Folate Metabolism
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Folate Metabolism
Folate metabolism is a network of biochemical reactions that transfers single-carbon units between molecules and connects nutrition with nucleotide synthesis, amino-acid metabolism, methylation, cellular redox balance, development, and disease. Folates function primarily through derivatives of tetrahydrofolate that carry one-carbon groups in different oxidation states. These reactions form the folate-dependent component of one-carbon metabolism and are closely linked with the methionine cycle, homocysteine metabolism, transsulfuration, and the metabolism of serine and glycine.
Folate metabolism is distributed among the cytoplasm, mitochondria, and nucleus. These interconnected compartments provide one-carbon units for purine and thymidylate synthesis, methionine regeneration, production of methyl donors, and maintenance of cellular metabolic balance. Because these processes are required for DNA synthesis and repair, gene regulation, cell division, and development, disturbances in folate availability or metabolism can have effects throughout the body.
Folate and One-Carbon Metabolism
Tetrahydrofolate and its derivatives act as carriers of one-carbon units derived from nutrients and amino acids. Serine and glycine are major contributors to this pool. Enzymes including serine hydroxymethyltransferases and members of the MTHFD enzyme family transfer and interconvert folate-bound carbon units, allowing them to be directed toward different metabolic needs.
One major destination is de novo nucleotide synthesis. 10-formyltetrahydrofolate contributes carbon atoms to purine synthesis, while 5,10-methylenetetrahydrofolate supplies the carbon used to produce thymidylate. Adequate folate metabolism is therefore closely connected with DNA replication and genome integrity. Folate deficiency can disturb nucleotide balance, promote inappropriate incorporation of uracil into DNA, and increase chromosome damage.
Mitochondrial folate metabolism is an important source of one-carbon units that can be exported as formate for use by cytosolic biosynthetic pathways. Cells can alter the direction and distribution of one-carbon flux when mitochondrial or cytosolic pathways are disrupted, illustrating the metabolic flexibility of the folate system.
Methionine, Homocysteine and Methylation
Folate metabolism is linked to the methionine cycle through 5-methyltetrahydrofolate. This folate form supplies a methyl group for remethylation of homocysteine to methionine, a reaction that also depends on vitamin B12.
Methionine is subsequently used to produce S-adenosylmethionine, a major cellular methyl donor. S-adenosylmethionine supports methylation of DNA, histones, proteins, lipids, and other molecules. Folate status can therefore influence epigenetic regulation by affecting the availability of methyl groups.
Folate, vitamin B12, choline, betaine, vitamin B6, riboflavin, methionine, and homocysteine participate in interconnected metabolic pathways. Deficiency or disruption of one component may consequently alter other parts of the one-carbon network. Vitamin B12 deficiency, for example, can impair normal folate utilization through the biochemical process often described as the methyl-folate trap.
Folate Transport and Cellular Retention
Dietary folates must be absorbed, transported into tissues, taken up by cells, and retained in metabolically useful forms. Important transport systems include the reduced folate carrier encoded by SLC19A1 and the proton-coupled folate transporter encoded by SLC46A1. Folate receptors provide additional mechanisms for cellular uptake in particular tissues.
The proton-coupled folate transporter has an important role in intestinal absorption and in supplying folate to the central nervous system. Severe disruption of this transporter can cause hereditary folate malabsorption and deficiencies affecting both systemic and cerebral folate availability.
Inside cells, folates can be converted to polyglutamated forms. Folylpolyglutamate synthetase adds glutamate residues, helping retain folates within cells and increasing their suitability as substrates for many folate-dependent enzymes. Gamma-glutamyl hydrolase performs the opposing reaction. The balance between these processes influences intracellular folate pools and responses to antifolate drugs.
Genetics of Folate Metabolism
Genetic variation contributes substantially to differences in folate metabolism among individuals. One of the most extensively studied genes is MTHFR, which encodes methylenetetrahydrofolate reductase. This enzyme produces 5-methyltetrahydrofolate and helps determine how folate-derived carbon is distributed between nucleotide synthesis and methionine regeneration.
Common MTHFR variants can influence blood folate concentrations, homocysteine levels, responses to folic-acid intake, and the activity of the broader one-carbon pathway. MTHFR also requires the riboflavin-derived cofactor FAD, creating an additional interaction between folate and vitamin B2 metabolism.
Variation in other genes—including MTR, MTRR, MTHFD1, SHMT1, SLC19A1, FPGS, and GGH—can also affect folate transport, methyl metabolism, intracellular folate retention, and responses to antifolate medications. Research increasingly treats folate metabolism as a multigene network rather than a pathway controlled by a single variant.
Rare inherited disorders can produce much more severe metabolic disturbances. Defects affecting MTHFR, methionine synthase, methionine synthase reductase, folate transporters, folate receptors, and other components of remethylation metabolism can cause neurological, developmental, hematological, or systemic disease.
Nutrition, Bioavailability and Folate Status
Folate status depends on dietary intake, the chemical form of folate consumed, intestinal absorption, genetics, nutritional status, and other physiological factors. Natural food folates and synthetic folic acid differ in bioavailability, leading to the use of dietary folate equivalents when estimating intake.
Serum folate reflects relatively recent intake, while red-blood-cell folate provides information about longer-term folate status. Homocysteine can also respond to folate availability, although it is influenced by several other nutrients and metabolic factors.
Folic-acid fortification has substantially increased population folate concentrations in countries where it has been implemented and has generally lowered circulating homocysteine. Population studies and laboratory methods for serum and red-cell folate are therefore important components of nutritional surveillance.
The intestinal microbiome provides another potential connection between nutrition and folate metabolism. Some microorganisms synthesize folates while others consume them. Research into probiotic and other folate-producing bacteria is examining whether microbial folate production can contribute meaningfully to host nutrition and one-carbon metabolism.
Pregnancy, Development and Neural-Tube Defects
Folate metabolism is particularly important during periods of rapid cell division and development. Maternal folate and related one-carbon nutrients contribute to nucleotide synthesis, methylation, placental function, fetal growth, and developmental programming.
A major public-health application is the prevention of neural-tube defects. Randomized trials and large population studies have demonstrated that folic-acid supplementation around conception can substantially reduce the occurrence or recurrence of neural-tube defects. These findings led to recommendations for periconceptional supplementation and, in many countries, folic-acid food fortification.
The biological mechanisms underlying neural-tube-defect prevention are complex. Research implicates nucleotide synthesis, methylation, folate transport, homocysteine metabolism, genetic variation, and interactions among multiple nutrients. Folate-receptor autoantibodies have also been investigated because they can interfere with folate binding and uptake.
Folate metabolism has broader associations with fertility, implantation, placental development, fetal growth, congenital abnormalities, and early brain development. Studies therefore increasingly examine the entire maternal one-carbon metabolic network rather than folate intake alone.
Brain Function and Cerebral Folate
The nervous system depends on effective folate transport and one-carbon metabolism. Folate-dependent pathways contribute to methylation, nucleotide metabolism, redox regulation, and other processes required for neuronal maintenance and development.
Cerebral folate deficiency can occur even when systemic folate status is less severely affected. Causes described in the literature include abnormalities of folate transport, folate-receptor autoantibodies, inherited metabolic disorders, and mitochondrial disease. Because folate must cross specialized biological barriers to reach the brain, disruption of transport mechanisms can have important neurological consequences.
Folate receptor-alpha autoantibodies have received particular attention because they may interfere with placental or cerebral folate transport. Research has explored their possible relationship with cerebral folate deficiency and some neurodevelopmental conditions, including autism spectrum disorders.
One-carbon metabolism is also being studied in brain aging and neurodegenerative disease. Folate, vitamin B12, choline, methionine metabolism, mitochondrial function, DNA repair, methylation, oxidative balance, and homocysteine form an interconnected network that may influence neurological health across the lifespan.
Folate Metabolism in Cancer
Cancer cells frequently alter one-carbon metabolism to support rapid proliferation. Folate pathways provide carbon units required for purine and thymidylate production while also contributing to methylation and redox regulation. Serine and glycine metabolism can therefore become closely coupled to the metabolic demands of tumor growth.
Mitochondrial enzymes such as MTHFD2 are frequently studied in cancer because they can support nucleotide synthesis, NADPH generation, redox control, and other processes associated with proliferating cells. Research has identified elevated or altered MTHFD2 activity in multiple tumor types and has investigated both its conventional metabolic functions and additional regulatory roles.
Folate receptor alpha is another major area of cancer research. Its elevated expression in some tumors, particularly certain ovarian cancers, makes it useful as a biomarker and as a route for selective drug delivery. Antibodies, antibody-drug conjugates, and other folate-receptor-targeted approaches are being developed to exploit differences between tumor and normal tissues.
The relationship between folate and cancer is therefore multifaceted. Folate is necessary for normal genome maintenance, but rapidly proliferating cancer cells can also depend heavily on folate-dependent reactions. This metabolic dependence has made the pathway an important therapeutic target.
Antifolate Drugs and Therapeutic Targeting
Antifolate drugs interfere with folate-dependent reactions and represent one of the oldest examples of targeting cellular metabolism therapeutically. Methotrexate, pemetrexed, and related compounds affect enzymes and pathways needed for nucleotide production and other folate-dependent processes.
Methotrexate is used in both cancer and inflammatory disease. Its effects extend beyond simple inhibition of dihydrofolate reductase and can involve purine metabolism, methylation pathways, oxidative balance, and inflammatory signaling. In rheumatoid arthritis, folic or folinic acid supplementation is commonly studied as a method for reducing treatment-related adverse effects.
Pemetrexed interacts with folate transport systems and inhibits enzymes involved in thymidylate and purine synthesis. Cellular uptake, polyglutamation, folate availability, and transporter expression can influence its activity.
Resistance to antifolate therapy can arise through altered drug transport, changes in target enzymes, altered polyglutamation, drug efflux, or restructuring of intracellular folate pools. Modern research is also investigating newer approaches that directly target enzymes such as SHMT and MTHFD2 or selectively deliver drugs through folate receptors.
Folate Metabolism in Systemic Health
The effects of folate-dependent one-carbon metabolism extend beyond development and cancer. Research has examined relationships with cardiovascular disease, blood pressure, diabetes, fatty liver disease, immune-cell function, and inflammatory processes.
Homocysteine metabolism has long provided a connection between folate status and cardiovascular research. Genetic variation in MTHFR, interactions with riboflavin, and other nutritional factors may modify this relationship.
In metabolic liver disease, folate-dependent methyl metabolism intersects with phospholipid synthesis and lipid handling. In immune cells, folate availability and receptor signaling may influence proliferation, differentiation, antimicrobial activity, and inflammatory responses. These findings emphasize that folate metabolism operates as part of a larger metabolic network rather than as an isolated vitamin pathway.
Conclusion
Folate metabolism links dietary nutrients with some of the most fundamental processes in cell biology. Through one-carbon metabolism, folate contributes to purine and thymidylate synthesis, methionine regeneration, S-adenosylmethionine production, methylation, amino-acid metabolism, redox regulation, and genome maintenance.
The pathway is shaped by diet, intestinal absorption, cellular transport, compartmentalized metabolism, genetic variation, interactions with other B vitamins, and microbial activity. Its importance is especially apparent during pregnancy and development, but disruptions can also affect neurological function, metabolic health, immune processes, and inherited disease.
Folate metabolism also illustrates the close relationship between normal physiology and therapeutic intervention. The same pathways that allow healthy cells to grow and maintain DNA can be exploited by rapidly proliferating tumors, while antifolate drugs and folate-receptor-targeted therapies deliberately manipulate these dependencies. Research on folate metabolism therefore spans nutrition, genetics, developmental biology, neuroscience, cancer biology, pharmacology, and public health.
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Core Folate and One-Carbon Metabolism
Influence of Nutrients Involved in One-Carbon Metabolism on DNA Methylation in Adults
| Multiple authors | Nutrition Reviews | 2020
Systematically examines evidence that folate and related one-carbon nutrients influence global and locus-specific DNA methylation in adults.
One-Carbon Metabolism in Health and Disease
| Gregory S. Ducker and Joshua D. Rabinowitz | Cell Metabolism | 2017
Provides a major overview of compartmentalized mammalian folate metabolism and its roles in purine synthesis, thymidylate production, methylation, amino-acid homeostasis, and redox defense.
Genetic and Epigenetic Contributions to Human Nutrition and Health: Managing Genome–Diet Interactions
| Multiple authors | Journal of Nutrition | 2017
Discusses folate metabolism as a biochemical link between dietary nutrients, nucleotide synthesis, S-adenosylmethionine production, DNA methylation, and genome regulation.
Mammals Divert Endogenous Genotoxic Formaldehyde Into One-Carbon Metabolism
| Guillermo Burgos-Barragan et al. | Nature | 2017
Demonstrates that detoxification of endogenous formaldehyde generates formate that can enter folate-dependent one-carbon metabolism and support nucleotide production.
Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway
| Gregory S. Ducker et al. | Cell Metabolism | 2016
Uses metabolic tracing and genetic manipulation to show how cells can reverse cytosolic folate-cycle flux when mitochondrial one-carbon production is disrupted.
One Carbon Metabolism and Epigenetics: Understanding the Specificity
| Samantha J. Mentch and Jason W. Locasale | Annals of the New York Academy of Sciences | 2016
Explains how folate and methionine metabolism regulate S-adenosylmethionine availability and thereby link nutritional status with DNA and histone methylation.
Epigenetics and Cellular Metabolism
| Multiple authors | Cell Metabolism | 2016
Reviews how folate, methionine, choline, and related nutrients regulate cellular methyl-donor production and epigenetic modifications.
Division of Labour: How Does Folate Metabolism Partition Between One-Carbon Metabolism and Amino Acid Oxidation?
| Multiple authors | Biochemical Journal | 2015
Explores how folate cofactors distribute one-carbon units among nucleotide synthesis, methylation, amino-acid oxidation, and NADPH generation.
The Folate-Coupled Enzyme MTHFD2 Is a Nuclear Protein and Promotes Cell Proliferation
| Multiple authors | Scientific Reports | 2015
Reports nuclear localization of MTHFD2 and suggests functions related to DNA replication and proliferation in addition to mitochondrial one-carbon metabolism.
Folate and DNA Methylation: A Review of Molecular Mechanisms and the Evidence for Folate's Role
| Krista S. Crider et al. | Advances in Nutrition | 2012
Reviews how folate supplies one-carbon groups for S-adenosylmethionine production and examines evidence linking folate status with DNA methylation.
Mthfs Is an Essential Gene in Mice and a Component of the Purinosome
| Multiple authors | Frontiers in Genetics | 2012
Shows that methenyltetrahydrofolate synthetase mobilizes 5-formyl-THF into active folate pools and associates with the cellular purine-synthesis machinery.
One-Carbon Metabolism–Genome Interactions in Folate-Associated Pathologies
| Multiple authors | Journal of Nutrition | 2009
Reviews reciprocal interactions between folate-dependent metabolism and the genome, including DNA synthesis, chromatin methylation, gene variants, and folate-responsive diseases.
Folate-Mediated One-Carbon Metabolism
| Patrick J. Stover and colleagues | Vitamins and Hormones | 2008
Reviews cytoplasmic, mitochondrial, and nuclear folate pathways involved in purine synthesis, thymidylate synthesis, homocysteine remethylation, and amino-acid metabolism.
Folate Deficiency Causes Uracil Misincorporation into Human DNA and Chromosome Breakage
| Bruce N. Ames and colleagues | Proceedings of the National Academy of Sciences | 1997
Demonstrates that folate deficiency disrupts thymidylate synthesis, increases uracil incorporation into DNA, and promotes chromosome breakage.
Correction of the DNA Synthesis Defect in Vitamin B12 Deficiency by Tetrahydrofolate
| Multiple authors | British Journal of Haematology | 1993
Tests mechanisms underlying defective folate utilization in vitamin B12 deficiency and provides evidence supporting the methyl-folate-trap hypothesis.
Characterization of the Folate-Dependent Mitochondrial Oxidation of Carbon 3 of Serine
| Multiple authors | Archives of Biochemistry and Biophysics | 1993
Characterizes mitochondrial conversion of serine-derived carbon into formate or carbon dioxide and its dependence on reduced folate cofactors.
In Vitro Evidence for the Involvement of Mitochondrial Folate Metabolism in the Supply of Cytoplasmic One-Carbon Units
| C. K. Barlowe and D. R. Appling | BioFactors | 1988
Provides early experimental evidence that mitochondria convert serine-derived one-carbon units to formate for export and cytosolic purine synthesis.
Vitamin B12-Folate Interrelationships
| B. Shane and E. L. Stokstad | Annual Review of Nutrition | 1985
Reviews the biochemical interdependence of cobalamin and folate and explains the methyl-folate-trap model of functional folate deficiency.
Genetics, MTHFR and Inherited Folate Disorders
5,10-Methylenetetrahydrofolate Reductase—The Key Allosteric Regulator in One-Carbon Metabolism
| Linnea K. M. Blomgren et al. | Biochemistry | 2026
Reviews MTHFR catalytic activity, evolutionary conservation, FAD dependence, and feedback regulation by S-adenosylmethionine, explaining how the enzyme directs folate-derived carbon toward methionine and methyl-donor synthesis.
First Revision of the Guidelines for the Diagnosis and Management of Remethylation Disorders
| Giorgia Olivieri et al. | Journal of Inherited Metabolic Disease | 2026
Provides updated guidance on inherited disorders affecting folate- and cobalamin-dependent remethylation, including severe MTHFR, MTR, and MTRR deficiencies.
MTHFR Gene Polymorphisms: A Single Gene with Wide-Ranging Clinical Implications—A Review
| Multiple authors | Review | 2025
Summarizes how common MTHFR variants alter production of 5-methyltetrahydrofolate, homocysteine remethylation, folate-cycle function, and susceptibility to numerous metabolic and developmental conditions.
Dynamic Inter-Domain Transformations Mediate the Allosteric Regulation of Human 5,10-Methylenetetrahydrofolate Reductase
| Linnea K. M. Blomgren et al. | Nature Communications | 2024
Uses structural analysis to show how SAM binding reorganizes human MTHFR and blocks its catalytic site, providing a molecular explanation for feedback control of one-carbon metabolism.
Hereditary Folate Malabsorption Presenting as Neutropenic Fever in a Newborn With a Novel SLC46A1 Mutation
| Fajr M. A. Sarhan et al. | Annals of Medicine and Surgery | 2022
Illustrates hematological, immune, and gastrointestinal consequences of defective proton-coupled folate transport during infancy.
A Deep Intronic Mutation in SLC46A1 Shared by Four Unrelated Japanese Patients With Hereditary Folate Malabsorption
| Multiple authors | Molecular Genetics and Metabolism | 2019
Identifies a recurrent splicing mutation that disrupts PCFT production and causes severe systemic and cerebral folate deficiency.
Hereditary Folate Malabsorption Due to a Mutation in the External Gate of the Proton-Coupled Folate Transporter SLC46A1
| Multiple authors | Journal of Biological Chemistry | 2018
Characterizes a disease-causing PCFT mutation and provides mechanistic insight into transporter gating and folate-substrate affinity.
Genetic Polymorphisms and Folate Status
| Multiple authors | Congenital Anomalies | 2017
Reviews how MTHFR and other folate-pathway polymorphisms affect circulating folate, homocysteine, folic-acid responses, and nutrient-gene interactions.
The Proton-Coupled Folate Transporter and Hereditary Folate Malabsorption
| Rongbao Zhao et al. | Molecular Aspects of Medicine | 2017
Reviews SLC46A1-mediated intestinal and brain folate transport and explains how loss of transporter function causes systemic and cerebral folate deficiency.
The Impact of MTHFR 677 C/T Genotypes on Folate Status Markers
| Natalie J. Colson et al. | European Journal of Nutrition | 2017
Meta-analyzes folic-acid intervention studies to determine how the MTHFR C677T genotype changes serum folate, homocysteine, and supplementation responses.
Hereditary Folate Malabsorption With a Novel Mutation on SLC46A1
| Jianmin Tan et al. | Medicine | 2017
Reports an SLC46A1 mutation causing severe impairment of intestinal and cerebral folate transport with response to folinic acid.
Common Polymorphisms That Affect Folate Transport or Metabolism Modify the Effect of the MTHFR 677C>T Polymorphism on Folate Status
| Multiple authors | Journal of Nutrition | 2016
Shows that folate status reflects interactions among multiple pathway variants rather than the MTHFR C677T genotype acting in isolation.
Assessing the Association Between MTHFR 677C>T and Blood Folate Concentrations
| Multiple authors | American Journal of Clinical Nutrition | 2015
Systematically reviews differences in serum, plasma, and red-blood-cell folate according to MTHFR C677T genotype.
Folate: Metabolism, Genes, Polymorphisms and the Associated Diseases
| Faakhra Nazki et al. | Gene | 2014
Reviews folate metabolism and genetic polymorphisms affecting DNA synthesis, methylation, homocysteine handling, and disease susceptibility.
Survival and Psychomotor Development With Early Betaine Treatment in Patients With Severe Methylenetetrahydrofolate Reductase Deficiency
| Eugene F. Diekman et al. | JAMA Neurology | 2014
Finds markedly better survival and neurological development when severe MTHFR deficiency is recognized and treated with betaine early in life.
Polymorphisms in 1-Carbon Metabolism, Epigenetics and Folate-Related Pathologies
| Multiple authors | Review | 2013
Examines how folate-pathway genetic variation interacts with nutrition to influence DNA synthesis, chromatin methylation, and disease risk.
Update and New Concepts in Vitamin-Responsive Disorders of Folate Transport and Metabolism
| Multiple authors | Journal of Inherited Metabolic Disease | 2012
Reviews SLC46A1, FTCD, MTHFR, MTR, MTRR, FOLR1, and DHFR deficiencies as vitamin-responsive inborn errors affecting folate biology.
Genetic Variation: Impact on Folate and Choline Bioefficacy
| Multiple authors | International Journal for Vitamin and Nutrition Research | 2011
Reviews how common variants in folate- and choline-metabolizing genes influence nutrient status, homocysteine, and individual responses to dietary intake.
Isolated Remethylation Disorders: Do Our Treatments Benefit Patients?
| Multiple authors | Journal of Inherited Metabolic Disease | 2010
Reviews folate- and cobalamin-dependent remethylation disorders and evaluates folate, betaine, methionine, and cobalamin treatment strategies.
Investigation of Inter-Individual Variability of the One-Carbon Folate Pathway: A Bioinformatic and Genetic Review
| Multiple authors | Pharmacogenomics Journal | 2009
Catalogs genetic variation across enzymes, transporters, and receptors of the folate pathway and discusses consequences for disease and drug responses.
[6S]-5-Methyltetrahydrofolate Increases Plasma Folate More Effectively Than Folic Acid in Women With MTHFR 677C>T Genotypes
| Multiple authors | British Journal of Pharmacology | 2009
Compares plasma responses to 5-MTHF and folic acid in women with differing MTHFR C677T genotypes.
Large-Scale Population-Based Metabolic Phenotyping of Thirteen Genetic Polymorphisms Related to One-Carbon Metabolism
| Åse Fredriksen et al. | Human Mutation | 2007
Examines more than 10,000 individuals to connect common MTHFR, MTR, MTRR, MTHFD1, BHMT, SLC19A1, and related variants with one-carbon metabolites.
Polymorphic Background of Methionine Synthase Reductase Modulates the Phenotype of a Disease-Causing Mutation
| Carmen Gherasim et al. | Human Mutation | 2007
Demonstrates that common MTRR polymorphisms can influence the biochemical effect of a pathogenic mutation affecting methionine synthase reactivation.
Pharmacokinetic Study on the Utilisation of 5-Methyltetrahydrofolate and Folic Acid in Patients With Coronary Artery Disease
| Multiple authors | British Journal of Pharmacology | 2004
Compares folic acid with direct 5-MTHF administration in individuals with MTHFR 677TT and reports differences in circulating folate pharmacokinetics.
Effect of Riboflavin Status on the Homocysteine-Lowering Effect of Folate in Relation to the MTHFR C677T Genotype
| Multiple authors | Clinical Chemistry | 2003
Demonstrates metabolic interaction between riboflavin and folate in homocysteine regulation because MTHFR requires the riboflavin-derived cofactor FAD.
Methylenetetrahydrofolate Reductase: A Common Human Polymorphism and Its Biochemical Implications
| Rowena G. Matthews | The Chemical Record | 2002
Explains the biochemistry of MTHFR and how common genetic variation changes folate partitioning between methionine regeneration and nucleotide synthesis.
Hereditary Folate Malabsorption: Family Report and Review of the Literature
| James Geller et al. | Medicine | 2002
Reviews systemic and neurological manifestations of inherited folate malabsorption and the biochemical basis for high-dose reduced-folate treatment.
The Methionine Synthase Reductase MTRR A66G Polymorphism Is a Novel Genetic Determinant of Plasma Homocysteine Concentrations
| Multiple authors | Atherosclerosis | 2001
Investigates how variation in MTRR, which regenerates active methionine synthase, influences homocysteine within folate-dependent remethylation metabolism.
A Common Polymorphism in Methionine Synthase Reductase Increases Risk of Premature Coronary Artery Disease
| C. A. Brown et al. | European Journal of Cardiovascular Prevention & Rehabilitation | 2000
Studies MTRR genetic variation and its relationship with folate-dependent methionine regeneration, homocysteine metabolism, and coronary disease.
Polymorphisms of Methylenetetrahydrofolate Reductase and Other Enzymes: Metabolic Significance, Risks and Impact on Folate Requirement
| Multiple authors | Journal of Nutrition | 1999
Reviews metabolic consequences of the MTHFR C677T polymorphism and considers how genotype may alter folate requirements and disease susceptibility.
Folate Transport, Receptors and Cellular Retention
Folate Receptor-β in Activated Macrophages: Ligand Binding and Receptor Recycling Kinetics
| Multiple authors | Molecular Pharmaceutics | 2014
Characterizes folate-receptor-beta binding, internalization, and recycling in activated macrophages, relevant to cellular folate uptake and targeted delivery.
Molecular Mechanisms of Adaptation to Folate Deficiency
| Multiple authors | Vitamins and Hormones | 2008
Reviews cellular adaptations involving DHFR, thymidylate synthase, FPGS, reduced folate carrier, PCFT, folate receptors, and ABC efflux transporters.
Enzymatic Synthesis and Function of Folylpolyglutamates
| Multiple authors | Molecular and Cellular Biochemistry | 1981
Reviews synthesis of folate polyglutamates and their functions in intracellular folate retention and as preferred cofactors for many folate-dependent enzymes.
Nutrition, Bioavailability, Fortification and Biomarkers
Pharmacokinetics of (6S)-5-Methyltetrahydrofolate Dicholine Salt Compared to Folic Acid
| Christiane Schön et al. | Food & Nutrition Research | 2025
Reports a randomized crossover study comparing absorption and plasma kinetics of a methylfolate salt with conventional folic acid.
How Food Matrices Modulate Folate Bioaccessibility: A Comprehensive Overview of Recent Advances and Challenges
| Fengyuan Liu et al. | Comprehensive Reviews in Food Science and Food Safety | 2024
Reviews how digestion, food structure, folate stability, and folate conjugase activity determine the fraction of dietary folate available for absorption.
The Evolution of Folate Supplementation—From One Size for All to Personalized, Precision, Poly-Paths
| Multiple authors | Nutrients | 2023
Discusses differences between folic acid and 5-MTHF and how transporter and metabolic genetics could support more individualized folate supplementation.
The Bioavailability of Various Oral Forms of Folate Supplementation in Healthy Populations and Animal Models
| Multiple authors | Advances in Nutrition | 2018
Systematically reviews comparative absorption and bioavailability studies involving folic acid, 5-MTHF, folinic acid, and other supplemental folate forms.
Folates: Chemistry, Analysis, Occurrence, Biofortification and Bioavailability
| Multiple authors | Food Chemistry | 2017
Reviews folate chemistry, biosynthesis, degradation, analytical measurement, food sources, crop engineering, and factors governing human bioavailability.
Biomarkers of Nutrition for Development—Folate Review
| Multiple authors | Journal of Nutrition | 2015
Provides a comprehensive review of folate biology, metabolism, serum folate, red-blood-cell folate, homocysteine, analytical methods, deficiency, and population assessment.
Contemporary Issues Surrounding Folic Acid Fortification Initiatives
| Multiple authors | Preventive Nutrition and Food Science | 2015
Reviews benefits and unresolved questions surrounding high folic-acid exposure, unmetabolized folic acid, vitamin B12 deficiency, and epigenetic effects.
The Effect of Folate Fortification on Folic Acid-Based Homocysteine-Lowering Intervention and Stroke Risk
| Multiple authors | Public Health Nutrition | 2014
Meta-analyzes trials to examine whether background folic-acid fortification modifies homocysteine reduction and potential stroke-prevention effects.
Exposure to Solar Ultraviolet Radiation Is Associated With a Decreased Folate Status in Women of Childbearing Age
| D. Borradale et al. | Journal of Photochemistry and Photobiology B | 2014
Reports an inverse association between measured personal UV exposure and serum folate following folic-acid supplementation.
Folate Bioavailability: Implications for Establishing Dietary Recommendations and Optimizing Status
| Multiple authors | American Journal of Clinical Nutrition | 2010
Reviews dietary and host factors controlling the absorption and biological utilization of natural food folates and synthetic folic acid.
Bioavailability and Bioefficacy of Folate and Folic Acid in Man
| Multiple authors | Proceedings of the Nutrition Society | 2009
Reviews food matrix, chemical folate forms, dosage, genetics, nutritional status, and gastrointestinal factors that determine folate bioavailability.
Folic Acid Metabolism in Human Subjects Revisited
| Multiple authors | British Journal of Nutrition | 2007
Re-examines where synthetic folic acid is reduced and methylated in humans and discusses limitations imposed by relatively low human DHFR activity.
Cellular Folate Vitamer Distribution During and After Correction of Vitamin B12 Deficiency
| Y. M. Smulders et al. | British Journal of Haematology | 2006
Examines intracellular folate forms during vitamin B12 deficiency and provides biochemical evidence for trapping of folate as 5-methyltetrahydrofolate.
[6S]5-Methyltetrahydrofolate or Folic Acid Supplementation and Absorption and Initial Elimination of Folate in Young and Middle-Aged Adults
| Multiple authors | European Journal of Clinical Nutrition | 2005
Uses isotope kinetics to investigate age-related differences in folic-acid absorption and folate turnover after supplementation.
Quantifying Folate Bioavailability: A Critical Appraisal of Methods
| Alida Melse-Boonstra et al. | Current Opinion in Clinical Nutrition and Metabolic Care | 2004
Reviews experimental methods for measuring folate absorption and bioavailability, including stable-isotope approaches.
The Short-Term Bioavailabilities of [6S]-5-Methyltetrahydrofolate and Folic Acid Are Equivalent in Men
| Kristina Pentieva et al. | Journal of Nutrition | 2004
Compares plasma folate responses after equivalent oral doses of natural 5-MTHF and synthetic folic acid.
Folic Acid Fortification, Folate Status and Plasma Homocysteine
| Jeanne I. Rader | Journal of Nutrition | 2002
Reviews population evidence showing how food fortification changed folate status and homocysteine concentrations.
Consumption of the Folate Breakdown Product Para-Aminobenzoylglutamate Contributes Minimally to Urinary Folate Catabolite Excretion in Humans
| Marie A. Caudill et al. | Journal of Nutrition | 2002
Uses isotope labeling to distinguish dietary intake of a folate catabolite from endogenous folate turnover.
Dietary Folate Equivalents: Interpretation and Application
| C. W. Suitor and L. B. Bailey | Journal of the American Dietetic Association | 2000
Explains dietary folate equivalents and the different bioavailability of natural food folate and folic acid used in fortified foods.
The Effect of Folic Acid Fortification on Plasma Folate and Total Homocysteine Concentrations
| Multiple authors | New England Journal of Medicine | 1999
Reports large increases in circulating folate and decreases in homocysteine after implementation of folic-acid fortification in the United States.
Pregnancy, Reproduction, Development and Neural-Tube Defects
Serum Folate Concentration Corresponding to the Red Blood Cell Folate Threshold for Increased Risk of Neural Tube Defects Among Ethiopian Women of Reproductive Age
| Multiple authors | Nutrition Research | 2025
Examines the relationship between serum folate and red-blood-cell folate concentrations to improve population assessment of folate sufficiency for neural-tube-defect prevention.
Estimating the Serum Folate Concentration that Corresponds to the Red Blood Cell Folate Threshold Associated with Optimal Neural Tube Defect Prevention
| Multiple authors | American Journal of Clinical Nutrition | 2023
Uses population biomarker data from southern India to relate serum folate concentrations to red-blood-cell folate thresholds used for neural-tube-defect prevention.
Influence of Maternal One Carbon Metabolites on Placental Programming and Long Term Health
| Multiple authors | Review | 2022
Discusses how maternal folate, vitamin B12, and other one-carbon nutrients can influence placental gene regulation, fetal development, DNA methylation, and later-life health.
Periconceptional Folic Acid Use Prevents Both Rare and Common Neural Tube Defects in China
| Multiple authors | Birth Defects Research | 2022
Analyzes a large Chinese pregnancy cohort and shows preventive effects of folic acid across several neural-tube-defect subtypes.
One Carbon Metabolism and Early Development: A Diet-Dependent Destiny
| Multiple authors | Trends in Endocrinology & Metabolism | 2021
Reviews how folate-cycle, methionine-cycle, and transsulfuration nutrients influence embryonic growth, nucleotide production, epigenetic programming, and developmental outcomes.
Maternal One-Carbon Metabolism During the Periconceptional Period and Human Foetal Brain Growth
| Multiple authors | Nutrients | 2021
Systematically reviews associations between maternal folate and related one-carbon biomarkers and fetal brain and head growth.
Folate Intake, Markers of Folate Status and Oral Clefts: Updated Systematic Reviews and Meta-Analyses
| Multiple authors | Birth Defects Research | 2021
Evaluates dietary folate, supplementation, fortification, blood folate, and MTHFR variants in relation to orofacial cleft risk.
The Search for Genetic Determinants of Human Neural Tube Defects
| Multiple authors | Review | 2020
Reviews genetic contributors to neural-tube defects, including variants in folate transporters, folate receptors, and one-carbon-metabolism enzymes.
From Embryo to Adult: One Carbon Metabolism in Stem Cells
| Multiple authors | Current Stem Cell Research & Therapy | 2020
Reviews folate and methionine metabolism in embryonic, fetal, adult, and cancer stem cells with emphasis on methylation and developmental programming.
Temporal Expression of Genes Involved in Folate Metabolism and Transport During Placental Development, Preeclampsia and Neural Tube Defects
| Multiple authors | Placenta | 2019
Measures placental expression of folate transporters and enzymes such as MTHFR, methionine synthase, and CBS across normal and complicated pregnancies.
Deletion of the Neural Tube Defect-Associated Gene Mthfd1l Disrupts One-Carbon and Central Energy Metabolism in Mouse Embryos
| Multiple authors | Journal of Biological Chemistry | 2018
Shows that loss of mitochondrial MTHFD1L impairs formate production and alters one-carbon, glycolytic, and TCA-cycle metabolism during embryogenesis.
Understanding Pluripotency Under Folic Acid Deficiency Using Embryonic Stem Cells as an In Vitro Model
| Multiple authors | Medical Hypotheses | 2018
Explores how folate availability may regulate stem-cell pluripotency through one-carbon metabolism and epigenetic methylation.
Nutrition, One-Carbon Metabolism and Neural Tube Defects: A Review
| Multiple authors | Nutrients | 2016
Reviews folate and other B vitamins involved in one-carbon metabolism and evaluates biochemical mechanisms connecting these nutrients with neural-tube closure.
One Carbon Metabolism in Pregnancy: Impact on Maternal, Fetal and Neonatal Health
| Multiple authors | Molecular and Cellular Endocrinology | 2016
Reviews folate and methionine cycles during pregnancy and their roles in nucleotide synthesis, methyl transfer, fetal growth, and developmental programming.
Early Pregnancy B Vitamin Status, One Carbon Metabolism, Pregnancy Outcome and Child Development
| Multiple authors | Biochimie | 2016
Reviews folate, vitamin B12, betaine, homocysteine, and related one-carbon metabolites during pregnancy and their associations with fetal growth and development.
Potential Role of Folate in Pre-Eclampsia
| Multiple authors | Nutrition Reviews | 2015
Reviews folate metabolism, homocysteine, DNA methylation, genome stability, and folate-pathway genetic variation in relation to pre-eclampsia.
Association Between MTHFD1 Polymorphisms and Neural Tube Defect Susceptibility
| Multiple authors | Gene | 2015
Examines variants of the multifunctional cytosolic folate enzyme MTHFD1 and their possible contribution to neural-tube-defect susceptibility.
Folate Metabolism and Human Reproduction
| Christian J. Thaler | Geburtshilfe und Frauenheilkunde | 2014
Reviews the influence of folate metabolism, MTHFR genotype, and homocysteine on ovarian function, implantation, embryogenesis, pregnancy, and assisted reproduction.
Folate Deficiency and Folic Acid Supplementation: The Prevention of Neural-Tube Defects and Congenital Heart Defects
| Andrew E. Czeizel et al. | Nutrients | 2013
Reviews evidence linking folate nutrition with neural-tube and congenital-heart development and discusses preventive effects of periconceptional supplementation.
The Diagnostic Utility of Folate Receptor Autoantibodies in Blood
| Multiple authors | Clinical Chemistry and Laboratory Medicine | 2013
Discusses assays for folate receptor-alpha autoantibodies and their potential role in impaired folate uptake during pregnancy and neurological development.
Methionine, Homocysteine, One Carbon Metabolism and Fetal Growth
| Multiple authors | Reviews in Endocrine and Metabolic Disorders | 2012
Reviews interactions among folate, methionine, B vitamins, methyl-group production, homocysteine, and fetal growth.
Overview of Homocysteine and Folate Metabolism: With Special References to Cardiovascular Disease and Neural Tube Defects
| Henk J. Blom and Yvo Smulders | Journal of Inherited Metabolic Disease | 2011
Provides an integrated overview of folate and homocysteine metabolism and explains why disturbances can affect developmental, vascular, neurological, skeletal, and oncological outcomes.
The Emerging Role of Epigenetic Mechanisms in the Etiology of Neural Tube Defects
| Multiple authors | Review | 2011
Explores how folate-dependent one-carbon metabolism may influence neural-tube development through DNA and chromatin methylation.
Folate-Mediated One-Carbon Metabolism and Its Effect on Female Fertility and Pregnancy Viability
| Margit Laanpere et al. | Nutrition Reviews | 2010
Reviews ovarian function, oocyte quality, implantation, embryo development, MTHFR variation, folate status, and homocysteine.
Periconceptional Folic Acid and Multivitamin Supplementation for the Prevention of Neural Tube Defects and Other Congenital Abnormalities
| Andrew E. Czeizel | Birth Defects Research | 2009
Reviews evidence from controlled trials of periconceptional supplementation and its effects on neural-tube and other congenital abnormalities.
Insights into Metabolic Mechanisms Underlying Folate-Responsive Neural Tube Defects
| Anna E. Beaudin and Patrick J. Stover | Birth Defects Research | 2009
Reviews how nutritional deficiency, folate transport, nucleotide synthesis, methylation, and genetic variation may interact to influence neural-tube closure.
Folic Acid, Methylation and Neural Tube Closure in Humans
| Henk J. Blom | Birth Defects Research | 2009
Examines folate metabolism, homocysteine, methylation, genetic variants, and folate-receptor mechanisms in relation to neural-tube-defect prevention.
National Neural Tube Defects Prevention Program in China
| Multiple authors | Food and Nutrition Bulletin | 2008
Reviews geographic variation in folate status in China and the public-health evidence underlying large-scale folic-acid interventions.
Impact of Folate and Homocysteine Metabolism on Human Reproductive Health
| Multiple authors | Human Reproduction Update | 2007
Reviews folate, homocysteine, methylation, oxidative stress, gametogenesis, fertility, and pregnancy complications.
Folate and Human Reproduction
| Multiple authors | American Journal of Clinical Nutrition | 2006
Reviews folate nutrition in pregnancy, lactation, and male reproduction together with homocysteine and folate-related genetic polymorphisms.
Autoantibodies Against Folate Receptors in Women with a Pregnancy Complicated by a Neural-Tube Defect
| Multiple authors | New England Journal of Medicine | 2004
Reports folate-receptor autoantibodies capable of blocking folate binding and uptake in women with neural-tube-defect-affected pregnancies.
Genetic Determinants of Folate and Vitamin B12 Metabolism: A Common Pathway in Neural Tube Defect and Down Syndrome?
| Jean-Louis Guéant et al. | Clinical Chemistry and Laboratory Medicine | 2003
Reviews MTHFR, MTR, MTRR, transcobalamin, folate, vitamin B12, and homocysteine as components of interconnected developmental pathways.
Polymorphisms in Genes Involved in Folate Metabolism as Maternal Risk Factors for Down Syndrome
| Multiple authors | American Journal of Human Genetics | 2000
Investigates maternal MTHFR and MTRR variants and proposes that altered folate-dependent methyl metabolism may influence meiotic chromosome segregation.
Prevention of Neural-Tube Defects with Folic Acid in China
| Robert J. Berry et al. | New England Journal of Medicine | 1999
Large population intervention demonstrating substantial reductions in neural-tube defects among women taking 400 micrograms of folic acid around conception.
A Common Variant in Methionine Synthase Reductase Combined With Low Cobalamin Increases Risk for Spina Bifida
| Multiple authors | Molecular Genetics and Metabolism | 1999
Shows an interaction between MTRR genotype and vitamin B12 status in a folate-dependent metabolic pathway associated with neural-tube development.
Folate Metabolism and Neural Tube Defects: A Review
Reviews folate one-carbon metabolism, genetically determined metabolic abnormalities, supplementation, and possible biochemical mechanisms underlying neural-tube defects.
Folate Metabolism and Neural Tube Defects
| N. Gordon | Brain & Development | 1995
Discusses folate and vitamin B12 metabolism and evaluates evidence linking periconceptional folic-acid status with neural-tube-defect risk.
Prevention of the First Occurrence of Neural-Tube Defects by Periconceptional Vitamin Supplementation
| Andrew E. Czeizel and István Dudás | New England Journal of Medicine | 1992
Reports a randomized trial showing prevention of first-occurrence neural-tube defects with a folic-acid-containing periconceptional multivitamin.
Prevention of Neural Tube Defects: Results of the Medical Research Council Vitamin Study
| MRC Vitamin Study Research Group | The Lancet | 1991
Landmark randomized trial demonstrating that periconceptional folic-acid supplementation substantially reduces recurrence of neural-tube defects.
Use of Folic Acid for Prevention of Spina Bifida and Other Neural Tube Defects
| Centers for Disease Control | MMWR | 1991
Summarizes early evidence supporting folic-acid supplementation before conception and during early pregnancy to prevent recurrent neural-tube defects.
Neurology, Aging, Autism and Cerebral Folate Disorders
Role of Folate Metabolism in Neurodegenerative Diseases: Insight from Experimental and Clinical Studies
| Meenakshi Umar et al. | Current Nutrition Reports | 2026
Reviews folate-mediated one-carbon metabolism in brain health and examines how disruptions in nucleotide synthesis, methylation, redox regulation, and homocysteine metabolism may contribute to Alzheimer's, Parkinson's, and other neurodegenerative diseases.
Folate Receptor Alpha Autoantibodies in Vector-Borne Disease Populations
| Multiple authors | Research Article | 2026
Investigates folate receptor-alpha autoantibodies as potential disruptors of brain folate transport and considers consequences for cerebral folate availability and one-carbon metabolism.
Folic Acid and Autism: Updated Evidences
| Cristiane Vasconcelos et al. | Nutritional Neuroscience | 2025
Updates evidence concerning folate biochemistry, prenatal exposure, neurodevelopment, and folate-related therapeutic approaches in autism.
Unveiling the Therapeutic Potential of Folate-Dependent One-Carbon Metabolism in Cancer and Neurodegeneration
| Multiple authors | Review | 2024
Provides an overview of cytosolic and mitochondrial folate cycles and examines their potential as therapeutic targets in cancer and neurological disease.
FOLR1-Related Cerebral Folate Transport Deficiency
| Multiple authors | GeneReviews | 2024
Reviews FOLR1 mutations, impaired transport of 5-MTHF into cerebrospinal fluid, diagnostic testing, and reduced-folate treatment.
Exploring the Complexities of 1C Metabolism: Implications in Aging and Neurodegenerative Diseases
| Multiple authors | Review | 2023
Discusses the interconnected folate, methionine, choline, and transsulfuration pathways and their relevance to mitochondrial dysfunction, aging, and neurodegeneration.
The Role of One-Carbon Metabolism in Healthy Brain Aging
| Multiple authors | Review | 2023
Reviews folate, vitamin B12, and choline as nutritional components of one-carbon metabolism and examines their relationships with DNA repair, methylation, lipid metabolism, and healthy brain aging.
Dihydrofolate Reductase Activity Controls Neurogenic Transitions in the Developing Neocortex
| Sulov Saha et al. | Development | 2023
Shows that reducing DHFR activity alters folate metabolites, histone methylation, and neural-progenitor differentiation in organoid and mouse models.
One-Carbon Metabolism: Pulling the Strings behind Aging and Neurodegeneration
| Multiple authors | Review | 2022
Reviews folate and methionine cycles in nucleotide synthesis, amino-acid homeostasis, glutathione production, cellular redox state, aging, and neurodegenerative disease.
Impaired Folate-Mediated One-Carbon Metabolism in Type 2 Diabetes, Late-Onset Alzheimer's Disease and Long COVID
| Multiple authors | Medicina | 2022
Examines biochemical pathways through which impaired folate-dependent one-carbon metabolism may contribute to several metabolically and neurologically complex disorders.
Cerebral Folate Deficiency Syndrome: Early Diagnosis, Intervention and Treatment Strategies
| Multiple authors | Review | 2022
Reviews cerebral folate transport, folate receptor-alpha autoimmunity, inborn errors of folate metabolism, diagnostic approaches, and treatment strategies.
Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorders: Diagnosis, Treatment and Prevention
| Multiple authors | Journal of Personalized Medicine | 2021
Reviews folate receptor-alpha autoantibodies and their potential to interfere with folate transport during pregnancy and across the blood-brain barrier.
Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin Treatment in Autism Spectrum Disorders
| Daniel A. Rossignol et al. | Journal of Personalized Medicine | 2021
Systematically reviews cerebral folate deficiency, folate receptor autoantibodies, and folinic-acid treatment in relation to impaired brain folate transport.
Folic Acid and Autism: A Systematic Review of the Current State of Knowledge
| Multiple authors | Cells | 2021
Reviews prenatal folate exposure, one-carbon metabolism, folate receptor autoantibodies, and folinic-acid interventions in autism research.
Prenatal Folic Acid Supplements and Offspring's Autism Spectrum Disorder: A Meta-Analysis and Meta-Regression
| Multiple authors | Journal of Autism and Developmental Disorders | 2021
Synthesizes epidemiological studies on timing and dosage of maternal folic-acid supplementation and subsequent autism-spectrum-disorder risk.
An Appraisal of Folates as Key Factors in Cognition and Ageing-Related Diseases
| Multiple authors | Critical Reviews in Food Science and Nutrition | 2019
Examines folate nutrition across the lifespan and discusses biochemical pathways potentially connecting folate status with cognitive aging.
Genetic Assessment and Folate Receptor Autoantibodies in Infantile-Onset Cerebral Folate Deficiency Syndrome
| Multiple authors | Molecular Genetics and Metabolism | 2018
Examines genetic and autoimmune mechanisms capable of reducing folate transport into the central nervous system.
Neurological Improvement Following Intravenous High-Dose Folinic Acid for Cerebral Folate Transporter Deficiency Caused by FOLR1 Mutation
| Multiple authors | European Journal of Paediatric Neurology | 2016
Reports restoration of cerebrospinal-fluid 5-MTHF and neurological improvement after intensive folinic-acid treatment.
Clinical, Etiological and Therapeutic Aspects of Cerebral Folate Deficiency
| Marta Molero-Luis et al. | Expert Review of Neurotherapeutics | 2015
Reviews causes of low cerebrospinal-fluid folate and discusses distinct aspects of brain folate transport, metabolism, diagnosis, and treatment.
Folates and Aging: Role in Mild Cognitive Impairment, Dementia and Depression
| Multiple authors | Ageing Research Reviews | 2015
Reviews folate-dependent nucleotide production, methylation, homocysteine metabolism, and possible links with neuropsychiatric disorders in older adults.
Maternal Folate Status as a Risk Factor for Autism Spectrum Disorders: A Review of Existing Evidence
| Elizabeth A. DeVilbiss et al. | British Journal of Nutrition | 2015
Reviews maternal folate exposure together with genetic and epigenetic mechanisms that could influence fetal neurodevelopment.
Clinical Recognition and Aspects of the Cerebral Folate Deficiency Syndromes
| Vincent Ramaekers et al. | Clinical Chemistry and Laboratory Medicine | 2013
Reviews causes of cerebral folate deficiency, including receptor autoantibodies, FOLR1 mutations, mitochondrial disorders, and folate-metabolism defects.
Molecular Characterization of Folate Receptor 1 Mutations Delineates Cerebral Folate Transport Deficiency
| M. Grapp et al. | Brain | 2012
Demonstrates how FOLR1 mutations prevent normal receptor localization and folate binding, producing severe brain-specific folate deficiency.
Genetic Causes of Cerebral Folate Deficiency: Clinical, Biochemical and Therapeutic Aspects
| Multiple authors | Molecular Genetics and Metabolism | 2012
Reviews inherited defects in folate transport and metabolism that reduce cerebral 5-MTHF and discusses biochemical diagnosis and treatment.
Folate and Methionine Metabolism in Autism: A Systematic Review
| Penelope A. E. Main et al. | American Journal of Clinical Nutrition | 2010
Reviews metabolite, genetic, and intervention studies examining possible alterations of folate-methionine metabolism in autism.
Homocysteine, Vitamin B12, Folate and Cognitive Functions
| Multiple authors | International Journal of Clinical Practice | 2009
Reviews relationships among folate, cobalamin, homocysteine metabolism, cognitive decline, and dementia.
Folate Receptor Alpha Defect Causes Cerebral Folate Transport Deficiency
| Multiple authors | American Journal of Human Genetics | 2009
Identifies FOLR1 mutations as a cause of severe cerebral folate deficiency, hypomyelination, movement abnormalities, and epilepsy.
Cancer Metabolism and Folate-Targeted Therapy
Folate Receptor-α Targeted Therapies in Ovarian Cancer: Recent Advances and Emerging Therapeutic Strategies
| Bishal Singh et al. | International Immunopharmacology | 2026
Examines folate receptor-alpha biology and the growing use of this folate-transport protein as a biomarker and therapeutic delivery route in ovarian cancer.
Methylenetetrahydrofolate Dehydrogenase 2 Promotes Cutaneous Squamous Cell Carcinoma Progression by Reprogramming Metabolism
| Wenqian Du et al. | International Journal of Biological Macromolecules | 2026
Reports that MTHFD2 supports glycolytic and redox metabolism in cutaneous squamous-cell carcinoma and interacts with additional growth pathways.
MTHFD2-Mediated Ubiquitination and Degradation of FOXO1 Promote Tongue Squamous Cell Carcinoma Progression
| Aikebaier Tuohuti et al. | Molecular Cancer Research | 2026
Examines both metabolic and non-metabolic functions of MTHFD2 in cancer progression and protein regulation.
MTHFD2: A Retrospective and a Glance into the Future
| Multiple authors | International Journal of Molecular Sciences | 2025
Reviews four decades of research on mitochondrial MTHFD2 and its roles in folate-dependent one-carbon metabolism, amino-acid metabolism, redox balance, cancer, and immune-cell biology.
Folate Receptor Alpha for Cancer Therapy: An Antibody and Antibody-Drug Conjugate Target Coming of Age
Reviews folate receptor-alpha biology, tissue distribution, folate uptake, cancer-associated overexpression, and the development of receptor-targeted antibodies and antibody-drug conjugates.
One-Carbon Metabolism in Cancer: Moonlighting Functions of Metabolic Enzymes and Anti-Tumor Therapy
| Multiple authors | Review | 2025
Reviews folate-cycle enzymes including MTHFD2 and SHMT2 and describes metabolic and non-metabolic roles in nucleotide synthesis, DNA repair, methylation, and tumor progression.
A Single Non-Coding SNP in FPGS Modulates Folate Drug Efficacy in Acute Lymphoblastic Leukemia
| Multiple authors | Research Article | 2025
Links a noncoding FPGS variant with methotrexate pharmacology, emphasizing the importance of folate polyglutamation in antifolate efficacy.
The Efficacy and Safety of Folate Receptor α-Targeted Antibody-Drug Conjugate Therapy in Patients With High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers
| Eun Taeg Kim et al. | Cancer Medicine | 2024
Evaluates clinical outcomes from therapies that exploit tumor expression of folate receptor-alpha for targeted delivery of cytotoxic drugs.
Mechanisms and Perspectives of B Vitamins Associated One Carbon Metabolism on Colorectal Cancer Risk
| Multiple authors | Review | 2024
Reviews how folate and vitamins B2, B6, and B12 support one-carbon metabolism and influence nucleotide synthesis, methylation, redox balance, gut microbiota, and colorectal carcinogenesis.
MTHFD2 in Healthy and Cancer Cells: Canonical and Non-Canonical Functions
| Multiple authors | Review | 2024
Examines mitochondrial MTHFD2 in normal proliferating tissues and cancer, including its metabolic, signaling, and regulatory functions.
Inhibition of Mitochondrial Folate Metabolism Drives Differentiation Through mTORC1-Mediated Purine Sensing
| Multiple authors | Research Article | 2024
Shows that restricting mitochondrial one-carbon metabolism lowers purine availability and alters mTORC1 signaling and differentiation in leukemia cells.
Targeting Serine-Glycine-One-Carbon Metabolism as a Vulnerability in Cancers
| Multiple authors | Review | 2023
Describes how serine and glycine feed folate-dependent one-carbon pathways and why enzymes such as SHMT and MTHFD have become attractive targets in cancer metabolism.
Therapeutic Strategies Targeting Folate Receptor α for Ovarian Cancer
| Multiple authors | Frontiers in Immunology | 2023
Reviews folate receptor-alpha function and therapeutic strategies exploiting its high expression in epithelial ovarian cancer.
Cycling Back to Folate Metabolism in Cancer
| Multiple authors | Nature Reviews Cancer | 2023
Reviews renewed interest in folate metabolism as a therapeutic target, emphasizing nucleotide synthesis, methionine metabolism, redox defense, and tumor-specific metabolic dependencies.
Folate Transport and One-Carbon Metabolism in Targeted Therapies of Epithelial Ovarian Cancer
| Multiple authors | Review | 2022
Connects folate transport with serine catabolism, mitochondrial one-carbon metabolism, nucleotide synthesis, and therapeutic targeting in ovarian cancer.
Folate Enzyme MTHFD2 Links One-Carbon Metabolism to Unfolded Protein Response in Glioblastoma
| Zhiyuan Zhu et al. | Cancer Letters | 2022
Demonstrates that MTHFD2 supports glioblastoma metabolism and connects mitochondrial folate metabolism with broader stress-response pathways.
Deacetylation of MTHFD2 by SIRT4 Senses Stress Signal to Inhibit Cancer Cell Growth by Remodeling Folate Metabolism
| Multiple authors | Cell Death & Disease | 2022
Describes nutrient-sensitive regulation of MTHFD2 protein stability and links folate availability with NADPH production and cellular redox balance.
Folate-Mediated One-Carbon Metabolism: A Targeting Strategy in Cancer Therapy
| Multiple authors | Drug Discovery Today | 2021
Reviews SHMT2, MTHFD2, nucleotide synthesis, methylation, and redox regulation as components of folate metabolism that may be therapeutically targeted in cancer.
Serine, Glycine and One-Carbon Metabolism in Cancer
| Multiple authors | International Journal of Oncology | 2021
Reviews how serine and glycine provide one-carbon units to tetrahydrofolate and support nucleotide synthesis, methylation reactions, glutathione production, and cancer-cell proliferation.
Folate Metabolism: A Re-Emerging Therapeutic Target in Haematological Cancers
| Multiple authors | Leukemia | 2021
Reviews cytosolic and mitochondrial folate metabolism in blood cancers and discusses classic antifolates and newer strategies targeting one-carbon enzymes.
Advancements in Folate Receptor Targeting for Anti-Cancer Therapy: A Small Molecule-Drug Conjugate Approach
| Multiple authors | Drug Discovery Today | 2021
Reviews folate-receptor-mediated delivery of small-molecule drug conjugates and principles for designing folate-targeted anticancer therapeutics.
The Folate Cycle Enzyme MTHFD2 Induces Cancer Immune Evasion Through PD-L1 Up-Regulation
| Multiple authors | Nature Communications | 2021
Links MTHFD2-driven folate metabolism to nucleotide-sugar production, protein O-GlcNAcylation, cMYC stability, and tumor PD-L1 expression.
Reprogramming of Serine, Glycine and One-Carbon Metabolism in Cancer
| Multiple authors | Review | 2020
Reviews how serine and glycine supply one-carbon units to folate metabolism and how cancer cells reprogram cytosolic and mitochondrial pathways to support proliferation and redox balance.
Association Between One-Carbon Metabolism-Related Vitamins and Risk of Breast Cancer
| Jie Zeng et al. | Clinical Breast Cancer | 2020
Meta-analyzes prospective studies examining dietary folate and related B vitamins in relation to breast-cancer risk.
More Than a Metabolic Enzyme: MTHFD2 as a Novel Target for Anticancer Therapy?
| Multiple authors | Frontiers in Oncology | 2020
Reviews the canonical folate-cycle and emerging non-metabolic functions of MTHFD2 and evaluates the enzyme as an anticancer target.
Enzymes Involved in Folate Metabolism and Its Implication for Cancer Treatment
| Multiple authors | Oncology Reviews | 2020
Focuses on FPGS and gamma-glutamyl hydrolase as regulators of intracellular folate retention and responses to methotrexate and fluoropyrimidines.
Cisplatin Inhibits SIRT3-Deacetylation MTHFD2 to Disturb Cellular Redox Balance in Colorectal Cancer Cell
| Multiple authors | Cell Death & Disease | 2020
Shows that post-translational regulation of MTHFD2 alters folate-dependent NADPH production and oxidative-stress responses.
Modulation of Redox Homeostasis by Inhibition of MTHFD2 in Colorectal Cancer
| Multiple authors | Journal of the National Cancer Institute | 2019
Demonstrates how mitochondrial MTHFD2 contributes to folate-dependent NADPH production, redox balance, cancer-cell survival, and metastasis.
Cancer Stem-Like Properties and Gefitinib Resistance Are Dependent on Purine Synthetic Metabolism Mediated by MTHFD2
| Multiple authors | Oncogene | 2019
Connects mitochondrial folate metabolism with purine synthesis, stem-like properties, and acquired drug resistance in lung cancer.
Loss of ALDH1L1 Folate Enzyme Confers a Selective Metabolic Advantage for Tumor Progression
| Sergey A. Krupenko and Natalia I. Krupenko | Chemico-Biological Interactions | 2019
Reviews how loss of ALDH1L1 can redirect folate one-carbon units toward biosynthetic reactions that support proliferation and tumor progression.
The Role of Single-Nucleotide Polymorphisms in the Function of Candidate Tumor Suppressor ALDH1L1
| Multiple authors | Frontiers in Genetics | 2019
Reviews common ALDH1L1 variants and their possible effects on folate metabolism, enzyme function, cancer susceptibility, and nutritional responses.
One-Carbon Metabolism and Colorectal Cancer Metabolism
| Multiple authors | Current Colorectal Cancer Reports | 2018
Places the folate cycle, methionine cycle, and transsulfuration pathway within the larger metabolic reprogramming characteristic of colorectal cancer.
ALDH1L1 and ALDH1L2 Folate Regulatory Enzymes in Cancer
| Multiple authors | Advances in Experimental Medicine and Biology | 2018
Reviews cytosolic ALDH1L1 and mitochondrial ALDH1L2 as regulators of 10-formyl-THF disposal, one-carbon flux, tumor metabolism, and cancer progression.
One-Carbon Metabolism in Cancer
| Multiple authors | British Journal of Cancer | 2017
Reviews folate-dependent transfer of one-carbon units from serine and glycine into nucleotide synthesis, methionine recycling, methylation, and cancer growth.
The Importance of Mitochondrial Folate Enzymes in Human Colorectal Cancer
| Multiple authors | Oncology Reports | 2017
Reports coordinated elevation of SHMT2, MTHFD2, and ALDH1L2 in colorectal tumors and examines their relationship with prognosis.
Targeting Folate Receptor Alpha for Cancer Treatment
| Multiple authors | Oncotarget | 2016
Reviews the biological properties of folate receptor-alpha and its potential as a diagnostic marker and therapeutic target in several cancers.
Suppression of MTHFD2 in MCF-7 Breast Cancer Cells Increases Glycolysis, Dependency on Exogenous Glycine, and Sensitivity to Folate Depletion
| Multiple authors | Journal of Proteome Research | 2016
Shows how loss of mitochondrial MTHFD2 reshapes glucose and glycine metabolism and increases cellular vulnerability to folate limitation.
One-Carbon Metabolism and Colorectal Cancer: Potential Mechanisms of Chemoprevention
| Matthew P. Hanley and Daniel W. Rosenberg | Current Pharmacology Reports | 2015
Examines folate's dual roles in nucleotide synthesis and methylation and their complex relationship with colorectal carcinogenesis.
A Current Review of Folate Receptor Alpha as a Potential Tumor Target in Non-Small-Cell Lung Cancer
| Multiple authors | OncoTargets and Therapy | 2015
Reviews folate receptor-alpha expression in lung cancer and therapeutic strategies that exploit receptor-mediated folate uptake.
Serine and Glycine Metabolism in Cancer
| Multiple authors | Trends in Biochemical Sciences | 2014
Discusses serine and glycine metabolism as major suppliers of one-carbon groups to the folate cycle and their importance for tumor growth.
Metabolic Enzyme Expression Highlights a Key Role for MTHFD2 and the Mitochondrial Folate Pathway in Cancer
| Multiple authors | Nature Communications | 2014
Identifies mitochondrial one-carbon metabolism and MTHFD2 as broadly upregulated metabolic features across numerous human cancers.
How Folate Metabolism Affects Colorectal Cancer Development and Treatment
| Multiple authors | Cancer Letters | 2014
Reviews heterogeneity in folate metabolism, MTHFR variation, colorectal carcinogenesis, folate fortification, and responses to chemotherapy.
Folate-Genetics and Colorectal Neoplasia: What We Know and Need to Know Next
| Jane C. Figueiredo et al. | Molecular Nutrition & Food Research | 2013
Reviews genetic variation in MTHFR, MTR, MTRR, SLC19A1, SHMT1, MTHFD1, TYMS, and other folate-pathway genes in colorectal neoplasia.
The Human Proton-Coupled Folate Transporter: Biology and Therapeutic Applications to Cancer
| Sita Kugel Desmoulin et al. | Cancer Biology & Therapy | 2012
Reviews PCFT-mediated folate absorption, hereditary folate malabsorption, transporter structure, and exploitation of acidic tumor environments for antifolate delivery.
One-Carbon Metabolism and Breast Cancer: An Epidemiological Perspective
| Xinran Xu and Jia Chen | Journal of Genetics and Genomics | 2009
Reviews folate-related nutrients, folate-pathway polymorphisms, DNA synthesis, and methylation in relation to breast-cancer risk and survival.
Association of Folate-Pathway Gene Polymorphisms With the Risk of Prostate Cancer
| Multiple authors | Cancer Epidemiology Biomarkers & Prevention | 2009
Evaluates variants in MTHFR, MTR, MTRR, MTHFD1, SLC19A1, SHMT1, and other folate-related genes in relation to prostate-cancer risk.
Folate Receptor Beta Is Expressed by Tumor-Associated Macrophages and Constitutes a Marker for M2 Macrophages
| Multiple authors | Cancer Research | 2009
Shows that FOLR2 expression and folate uptake are enhanced in subsets of activated macrophages and tumor-associated macrophages.
Human Reduced Folate Carrier: Translation of Basic Biology to Cancer Etiology and Therapy
| Multiple authors | Cancer Metastasis Reviews | 2007
Reviews SLC19A1 reduced-folate-carrier biology and its central role in cellular folate uptake and antifolate chemotherapy.
Polymorphisms in Genes Involved in Folate Metabolism and Colorectal Neoplasia: A HuGE Review
| Linda Sharp and Julian Little | American Journal of Epidemiology | 2004
Reviews variants in MTHFR, MTR, MTRR, CBS, thymidylate synthase, and other folate-related genes in colorectal neoplasia.
Antifolates, Methotrexate and Pharmacogenetics
Role of Mitochondrial and Cytosolic Folylpolyglutamate Synthetase in One-Carbon Metabolism and Antitumor Efficacy of Mitochondrial-Targeted Antifolates
| Multiple authors | Molecular Cancer Therapeutics | 2024
Investigates compartment-specific folate polyglutamation and its importance for mitochondrial SHMT2-targeted and cytosolic antifolate activity.
Structural Basis of Antifolate Recognition and Transport by PCFT
| Multiple authors | Nature | 2021
Uses cryo-electron microscopy to reveal how SLC46A1 recognizes and transports folate-related compounds and the antifolate pemetrexed.
Methotrexate Mechanism in Treatment of Rheumatoid Arthritis
| Multiple authors | Joint Bone Spine | 2019
Reviews methotrexate's antifolate actions alongside additional mechanisms responsible for its anti-inflammatory effects in rheumatoid arthritis.
Folate Supplementation for Methotrexate Therapy in Patients With Rheumatoid Arthritis: A Systematic Review
| Multiple authors | Journal of Clinical Rheumatology | 2018
Reviews evidence that folic or folinic acid supplementation can reduce several adverse effects of methotrexate without substantially compromising therapeutic efficacy.
Folylpoly-γ-glutamate Synthetase: A Key Determinant of Folate Homeostasis and Antifolate Resistance in Cancer
| Multiple authors | Drug Resistance Updates | 2016
Reviews FPGS-mediated polyglutamylation, which retains folate cofactors inside cells and influences folate homeostasis and resistance to antifolate drugs.
Effect of the Polymorphism of Folylpolyglutamate Synthetase on Treatment of High-Dose Methotrexate in Pediatric Patients With Acute Lymphocytic Leukemia
| Multiple authors | Medical Science Monitor | 2016
Examines how variation in FPGS may influence methotrexate disposition and treatment outcomes in childhood leukemia.
Cancer Metabolism and Oxidative Stress: Insights into Carcinogenesis and Chemotherapy via the Non-DHFR Effects of Methotrexate
| Multiple authors | BBA Clinical | 2015
Reviews methotrexate effects on folate-dependent nucleotide metabolism, mitochondrial function, oxidative stress, and redox pathways beyond direct DHFR inhibition.
Biology of the Major Facilitative Folate Transporters SLC19A1 and SLC46A1
| Multiple authors | Current Topics in Membranes | 2014
Reviews the reduced folate carrier and proton-coupled folate transporter, including their roles in tissue folate uptake, intestinal absorption, and antifolate transport.
The Major Facilitative Folate Transporters SLC19A1 and SLC46A1: Biology and Role in Antifolate Chemotherapy of Cancer
| Multiple authors | Drug Metabolism and Pharmacokinetics | 2014
Describes molecular regulation of the two major folate transport systems and their importance for normal folate physiology and chemotherapy resistance.
Methotrexate Catabolism to 7-Hydroxymethotrexate in Rheumatoid Arthritis Is Reduced by Folic Acid Supplementation
| Multiple authors | Arthritis & Rheumatism | 2009
Examines methotrexate metabolism and demonstrates that folic-acid supplementation can modify formation of the drug metabolite 7-hydroxymethotrexate.
Methotrexate in Rheumatoid Arthritis: Folate Supplementation Should Always Be Given
| Multiple authors | BioDrugs | 2007
Explains how methotrexate disrupts folate-dependent amino-acid, purine, pyrimidine, and methylation reactions and reviews the rationale for folate supplementation.
Pemetrexed: Biochemical and Cellular Pharmacology, Mechanisms, and Clinical Applications
| Multiple authors | Molecular Cancer Therapeutics | 2007
Reviews the antifolate pemetrexed, its transport by folate carriers, intracellular polyglutamation, and inhibition of thymidylate and purine synthesis.
Exploratory Analysis of Four Polymorphisms in Human GGH and FPGS Genes and Their Effect in Methotrexate-Treated Rheumatoid Arthritis Patients
| Multiple authors | Pharmacogenomics | 2007
Studies genetic variation in the opposing enzymes controlling intracellular polyglutamation and deglutamation of folate and methotrexate.
Molecular Basis of Antifolate Resistance
| Yehuda G. Assaraf | Cancer and Metastasis Reviews | 2007
Reviews resistance mechanisms involving folate transporters, DHFR, thymidylate synthase, FPGS, drug efflux, and altered folate pools.
Gamma-Glutamyl Hydrolase and Drug Resistance
| Erasmus Schneider and Thomas J. Ryan | Clinica Chimica Acta | 2006
Reviews gamma-glutamyl hydrolase, an enzyme that removes polyglutamate chains from intracellular folates and antifolates and thereby influences folate retention and drug resistance.
5,10-Methylenetetrahydrofolate Reductase Polymorphisms and Pharmacogenetics
| Young-In Kim | Nutrition Reviews | 2005
Examines MTHFR polymorphisms and other folate-pathway variants as determinants of folate metabolism, disease risk, and drug responses.
The Pharmacogenetics of Methotrexate in Inflammatory Bowel Disease
| Multiple authors | Pharmacogenetics and Genomics | 2005
Tests MTHFR, SLC19A1, and GGH variants as determinants of methotrexate efficacy and toxicity in inflammatory bowel disease.
Folate During Antifolate Chemotherapy: What We Know and Do Not Know
| Multiple authors | Nutrition and Cancer | 2005
Discusses interactions between dietary folate, supplementation, tumor folate metabolism, and the therapeutic and toxic effects of antifolate chemotherapy.
Folate, Homocysteine, and Cobalamin Status in Patients with Rheumatoid Arthritis Treated with Methotrexate
| Multiple authors | Journal of Rheumatology | 2004
Reports that methotrexate alters red-cell folate and homocysteine metabolism and examines the protective effect of low-dose folic-acid supplementation.
Identification of Single Nucleotide Polymorphisms in the Human Gamma-Glutamyl Hydrolase Gene and Characterization of Promoter Polymorphisms
| Karen J. Chave et al. | Gene | 2003
Characterizes genetic variation in GGH, an enzyme that removes glutamate residues from intracellular folates and methotrexate polyglutamates.
Deaza Analogs of Folic Acid as Antitumor Agents
| Multiple authors | Current Medicinal Chemistry | 2003
Reviews antifolate compounds targeting DHFR, thymidylate synthase, and GAR transformylase while considering transport and polyglutamation.
Recent Advances in the Chemistry and Biology of Folylpoly-γ-glutamate Synthetase Substrates and Inhibitors
| Multiple authors | Current Medicinal Chemistry | 2003
Reviews structural requirements governing FPGS substrates and inhibitors and the enzyme's importance for natural folate metabolism and antifolate chemotherapy.
Recent Advances in the Understanding of the Mechanism of Membrane Transport of Folates and Antifolates
| Multiple authors | Seminars in Oncology | 1999
Reviews reduced-folate-carrier transport, cellular folate accumulation, folate polyglutamation, and mechanisms of resistance to antifolate drugs.
Folate and Antifolate Pharmacology
| Multiple authors | Seminars in Oncology | 1997
Reviews normal folate homeostasis and contrasts it with transport, metabolism, intracellular targets, and resistance mechanisms of classical and newer antifolates.
Cardiovascular, Metabolic, Immune and Systemic Health
Folate Receptor Beta Drives NLRP3 Inflammasome Activation and Pyroptosis in Macrophages Independent of Folate Binding
| Lisa M. Rogers et al. | Journal of Immunology | 2026
Shows that FOLR2 can regulate macrophage inflammatory signaling and gene expression through mechanisms partly independent of extracellular folate binding.
Folate Receptor Beta Performs an Immune Checkpoint Function in Activated Macrophages
| Multiple authors | Research Article | 2025
Investigates signaling functions of macrophage folate receptor beta beyond its traditional role in folate uptake.
One-Carbon Metabolism Nutrients, Genetic Variation, and Diabetes Mellitus
| Multiple authors | Review | 2024
Reviews interactions among folate, choline, betaine, vitamins B6 and B12, homocysteine, and one-carbon-metabolism gene variants in the development of diabetes.
Folate Receptor Beta Signaling in the Regulation of Macrophage Antimicrobial Immune Response: A Scoping Review
| Multiple authors | Scoping Review | 2024
Examines folate receptor-beta expression in activated macrophages and explores how folate signaling may influence inflammatory and antimicrobial immune responses.
One Carbon Metabolism and Its Implication in Health and Immune Functions
| Multiple authors | Review | 2024
Examines how folate and methionine cycles influence nucleotide production, protein modification, epigenetic regulation, homocysteine metabolism, and immune-cell differentiation.
Methylenetetrahydrofolate Reductase, the One-Carbon Cycle, and Cardiovascular Risks
| Multiple authors | Nutrients | 2021
Reviews MTHFR polymorphisms, homocysteine, folate metabolism, methylation, inflammation, and possible connections with cardiovascular disease.
Evidence of a Role for One-Carbon Metabolism in Blood Pressure
| Multiple authors | Advances in Nutrition | 2020
Reviews evidence connecting the folate-metabolizing MTHFR enzyme, B-vitamin nutrition, and genetic susceptibility to hypertension.
1-Carbon Cycle Metabolites Methylate Their Way to Fatty Liver
| Multiple authors | Trends in Endocrinology & Metabolism | 2017
Reviews the relationship between folate-linked methyl metabolism, S-adenosylmethionine, phosphatidylcholine production, and hepatic lipid accumulation.
Serine Is an Essential Metabolite for Effector T Cell Expansion
| Multiple authors | Cell Metabolism | 2017
Shows that serine feeds folate-dependent one-carbon metabolism and supplies glycine and carbon units required for nucleotide synthesis in proliferating T cells.
Novel Approaches to Investigate One-Carbon Metabolism and Related B-Vitamins in Blood Pressure
| Multiple authors | Nutrients | 2016
Reviews relationships among MTHFR, folate, riboflavin, 5-methyltetrahydrofolate, endothelial nitric-oxide signaling, and blood-pressure regulation.
Riboflavin Status, MTHFR Genotype and Blood Pressure: Current Evidence and Implications for Personalised Nutrition
| Multiple authors | Proceedings of the Nutrition Society | 2016
Examines how riboflavin status modifies consequences of MTHFR C677T and discusses genotype-specific nutritional approaches to folate metabolism.
Mitochondrial Biogenesis and Proteome Remodeling Promote One-Carbon Metabolism for T Cell Activation
| Multiple authors | Cell | 2016
Demonstrates that activated T cells strongly induce mitochondrial folate and one-carbon enzymes to provide nucleotides needed for clonal expansion.
Blood Pressure in Treated Hypertensive Individuals With the MTHFR 677TT Genotype Is Responsive to Intervention With Riboflavin
| Carol P. Wilson et al. | Hypertension | 2013
Reports a genotype-targeted trial showing that riboflavin, the FAD precursor required by MTHFR, can modify blood pressure in people carrying the MTHFR 677TT genotype.
Folate Metabolism and Cardiovascular Disease
| Yvo M. Smulders and Coen D. A. Stehouwer | Seminars in Vascular Medicine | 2005
Reviews folate absorption, intracellular metabolism, methylation, DNA synthesis, homocysteine, and possible cardiovascular consequences.
Microbiome, Microbial, Plant and Biotechnology Research
A Systematic Review of Folate and the Human Enteric Microbiome: Biological Mechanisms and Clinical Implications
| Multiple authors | Systematic Review | 2026
Reviews evidence that intestinal microbes both synthesize and consume folate, creating a microbiome-folate axis capable of influencing host one-carbon metabolism, methylation, genomic stability, immunity, and metabolic disease.
MASLD: Insights on the Role of Folate in Hepatic Lipid Metabolism
| Multiple authors | Review | 2025
Explores how folate-dependent one-carbon metabolism, methyl-group availability, gut microbial folate production, and phospholipid metabolism interact with hepatic lipid accumulation and metabolic liver disease.
Folate From Probiotic Bacteria and Its Therapeutic Applications
| Multiple authors | Applied Microbiology and Biotechnology | 2025
Reviews microbial folate synthesis by probiotic organisms and potential contributions of microbial folates to host nutrition and one-carbon metabolism.
Folate-Producing Bifidobacteria: Metabolism, Genetics, and Relevance
| Multiple authors | Microbial Biotechnology | 2024
Reviews folate biosynthetic genes across Bifidobacterium species and their potential use in probiotic and food-biofortification strategies.
Hypothetical Regulation of Folate Biosynthesis and Strategies for Folate Overproduction in Lactic Acid Bacteria
| Multiple authors | Microorganisms | 2024
Reviews regulation of microbial folate biosynthesis and strategies for selecting or engineering folate-overproducing lactic-acid bacteria.
Synthetic Biology-Driven Microbial Production of Folates: Advances and Perspectives
| Multiple authors | Bioresource Technology | 2021
Reviews metabolic engineering, biosensors, adaptive evolution, and synthetic-biology methods for increasing microbial production of folate vitamers.
Evolution of Folate Biosynthesis and Metabolism Across Algae and Land Plant Lineages
| Multiple authors | Scientific Reports | 2019
Compares genes and pathway organization involved in folate biosynthesis and metabolism across major plant and algal evolutionary lineages.
Formation of Folates by Microorganisms: Towards the Biotechnological Production of This Vitamin
| José Luis Revuelta et al. | Applied Microbiology and Biotechnology | 2018
Reviews microbial folate biosynthetic pathways and engineering strategies for industrial production and natural food biofortification.
Folate Biosynthesis Pathway: Mechanisms and Insights Into Drug Design for Infectious Diseases
| Multiple authors | Future Medicinal Chemistry | 2018
Reviews structural and mechanistic differences in microbial folate enzymes that can be exploited for pathogen-selective drug development.
Folates in Plants: Research Advances and Progress in Crop Biofortification
| Multiple authors | Frontiers in Chemistry | 2017
Reviews plant folate metabolism, physiological functions, environmental responses, and genetic approaches for increasing folate content in crops.
Folate Biosynthesis, Reduction, and Polyglutamylation and the Interconversion of Folate Derivatives
| Multiple authors | EcoSal Plus | 2015
Reviews bacterial production of dihydrofolate, reduction to tetrahydrofolate, folate polyglutamation, and interconversion of active one-carbon cofactors.
Folate Biosynthesis, Turnover, and Transport in Plants
| Andrew D. Hanson and Jesse F. Gregory III | Annual Review of Plant Biology | 2011
Reviews plant folate synthesis genes, subcellular compartmentation, degradation, transport, storage, and applications to food biofortification.
Tetrahydrofolate Biosynthesis and Distribution in Higher Plants
| T. Sahr et al. | Biochemical Society Transactions | 2005
Describes the unusual compartmentation of plant tetrahydrofolate synthesis among plastids, cytosol, and mitochondria.
One-Carbon Metabolism in Plants: Regulation of Tetrahydrofolate Synthesis During Germination and Seedling Development
| Multiple authors | Plant Physiology | 2003
Shows that folate biosynthesis changes with tissue proliferation, photosynthetic development, and demand for nucleotide and methyl-group synthesis.
The Folic Acid Biosynthesis Pathway in Bacteria: Evaluation of Potential for Antibacterial Drug Discovery
| Alun Bermingham and Jeremy P. Derrick | BioEssays | 2002
Reviews enzymes converting GTP and PABA into dihydrofolate and evaluates their structural suitability as antimicrobial drug targets.
Synthesis and Turnover of Folates in Plants
| Andrew D. Hanson and Jesse F. Gregory III | Current Opinion in Plant Biology | 2002
Reviews plant folate synthesis, intracellular compartmentation, turnover, transport, and emerging genomic approaches.
Folates and One-Carbon Metabolism in Plants and Fungi
| Multiple authors | Trends in Plant Science | 1997
Reviews folate-dependent synthesis of purines, thymidylate, serine, methionine, and formylmethionyl-tRNA in plant and fungal systems.
Methods, Measurement and Computational Models
Computational Modelling Folate Metabolism and DNA Methylation: Implications for Understanding Health and Ageing
| Multiple authors | Briefings in Bioinformatics | 2018
Reviews mathematical models connecting the folate cycle, methionine metabolism, methyl-donor production, and DNA methylation.
Analytical Recovery of Folate Degradation Products Formed in Human Serum and Plasma at Room Temperature
| Rita Hannisdal et al. | Journal of Nutrition | 2009
Demonstrates degradation of 5-MTHF after blood collection and identifies products relevant to accurate laboratory measurement of folate status.
Mathematical Models of Folate-Mediated One-Carbon Metabolism
| H. F. Nijhout et al. | Vitamins and Hormones | 2008
Reviews mathematical approaches for understanding regulation, compartmentation, nutritional variation, and genetic variation across the complex folate network.
A Mathematical Model Gives Insights Into Nutritional and Genetic Aspects of Folate-Mediated One-Carbon Metabolism
| Michael C. Reed et al. | Journal of Nutrition | 2006
Models the effects of nutrient availability and genetic differences on folate pools, methylation capacity, homocysteine, and nucleotide synthesis.
Simple Method for the Quantitative Analysis of Endogenous Folate Catabolites by LC-MS/MS
| Multiple authors | Journal of Chromatography B | 2006
Establishes a mass-spectrometric approach for measuring folate degradation products in serum and urine.
Quantitation of In Vivo Human Folate Metabolism
| Multiple authors | American Journal of Clinical Nutrition | 2004
Uses radiolabeled folate and kinetic modeling to estimate human folate absorption, tissue stores, biliary recycling, polyglutamation, and catabolism.
Microbiological Assay on Microtitre Plates of Folate in Serum and Red Cells
| Multiple authors | Journal of Clinical Pathology | 1992
Describes a microbiological method for measuring serum and red-cell folate and evaluates assay precision, recovery, and response to different folate forms.
The Quantitative Analysis of Endogenous Folate Catabolites in Human Urine
| Multiple authors | Analytical Biochemistry | 1992
Develops methods to quantify p-aminobenzoylglutamate and related compounds generated during normal folate breakdown and turnover.
Stable-Isotope Methods for Assessment of Folate Bioavailability
| Jesse F. Gregory III et al. | American Journal of Clinical Nutrition | 1990
Establishes isotope-tracer approaches for studying folate absorption and metabolism in humans without relying solely on changes in total circulating folate.
