope: Retrospective review and treatment-maintenance observations.

Biochemical improvement need not produce neurologic benefit

Condition: biomarker_context · Moderate biochemical B12 deficiency without anemia or relevant symptoms in older adults.

Normal role: B12 coenzymes support methionine synthase and methylmalonyl-CoA mutase; clinical measurements do not directly quantify every tissue reaction.

Recorded consequence: Supplementation changed status markers without measurable improvement in selected neurologic/cognitive outcomes.

Scope: Randomized 12-month trial in adults at least 75 years old.

B12 and folic acid change markers without guaranteed cognitive benefit

Condition: biomarker_context · Mild B12 deficiency in older trial participants.

Normal role: B12 coenzymes support methionine synthase and methylmalonyl-CoA mutase; clinical measurements do not directly quantify every tissue reaction.

Recorded consequence: Biochemical correction differed from measured cognition.

Scope: Randomized 24-week B12, B12-plus-folic-acid, or placebo trial.

Methylcobalamin response depends on the endpoint

Condition: biomarker_context · Borderline plasma B12 in older nondemented adults with diabetes.

Normal role: B12 coenzymes support methionine synthase and methylmalonyl-CoA mutase; clinical measurements do not directly quantify every tissue reaction.

Recorded consequence: Metabolites improved without significant prevention of cognitive decline.

Scope: Randomized 27-month methylcobalamin trial.

B12 recovery can reveal an accompanying iron shortage

Condition: nutrient_deficiency · Cobalamin deficiency followed by cobalamin therapy.

Normal role: B12 coenzymes support methionine synthase and methylmalonyl-CoA mutase; clinical measurements do not directly quantify every tissue reaction.

Recorded consequence: Iron-status results shifted and more participants met iron-deficiency criteria.

Scope: Before/after clinical series of 75 patients.

Oral and injected cyanocobalamin can both work in a studied regimen

Condition: nutrient_deficiency · Newly diagnosed cobalamin deficiency.

Normal role: B12 coenzymes support methionine synthase and methylmalonyl-CoA mutase; clinical measurements do not directly quantify every tissue reaction.

Recorded consequence: Both routes produced clinical and biochemical improvement.

Scope: Small randomized 120-day study, with five post-randomization folate-deficient exclusions.

Nitrous oxide can impair B12-related function despite normal serum B12

Condition: machinery_impairment · Perioperative nitrous oxide exposure in cardiac surgery.

Normal role: B12 coenzymes support methionine synthase and methylmalonyl-CoA mutase; clinical measurements do not directly quantify every tissue reaction.

Recorded consequence: Megaloblastic marrow and abnormal deoxyuridine suppression were observed despite normal serum B12.

Scope: Small prospective surgical exposure study.

Selected infants showed biochemical and motor responses

Condition: biomarker_context · Referred infants with symptoms or developmental concerns and elevated total homocysteine by study criteria.

Normal role: B12 coenzymes support methionine synthase and methylmalonyl-CoA mutase; clinical measurements do not directly quantify every tissue reaction.

Recorded consequence: B12 markers and short-term motor outcomes improved with hydroxocobalamin.

Scope: Randomized one-month trial in 79 selected infants.

The sources

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

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source

Recorded disagreements

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

Open questions in this collection

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

Calcium rescue is compatible with interference in calcium-dependent ileal handling, but the two human interventions do not directly identify a molecular metformin-CUBN interaction.Binding calcium in the receptor structure and increased circulating tracer with calcium are distinct observations; the causal bridge remains untested in these clinical experiments.
The seven-person acute pilot does not establish whether calcium supplementation prevents chronic metformin-associated B12 deficiency.Healthy participants, short drug exposure and tracer endpoint; no chronic deficiency-prevention outcome.
Receptor-independent high-dose oral absorption is not quantified in this module.No directly verified primary uptake experiment for that route was selected; clinical oral-versus-injection outcomes belong to the clinical module.
The magnitude of renal B12 reserve mobilization in humans is unresolved by the megalin-knockout experiment.Mouse content and urinary loss, with rodent lysosomal localization, do not demonstrate a quantified human reserve contribution.
Which intracellular mechanisms account for each neurologic phenotype and incomplete recovery?Clinical response series establish a pattern but do not isolate methylation, myelin chemistry, mitochondrial injury or other mediators in each patient.
How should circulating B12, holotranscobalamin, MMA and homocysteine be combined for each population and kidney state?Assay performance in selected clinical deficiency cannot be transferred unchanged to all borderline or supplemented populations.
Does restored erythroblast iron utilization explain the observed iron-status changes during B12 repletion?The before/after series supports the interaction but did not directly measure erythroblast iron flux or all competing explanations.
Which patients gain neurologic or cognitive benefit beyond improved biochemical markers?Symptomatic deficiency, asymptomatic older adults, diabetes and referred infants differ in exposure and outcomes. These trials are not head-to-head B12-form comparisons.
How much do specific absorption steps mediate clinical drug-associated B12 deficiency?The long-term metformin and acid-suppression studies did not directly test each intestinal mechanism; short-term receptor or tracer studies cannot supply a universal attributable fraction.
The physiological exclusivity and tissue importance of FDX1 as the MMAB electron donor remain undetermined by the cited reconstitution.Biochemical competence is not in-vivo necessity.
Normal-human tissue shares of B12-dependent versus alternative propionate utilization remain unresolved.The comparative experiments use fibroblast and transformed cell lines.
These records do not establish that nutritional B12 neuropathy is caused universally by MMA accumulation, defective myelin lipids, or reduced SAM:SAH.Kidney genetic-disease models and adipocyte lipid pools do not establish a neuronal causal chain; existing Mtrr-mouse record shows tissue-specific SAM:SAH preservation.
The dominant physiological electron donor to human MMACHC, and the quantitative contribution of free-flavin versus protein-mediated decyanation in cells, remain unresolved by these reconstitutions.Alternative in-vitro donor systems are demonstrated without comparative intact-human flux measurements.
These studies do not establish a universal riboflavin, NADPH, or glutathione threshold required for response to B12 supplementation.Cross-nutrient biochemical dependence is not a clinical depletion/repletion threshold.
Cobalamin upper-ligand identity in the 2021 transport assay is not resolved from the retrieved main text.Methods label the reagent cobalamin; umbrella vitamin-b12 is retained instead of assuming cyanocobalamin.
The 2018 epi-cblC study labels its methylation-inhibitor exposure inconsistently as 5-azacytidine versus 5-aza-2′-deoxycytidine.This is within-paper reagent-reporting ambiguity, not a genuine opposing scientific finding; no drug-specific mechanism was extracted.
A complete directional handoff from the lysosomal transporter through MMACHC/MMADHC to both destination enzymes is not proven by isolated localization or binding assays.Localization, chemical processing, coordination and final delivery are distinct experimental endpoints.

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

Evidence, AI assistance and curation standards

Vitamin B12 (cobalamins)

The mechanisms

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.

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%.

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.

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.

In the same crossover experiment, jejunal release of labeled liver cobalamins was near 90% after either omeprazole or placebo, despite earlier gastric effects.

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.

Pancreatic protease incubation at pH 8 partially degraded human R protein and lowered its cobalamin affinity approximately 150-fold.

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.

The pancreatic protease incubations that altered R protein did not alter the tested human intrinsic factor binding parameters.

In three patients with pancreatic insufficiency, oral cobinamide 100 nmol corrected malabsorption of 0.4 nmol radiocobalamin in Schilling tests, comparably to trypsin.

Human renal cubilin and AMN copurified and coeluted as a tightly associated complex that required denaturing conditions for separation.

Human renal cubilin and AMN remained associated during coelution in EDTA, indicating that their mutual association did not require calcium under these conditions.

The 3.3-angstrom human IF-cobalamin/CUB5-8 structure showed two separated cubilin CUB domains engaging the two intrinsic factor domains.

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.

The human cubilin P1297L CUB5-8 fragment showed severalfold higher dissociation constant for IF-cobalamin than wild type, mainly from a lower association rate.

Mapping and sequencing identified two independent disease-specific CUBN mutations across 17 Finnish families with selective intestinal cobalamin malabsorption.

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.

Biallelic GIF mutations in seven families with juvenile cobalamin deficiency identified inherited intrinsic-factor deficiency in cases initially suspected to have receptor-mediated IGS.

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.

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.

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.

Purified human placental receptor and recombinant CD320 extracellular domain bound transcobalamin-cobalamin; high-affinity binding did not require the cytoplasmic domain or membrane orientation.

The human receptor identified as CD320 binds transcobalamin-cobalamin at the plasma membrane and internalizes the carrier-vitamin complex by endocytosis.

Fibroblasts from five asymptomatic newborns with elevated methylmalonic acid and homozygous CD320 p.Glu88del showed reduced uptake of holo-transcobalamin.

Replacing the missing Glu88 codon by site-directed mutagenesis restored receptor function in the CD320 reconstruction experiments.

Megalin-deficient mice excreted approximately fourfold more urinary B12 than controls, consistent with defective renal recovery of transcobalamin-B12.

Kidney cortex B12 content in megalin-deficient mice was approximately fourfold lower than in controls.

In the comparative diabetes study, adding oral calcium after three months of metformin reversed the decline in serum holo-transcobalamin.

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).

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).

Human AMN coexpressed with rat cubilin 1-1389 enabled IF-B12 internalization in CHO-K1 cells; either intact FXNPXF cytoplasmic motif supported uptake.

Disruption of both human AMN FXNPXF motifs impaired IF-B12 internalization and degradation in CHO-K1 cells despite preserved cubam surface expression.

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.

Type II antibodies prevented absorption in pernicious-anemia patients when added to a preformed intrinsic-factor-B12 complex.

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.

Transfection with wild-type LMBD1 restored cobalamin coenzyme synthesis and function in cultured fibroblasts from individuals with the cblF defect.

The human disorder assigned to pathogenic ABCD4 mutations showed failure of lysosomal vitamin B12 release, resembling the cblF cellular defect.

In HuH7 cells expressing human ABCD4-HA, adding LMBD1-GFP shifted ABCD4 from an ER-like distribution toward LAMP1-positive lysosomes.

CRISPR LMBRD1 knockout in HEK293 cells reduced the ABCD4 signal overlapping lysosomal fractions to about 40% of control, while total ABCD4 was similar.

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.

Reconstituted human ABCD4 moved cobalamin from liposome interior to exterior with external ATP; the ATPase-defective K427A control lacked this activity.

LMBD1-only proteoliposomes had no detectable cobalamin transport in the same reconstitution system in which ABCD4 transported cobalamin.

Purified human ABCD4 N141K lost detectable cobalamin transport in liposomes, despite ATPase activity comparable with wild type.

Purified human ABCD4 Y319C lost detectable cobalamin transport in liposomes, together with loss of ATPase activity.

Human MMACHC converted bound cyanocobalamin to cob(II)alamin during NADPH-supported reductive decyanation; EPR identified the product in a base-off coordination state.

Recombinant human MTRR with NADPH supported MMACHC-bound cyanocobalamin conversion to cob(II)alamin; free cyanocobalamin was not detectably reduced without MMACHC.

Recombinant human NDOR1/NR1 with NADPH supported MMACHC-bound cyanocobalamin conversion to cob(II)alamin; free cyanocobalamin was not detectably reduced without MMACHC.

Human MMACHC transfers the methyl group from methylcobalamin to glutathione, yielding cob(I)alamin and the corresponding glutathione thioether; reported turnover was 11.7 +/- 0.2 per hour at 20 C.

Human MMACHC transfers the 5′-deoxyadenosyl group from adenosylcobalamin to glutathione, yielding cob(I)alamin and the corresponding glutathione thioether; reported turnover was 0.174 +/- 0.006 per hour at 20 C.

In the human MMACHC dealkylation study, cysteine and homocysteine did not substitute for glutathione as the thiol co-substrate.

Human MMACHC residues 1–244 supported cyanocobalamin decyanation with FMN or FAD plus NADPH, without a separately supplied flavoprotein reductase; reduced FMN also supported the reaction.

Purified human CblC/MMACHC supported GSH-dependent decyanation of cyanocobalamin to cob(II)alamin efficiently under anaerobic conditions; the human reaction was oxygen-sensitive.

Purified human CblC/MMACHC supported GSH-dependent reduction of aquocobalamin to cob(II)alamin efficiently under anaerobic conditions; the human reaction was oxygen-sensitive.

Bovine aortic endothelial cells converted cobalt-57-labeled adenosylcobalamin into labeled methylcobalamin during metabolic labeling.

Fibroblasts from three cblC patients had little or no conversion of cobalt-57-labeled propylcobalamin into adenosylcobalamin and methylcobalamin, whereas control skin fibroblasts converted the probe.

In cblD-MMA/HC fibroblasts, an MMADHC construct with improved mitochondrial targeting increased adenosylcobalamin formation relative to the targeting comparator.

In cblD-MMA/HC fibroblasts, an MMADHC construct with improved mitochondrial targeting decreased methylcobalamin formation relative to the targeting comparator.

MMADHC expression/translation-reinitiation experiments in cblD patient fibroblasts indicated that sequence after Met116 was sufficient to support methylcobalamin synthesis.

Human MMADHC delta123 carrying T182N showed strongly reduced complex formation with full-length human MMACHC after MeCbl/GSH incubation, compared with matched delta123 MMADHC.

Human MMADHC donated the Cys261 sulfur ligand to MMACHC-bound cob(II)alamin, forming an interprotein complex that oxidized to thiolato-cob(III)alamin.

Reduced, full-length human MMADHC bound free aquocobalamin in vitro with a reported KD of 1.0 +/- 0.4 micromolar and formed a base-on thiolato-cob(III)alamin species.

PRDX1 splice-acceptor variants c.515-1G>T or c.515-2A>T were linked to exon-6/termination-signal skipping and antisense readthrough across MMACHC in epi-cblC fibroblasts.

In CHU-12122 epi-cblC fibroblasts, the promoter-hypermethylated paternal MMACHC allele was transcriptionally silent; only the maternal coding-mutant allele was detected in transcripts.

PRDX1-targeting siRNA restored detectable MMACHC expression in WG3838 epi-cblC fibroblasts, unlike control siRNA.

Human ABCD4 Y482A showed markedly impaired association with LMBD1 in HEK293T co-immunoprecipitation compared with wild-type ABCD4.

Human ABCD4 Y482A coexpressed with LMBD1 in HEK293T cells showed a reticular distribution without normal LAMP1 overlap.

Purified human MMAB uses ATP to adenosylate cob(I)alamin to adenosylcobalamin.

Purified human MTRR coupled cob(II)alamin reduction to MMAB-dependent adenosylcobalamin synthesis in vitro.

Human [2Fe-2S] ferredoxin FDX1 supplied electrons for MMAB-dependent adenosylcobalamin synthesis in the FDXR/NADPH reconstitution.

R186Q human MMAB showed no detectable adenosylcobalamin synthesis with FDX1/FDXR/NADPH, although a strong chemical reductant supported activity.

Purified human MMAA displayed intrinsic GTPase activity modulated by human MMUT.

Human MMAA formed a stable complex preferentially with apo-MMUT and with GMPPNP rather than GDP.

Human MMAA G188R retained basal GTPase activity but lost the detected MMUT interaction.

Adding human MMAA at reaction initiation protected recombinant human MMUT against catalytic inactivation.

Adding MMAA after 60 minutes restored activity in an inactivated human MMUT reaction through GTP hydrolysis.

Adenosylcobalamin-loaded human MMUT converts (R)-methylmalonyl-CoA to succinyl-CoA in the coupled enzyme assay.

The human MMUT-MMAA structure showed MMAA stabilizing a roughly 180-degree rotation that exposed the MMUT B12-binding domain.

A human MMAA/MMAB repair mixture with GTP and ATP transferred cob(II)alamin from MMUT to MMAB in anaerobic spectroscopy.