What is folate?

What is Folate?

Folate is a water-soluble B-vitamin (vitamin B9) that serves as an essential cofactor for DNA and RNA synthesis, amino acid metabolism, and methylation reactions throughout the body. 1

Chemical Structure and Forms

Folate is a generic term referring to a family of molecules that vary based on their oxidation state, one-carbon substitution groups (methyl, methylene, methenyl, formyl, formimino), and glutamate side-chain length. 1 This family includes:

• Naturally occurring folates found in foods 1
• Synthetic folic acid used in supplements and fortified foods 1, 2
• Biologically active forms including folinic acid and 5-methyltetrahydrofolate (5-MTHF) 1

The chemical structure consists of a pteridine ring linked by a methylene bridge to para-aminobenzoic acid, which is joined by a peptide linkage to glutamic acid. 2

Critical Biological Functions

Folate, as tetrahydrofolate, is required for the body to make DNA and RNA and metabolize amino acids. 1 Specific functions include:

• One-carbon metabolism in the cytoplasm: Required for synthesis of purines and thymidylate, and remethylation of homocysteine to methionine 1
• Mitochondrial one-carbon metabolism: Required for synthesis of formylated methionyl-tRNA 1
• Methylation reactions: Provides methyl donors for biosynthetic methylation of DNA and histones, influencing gene expression and neurotransmitter synthesis 1
• Cell division and growth: Essential for mitotic cell division, particularly important in rapidly proliferating tissues including fetal development 1

The transfer of one-carbon units appears to be the only function of folate coenzymes in the body. 1

Absorption and Metabolism

Folates are absorbed in the duodenum and jejunum through a pH-dependent carrier-mediated process. 1 Key metabolic points:

• Dietary folate polyglutamates are hydrolyzed into monoglutamate forms before absorption 1
• Folic acid is converted in the liver to dihydrofolic acid and eventually to tetrahydrofolic acid with the aid of DPNH and folate reductases 2
• Vitamin C improves folate bioavailability by limiting degradation of natural folate coenzymes and folic acid supplements in the stomach 1
• After oral administration, folic acid appears in plasma within 15-30 minutes, with peak levels reached within 1 hour 2

Dietary Sources and Requirements

Nutritional sources of folate include pulses (edible seeds from legumes), leafy green vegetables, eggs, nuts, and whole grain products. 1 Specific requirements:

• General population: Dietary Reference Intake (DRI) of 250-400 μg/day of dietary folate equivalents (DFE) 1
• EFSA recommendation: 330 μg DFE for adults 1
• Pregnant and lactating women: Approximately twice the standard requirement (500-600 μg DFE/day) 1
• Neural tube defect prevention: 400 μg/day of folic acid for women planning pregnancy 1, 3

Dietary Folate Equivalents (DFE)

Food folates have lower bioavailability than synthetic folic acid. 1 The conversion is:

• 1 μg DFE = 1 μg food folate
• 1 μg DFE = 0.6 μg folic acid from fortified food or supplement with food
• 1 μg DFE = 0.5 μg folic acid supplement on empty stomach or IV 1

Assessment of Folate Status

Folate status is conventionally assessed by measuring levels in serum/plasma or red blood cells (RBC). 1, 3

• Serum/plasma folate: Earliest indicator of altered folate exposure, reflects recent dietary intake 1, 3
• RBC folate: Sensitive marker of long-term folate status, reflects folate accumulation during preceding 3 months and tissue stores 1, 3
• Normal ranges: Serum folate ≥10 nmol/L (4.4 ng/mL); RBC folate ≥340 nmol/L (150 ng/mL) 3
• Gold standard measurement: Microbiological assay using Lactobacillus rhamnosus 1, 3

Plasma homocysteine concentrations are also measured as a functional marker of folate status, though this is also affected by vitamins B2, B6, and B12 status and renal impairment. 1

Clinical Significance and Deficiency

Folate deficiency can lead to megaloblastic anemia, pancytopenia, glossitis, angular stomatitis, oral ulcers, and neuropsychiatric manifestations. 3 The deficiency impairs thymidylate synthesis, leading to defective DNA synthesis that causes megaloblast formation and macrocytic anemia. 2

Populations at particular risk include:

• Preterm infants (show low serum folate in first 2-3 months of life) 1
• Patients after distal ileum resection, gastrectomy, or bariatric surgery 1
• Women of childbearing age (for neural tube defect prevention) 1
• Individuals with MTHFR polymorphism 4

Important Clinical Considerations

When measuring folate, always assess vitamin B12 status simultaneously, as folate supplementation can mask B12 deficiency. 3 Both deficiencies can cause elevated homocysteine levels, but isolated folate deficiency is differentiated by normal cobalamin and methylmalonic acid (MMA) levels. 1

Total daily folate consumption should be kept below 1 mg per day to avoid potential complications, including masking vitamin B12 deficiency. 3 However, women with a history of neural tube defects may require 4 mg/day under medical supervision. 1

Folate forms are susceptible to degradation by light, temperature, pH, and oxygen, requiring careful pre-analytical precautions during sample collection and preparation. 1, 3