Methylenetetrahydrofolate reductase / MTHFR

cross_nutrient

B2-FAD, folate and nicotinamide-containing NADPH participate in one reaction.

evidence_location

Results: kinetics, FAD occupancy and SAM inhibition; Table 1; Figs 2-4, 6

experimental_model

Recombinant human MTHFR expressed in Sf9 cells; mass spectrometry, 2.5-A structure, HPLC activity assays.

exposure

Purified-enzyme assay

limitations

Biochemical evidence does not establish a dietary threshold or supplementation benefit.

nutrient_topic

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

organism

Homo sapiens

plain_language

The enzyme makes the methylfolate used in homocysteine recycling.

primary_references

[froese2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition. (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2

tissue_or_cell_type

Purified recombinant enzyme; no intact tissue

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1010–1022

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MTHFR expressed in Sf9 cells; mass spectrometry, 2.5-A structure, HPLC activity assays. · source_derived_draft · unverified_draft

### b2-mthfr-methylfolate-production HPLC assays measured human MTHFR reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate using NADPH. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The enzyme makes the methylfolate used in homocysteine recycling. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Recombinant human MTHFR expressed in Sf9 cells; mass spectrometry, 2.5-A structure, HPLC activity assays. limitations: Biochemical evidence does not establish a dietary threshold or supplementation benefit. exposure: Purified-enzyme assay cross_nutrient: B2-FAD, folate and nicotinamide-containing NADPH participate in one reaction. evidence_location: Results: kinetics, FAD occupancy and SAM inhibition; Table 1; Figs 2-4, 6 [froese2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition. (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2

cross_nutrient

Folate reduction uses nicotinamide reducing equivalents.

experimental_model

Recombinant human MTHFR; kinetics and structures.

limitations

Affinity does not quantify cellular flux.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

MTHFR strongly preferred NADPH in this assay.

primary_references

[froese-2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2

tissue_or_cell_type

Purified protein

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 435–445

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MTHFR; kinetics and structures. · source_derived_draft · unverified_draft

### folate-methyl-nadph-preference Purified full-length human MTHFR had apparent Km values of 35.5 micromolar for NADPH and 3760 micromolar for NADH. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: MTHFR strongly preferred NADPH in this assay. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Recombinant human MTHFR; kinetics and structures. limitations: Affinity does not quantify cellular flux. cross_nutrient: Folate reduction uses nicotinamide reducing equivalents. [froese-2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2

cross_nutrient

B2-FAD supports a folate-processing enzyme.

evidence_location

Results: kinetics, FAD occupancy and SAM inhibition; Table 1; Figs 2-4, 6

experimental_model

Recombinant human MTHFR expressed in Sf9 cells; mass spectrometry, 2.5-A structure, HPLC activity assays.

exposure

Purified-enzyme assay

limitations

Biochemical evidence does not establish a dietary threshold or supplementation benefit.

nutrient_topic

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

organism

Homo sapiens

plain_language

MTHFR carries a B2-derived FAD cofactor.

primary_references

[froese2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition. (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2

tissue_or_cell_type

Purified recombinant enzyme; no intact tissue

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 996–1008

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MTHFR expressed in Sf9 cells; mass spectrometry, 2.5-A structure, HPLC activity assays. · source_derived_draft · unverified_draft

### b2-mthfr-fad-occupancy Native mass spectrometry and crystallography identified FAD bound to recombinant human MTHFR catalytic domains. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: MTHFR carries a B2-derived FAD cofactor. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Recombinant human MTHFR expressed in Sf9 cells; mass spectrometry, 2.5-A structure, HPLC activity assays. limitations: Biochemical evidence does not establish a dietary threshold or supplementation benefit. exposure: Purified-enzyme assay cross_nutrient: B2-FAD supports a folate-processing enzyme. evidence_location: Results: kinetics, FAD occupancy and SAM inhibition; Table 1; Figs 2-4, 6 [froese2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition. (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2

cross_nutrient

Methionine/SAM feedback regulates the B2-dependent folate step.

evidence_location

Results: kinetics, FAD occupancy and SAM inhibition; Table 1; Figs 2-4, 6

experimental_model

Recombinant human MTHFR expressed in Sf9 cells; mass spectrometry, 2.5-A structure, HPLC activity assays.

exposure

Purified-enzyme assay

limitations

In-vitro regulation; phosphorylation itself did not materially reduce catalytic turnover in this assay.

nutrient_topic

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

organism

Homo sapiens

plain_language

A methionine-cycle product regulates methylfolate production.

primary_references

[froese2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition. (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2

tissue_or_cell_type

Purified recombinant enzyme; no intact tissue

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1024–1036

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MTHFR expressed in Sf9 cells; mass spectrometry, 2.5-A structure, HPLC activity assays. · source_derived_draft · unverified_draft

### b2-mthfr-sam-inhibition SAM inhibited recombinant human MTHFR; phosphorylated protein was more sensitive to this inhibition than phosphatase-treated protein. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A methionine-cycle product regulates methylfolate production. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Recombinant human MTHFR expressed in Sf9 cells; mass spectrometry, 2.5-A structure, HPLC activity assays. limitations: In-vitro regulation; phosphorylation itself did not materially reduce catalytic turnover in this assay. exposure: Purified-enzyme assay cross_nutrient: Methionine/SAM feedback regulates the B2-dependent folate step. evidence_location: Results: kinetics, FAD occupancy and SAM inhibition; Table 1; Figs 2-4, 6 [froese2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition. (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2

cross_nutrient

B2-derived FAD affects folate-enzyme stability.

experimental_model

Recombinant human MTHFR; kinetics and structures.

exposure

FAD before versus after heating

limitations

Heat challenge is not physiological riboflavin deficiency.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

Flavin protected the enzyme during heat stress.

primary_references

[froese-2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2

tissue_or_cell_type

Purified protein

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 447–458

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MTHFR; kinetics and structures. · source_derived_draft · unverified_draft

### folate-methyl-fad-heat-protection FAD supplied before a 46 C, five-minute incubation preserved more MTHFR activity than FAD added after heating. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Flavin protected the enzyme during heat stress. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Recombinant human MTHFR; kinetics and structures. limitations: Heat challenge is not physiological riboflavin deficiency. exposure: FAD before versus after heating cross_nutrient: B2-derived FAD affects folate-enzyme stability. [froese-2018] Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition (2018). https://pubmed.ncbi.nlm.nih.gov/29891918/ DOI: 10.1038/s41467-018-04735-2

experimental_model

Recombinant human MTHFR; cryo-EM and biochemistry.

limitations

Does not imply SAH promotes all methyltransferases.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

The SAH-bound structure leaves the catalytic site accessible.

primary_references

[mthfr-allostery-2024] Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase (2024). https://pubmed.ncbi.nlm.nih.gov/38622112/ DOI: 10.1038/s41467-024-47174-y

tissue_or_cell_type

Purified protein

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 471–480

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MTHFR; cryo-EM and biochemistry. · source_derived_draft · unverified_draft

### folate-methyl-sah-active-state Single SAH occupancy accompanied a flexible catalytic domain with an exposed active site in human MTHFR structures. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The SAH-bound structure leaves the catalytic site accessible. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Recombinant human MTHFR; cryo-EM and biochemistry. limitations: Does not imply SAH promotes all methyltransferases. [mthfr-allostery-2024] Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase (2024). https://pubmed.ncbi.nlm.nih.gov/38622112/ DOI: 10.1038/s41467-024-47174-y

experimental_model

Recombinant human MTHFR; cryo-EM and biochemistry.

limitations

Not a whole-body SAM threshold.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

SAM switches MTHFR into a closed shape.

primary_references

[mthfr-allostery-2024] Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase (2024). https://pubmed.ncbi.nlm.nih.gov/38622112/ DOI: 10.1038/s41467-024-47174-y

tissue_or_cell_type

Purified protein

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 460–469

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human MTHFR; cryo-EM and biochemistry. · source_derived_draft · unverified_draft

### folate-methyl-sam-dual-binding Dual SAM binding rearranged the human MTHFR linker and inserted a loop that blocked catalytic substrate access. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: SAM switches MTHFR into a closed shape. organism: Homo sapiens tissue_or_cell_type: Purified protein experimental_model: Recombinant human MTHFR; cryo-EM and biochemistry. limitations: Not a whole-body SAM threshold. [mthfr-allostery-2024] Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase (2024). https://pubmed.ncbi.nlm.nih.gov/38622112/ DOI: 10.1038/s41467-024-47174-y

cross_nutrient

Folate-cycle biomarker response was genotype dependent.

experimental_model

Genotype-stratified randomized trial; 35 TT, 26 CT and 28 CC adults selected, ages 18-65.

exposure

1.6 mg/day riboflavin versus placebo for 12 weeks; experimental regimen.

genotype

MTHFR 677CC or 677CT

limitations

Null findings in modest samples do not prove an effect is impossible; context differs from the TT arm.

nutrient_topic

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

organism

Homo sapiens

plain_language

A better B2 test result did not automatically lower homocysteine in everyone.

primary_references

[b2-mcnulty2006] Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism (2006). https://pubmed.ncbi.nlm.nih.gov/16380544/ DOI: 10.1161/circulationaha.105.580332

tissue_or_cell_type

Human clinical setting

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1500–1512

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Genotype-stratified randomized trial; 35 TT, 26 CT and 28 CC adults selected, ages 18-65. · source_derived_draft · unverified_draft

### b2-cc-ct-homocysteine-nonresponse No homocysteine response was observed in the CC or CT groups despite improved riboflavin-status measures in all genotype groups. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A better B2 test result did not automatically lower homocysteine in everyone. organism: Homo sapiens tissue_or_cell_type: Human clinical setting experimental_model: Genotype-stratified randomized trial; 35 TT, 26 CT and 28 CC adults selected, ages 18-65. limitations: Null findings in modest samples do not prove an effect is impossible; context differs from the TT arm. exposure: 1.6 mg/day riboflavin versus placebo for 12 weeks; experimental regimen. cross_nutrient: Folate-cycle biomarker response was genotype dependent. genotype: MTHFR 677CC or 677CT [b2-mcnulty2006] Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism (2006). https://pubmed.ncbi.nlm.nih.gov/16380544/ DOI: 10.1161/circulationaha.105.580332

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Genetic variation modifies retention of the B2-derived cofactor at a folate enzyme.

evidence_location

Results: FAD loss; Figs 1-3

experimental_model

Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays.

exposure

Purified-enzyme assay

limitations

The diluted purified-protein experiment does not measure intracellular cofactor occupancy in every 677TT carrier.

nutrient_topic

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

organism

Homo sapiens

plain_language

This variant loses its cofactor more readily in the dilution experiment.

primary_references

[yamada2001] Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. (2001). https://pubmed.ncbi.nlm.nih.gov/11742092/ DOI: 10.1073/pnas.261469998

tissue_or_cell_type

Purified recombinant enzyme; no intact tissue

trigger_kind

machinery_impairment Imported condition classification; unverified.

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1038–1050

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays. · source_derived_draft · unverified_draft

### b2-mthfr-ala222val-fad-loss Ala222Val MTHFR released FAD about three times faster than wild type after dilution; concentration dependence supported dimer dissociation before cofactor loss. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: This variant loses its cofactor more readily in the dilution experiment. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays. limitations: The diluted purified-protein experiment does not measure intracellular cofactor occupancy in every 677TT carrier. exposure: Purified-enzyme assay cross_nutrient: Genetic variation modifies retention of the B2-derived cofactor at a folate enzyme. evidence_location: Results: FAD loss; Figs 1-3 [yamada2001] Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. (2001). https://pubmed.ncbi.nlm.nih.gov/11742092/ DOI: 10.1073/pnas.261469998

cross_nutrient

Bounds extrapolation of B2-cofactor loss across MTHFR variants.

evidence_location

Results: FAD loss; Figs 1-3

experimental_model

Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays.

exposure

Purified-enzyme assay

limitations

Normal result under tested in-vitro conditions does not exclude all cellular effects of A1298C.

nutrient_topic

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

organism

Homo sapiens

plain_language

The two common MTHFR variants did not share the same cofactor-retention phenotype.

primary_references

[yamada2001] Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. (2001). https://pubmed.ncbi.nlm.nih.gov/11742092/ DOI: 10.1073/pnas.261469998

tissue_or_cell_type

Purified recombinant enzyme; no intact tissue

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1080–1092

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays. · source_derived_draft · unverified_draft

### b2-mthfr-glu429ala-retention Glu429Ala MTHFR showed FAD-release behavior indistinguishable from wild type under the tested dilution conditions. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The two common MTHFR variants did not share the same cofactor-retention phenotype. organism: Homo sapiens tissue_or_cell_type: Purified recombinant enzyme; no intact tissue experimental_model: Baculovirus-produced purified human wild-type, Ala222Val, Glu429Ala and double-mutant MTHFR; dilution/cofactor-release assays. limitations: Normal result under tested in-vitro conditions does not exclude all cellular effects of A1298C. exposure: Purified-enzyme assay cross_nutrient: Bounds extrapolation of B2-cofactor loss across MTHFR variants. evidence_location: Results: FAD loss; Figs 1-3 [yamada2001] Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. (2001). https://pubmed.ncbi.nlm.nih.gov/11742092/ DOI: 10.1073/pnas.261469998

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Four-year follow-up of 83 prior participants; 31 TT participants underwent repeat intervention with former treatment assignments reversed.

exposure

1.6 mg/day for 16 weeks in 2004 and again in 2008 with reversed allocations; not four years of continuous supplementation.

limitations

Follow-up selection, small TT sample and changing antihypertensive treatment limit inference; overlaps earlier cohort.

nutrient_topic

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

organism

Homo sapiens

plain_language

The earlier participants were studied again; this supports repeat responsiveness but is not an independent population or continuous four-year treatment.

primary_references

[b2-wilson2012] Riboflavin offers a targeted strategy for managing hypertension in patients with the MTHFR 677TT genotype: a 4-y follow-up (2012). https://pubmed.ncbi.nlm.nih.gov/22277556/ DOI: 10.3945/ajcn.111.026245

tissue_or_cell_type

Human clinical setting

trigger_kind

machinery_impairment Imported condition classification; unverified.

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1540–1550

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Four-year follow-up of 83 prior participants; 31 TT participants underwent repeat intervention with former treatment assignments reversed. · source_derived_draft · unverified_draft

### b2-tt-bp-rechallenge A four-year follow-up with reversed intervention assignments in 31 TT participants again reported BP lowering during riboflavin administration. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: The earlier participants were studied again; this supports repeat responsiveness but is not an independent population or continuous four-year treatment. organism: Homo sapiens tissue_or_cell_type: Human clinical setting experimental_model: Four-year follow-up of 83 prior participants; 31 TT participants underwent repeat intervention with former treatment assignments reversed. limitations: Follow-up selection, small TT sample and changing antihypertensive treatment limit inference; overlaps earlier cohort. exposure: 1.6 mg/day for 16 weeks in 2004 and again in 2008 with reversed allocations; not four years of continuous supplementation. [b2-wilson2012] Riboflavin offers a targeted strategy for managing hypertension in patients with the MTHFR 677TT genotype: a 4-y follow-up (2012). https://pubmed.ncbi.nlm.nih.gov/22277556/ DOI: 10.3945/ajcn.111.026245

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Gene-cofactor clinical interaction; mechanism mediation was not demonstrated.

experimental_model

91 hypertensive adults with MTHFR 677TT and no overt cardiovascular disease; randomized trial on usual antihypertensive treatment.

exposure

1.6 mg/day riboflavin versus placebo for 16 weeks; experimental regimen.

limitations

Selected TT population; no proof of universal BP benefit, event reduction or a specific NO/methylation mechanism. Null diastolic endpoint retained.

nutrient_topic

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

organism

Homo sapiens

plain_language

A genotype-targeted trial found a systolic blood-pressure benefit while participants continued their usual medicines.

primary_references

[b2-wilson2013] Blood pressure in treated hypertensive individuals with the MTHFR 677TT genotype is responsive to intervention with riboflavin: findings of a targeted randomized trial (2013). https://pubmed.ncbi.nlm.nih.gov/23608654/ DOI: 10.1161/hypertensionaha.111.01047

tissue_or_cell_type

Human clinical setting

trigger_kind

machinery_impairment Imported condition classification; unverified.

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1527–1538

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · 91 hypertensive adults with MTHFR 677TT and no overt cardiovascular disease; randomized trial on usual antihypertensive treatment. · source_derived_draft · unverified_draft

### b2-tt-bp-trial In hypertensive adults with MTHFR 677TT, the systolic treatment effect was 5.6±2.6 mmHg favoring riboflavin; the diastolic effect was not significant. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A genotype-targeted trial found a systolic blood-pressure benefit while participants continued their usual medicines. organism: Homo sapiens tissue_or_cell_type: Human clinical setting experimental_model: 91 hypertensive adults with MTHFR 677TT and no overt cardiovascular disease; randomized trial on usual antihypertensive treatment. limitations: Selected TT population; no proof of universal BP benefit, event reduction or a specific NO/methylation mechanism. Null diastolic endpoint retained. exposure: 1.6 mg/day riboflavin versus placebo for 16 weeks; experimental regimen. cross_nutrient: Gene-cofactor clinical interaction; mechanism mediation was not demonstrated. [b2-wilson2013] Blood pressure in treated hypertensive individuals with the MTHFR 677TT genotype is responsive to intervention with riboflavin: findings of a targeted randomized trial (2013). https://pubmed.ncbi.nlm.nih.gov/23608654/ DOI: 10.1161/hypertensionaha.111.01047

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

B2 cofactor supply interacts with folate-cycle enzyme genotype.

experimental_model

Genotype-stratified randomized trial; 35 TT, 26 CT and 28 CC adults selected, ages 18-65.

exposure

1.6 mg/day riboflavin versus placebo for 12 weeks; experimental regimen.

genotype

MTHFR 677TT; common variant rather than complete loss of enzyme

limitations

Small genotype strata; subgroup magnitude is not an expected response for every TT carrier. The trial did not test cardiovascular events.

nutrient_topic

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

organism

Homo sapiens

plain_language

In this trial, improving B2 supply lowered a folate-pathway blood marker in people with two copies of the studied MTHFR variant.

primary_references

[b2-mcnulty2006] Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism (2006). https://pubmed.ncbi.nlm.nih.gov/16380544/ DOI: 10.1161/circulationaha.105.580332

tissue_or_cell_type

Human clinical setting

trigger_kind

machinery_impairment Imported condition classification; unverified.

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1486–1498

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Genotype-stratified randomized trial; 35 TT, 26 CT and 28 CC adults selected, ages 18-65. · source_derived_draft · unverified_draft

### b2-tt-homocysteine-response Riboflavin lowered plasma homocysteine in the MTHFR 677TT group by 22% overall; the lower-baseline-B2 subgroup showed a 40% decrease. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: In this trial, improving B2 supply lowered a folate-pathway blood marker in people with two copies of the studied MTHFR variant. organism: Homo sapiens tissue_or_cell_type: Human clinical setting experimental_model: Genotype-stratified randomized trial; 35 TT, 26 CT and 28 CC adults selected, ages 18-65. limitations: Small genotype strata; subgroup magnitude is not an expected response for every TT carrier. The trial did not test cardiovascular events. exposure: 1.6 mg/day riboflavin versus placebo for 12 weeks; experimental regimen. cross_nutrient: B2 cofactor supply interacts with folate-cycle enzyme genotype. genotype: MTHFR 677TT; common variant rather than complete loss of enzyme [b2-mcnulty2006] Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism (2006). https://pubmed.ncbi.nlm.nih.gov/16380544/ DOI: 10.1161/circulationaha.105.580332

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

B2/MTHFR connects folate-dependent remethylation with methionine-cycle biomarkers.

experimental_model

Archived samples from prior BP trials: 115 genotype-characterized adults; TT intervention subset 24 riboflavin and 23 placebo.

exposure

1.6 mg/day riboflavin or placebo for 16 weeks; LC-MS/MS plasma metabolites; secondary analysis, not a new independent trial.

limitations

Secondary sample analysis of prior BP trials; plasma SAM is not tissue SAM flux, DNA methylation, epigenetic silencing or a proved mediator of BP.

nutrient_topic

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

organism

Homo sapiens

plain_language

B2 changed selected circulating methylation-related metabolites; the study did not show that every tissue had been short of methyl groups.

primary_references

[b2-robinson2020] Impact of the MTHFR C677T polymorphism on one-carbon metabolites: Evidence from a randomised trial of riboflavin supplementation (2020). https://pubmed.ncbi.nlm.nih.gov/32330571/ DOI: 10.1016/j.biochi.2020.04.004

tissue_or_cell_type

Human clinical setting

trigger_kind

machinery_impairment Imported condition classification; unverified.

Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1514–1525

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Archived samples from prior BP trials: 115 genotype-characterized adults; TT intervention subset 24 riboflavin and 23 placebo. · source_derived_draft · unverified_draft

### b2-tt-plasma-sam-response In the 47-person TT intervention subset, riboflavin increased plasma SAM and cystathionine; no response was detected in the other measured one-carbon metabolites. Condition category: machinery_impairment nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: B2 changed selected circulating methylation-related metabolites; the study did not show that every tissue had been short of methyl groups. organism: Homo sapiens tissue_or_cell_type: Human clinical setting experimental_model: Archived samples from prior BP trials: 115 genotype-characterized adults; TT intervention subset 24 riboflavin and 23 placebo. limitations: Secondary sample analysis of prior BP trials; plasma SAM is not tissue SAM flux, DNA methylation, epigenetic silencing or a proved mediator of BP. exposure: 1.6 mg/day riboflavin or placebo for 16 weeks; LC-MS/MS plasma metabolites; secondary analysis, not a new independent trial. cross_nutrient: B2/MTHFR connects folate-dependent remethylation with methionine-cycle biomarkers. [b2-robinson2020] Impact of the MTHFR C677T polymorphism on one-carbon metabolites: Evidence from a randomised trial of riboflavin supplementation (2020). https://pubmed.ncbi.nlm.nih.gov/32330571/ DOI: 10.1016/j.biochi.2020.04.004