Role of Folate in Human body

Introduction and Chemical Nature

Definition: Folate (Vitamin B9) is a water-soluble vitamin belonging to the B-complex group,.
Forms:
- Folic Acid (Pteroylglutamic acid): This is the synthetic form found in fortified foods and supplements. It is a monoglutamate.
- Naturally Occurring Folates: These retain the core chemical structure but vary in their reduction state and the length of the glutamate chain (polyglutamates).
Bioavailability: Polyglutamates found in vegetables are generally less bioavailable than the pteroyl monoglutamate form (folic acid).
Active Coenzyme: Most folates are reduced to tetrahydrofolate (THF), which is the metabolically active form.

Intestinal Absorption:
- Folate is readily absorbed from the small intestine.
- Dietary polyglutamates must first be hydrolyzed and reduced to monoglutamate derivatives (dihydrofolates and tetrahydrofolates) by mucosal polyglutamate hydrolases in the small intestine before absorption,.
- A high-affinity proton-coupled folate transporter (PCFT) is essential for the absorption of folate in the intestine.
Transport and Storage:
- 5-methyltetrahydrofolate (5-MTHF) is the predominant form in which dietary folate enters the circulation.
- The vitamin undergoes enterohepatic recirculation, which prolongs its half-life.
- Folate is also synthesized by colonic bacteria.

Folate functions as a coenzyme in amino acid and nucleotide metabolism.
It acts as an acceptor and donor of one-carbon units.
Serine serves as an important one-carbon donor, allowing the entry of THF into the active one-carbon pool via 5,10-methylene-THF.

Folate is essential for the synthesis of nucleic acids.
Purine Synthesis: 10-formyl-THF is required for purine biosynthesis.
Pyrimidine Synthesis: 5,10-methylene-THF functions as a cofactor for the synthesis of thymidine (pyrimidine).
Consequently, folate is critical for normal cell growth, division, and repair.
Tissues with active cell division or regeneration, such as bone marrow and intestinal cells, have high folate requirements.

Folate is involved in the metabolism of several amino acids, including the interconversion of glycine and serine,.
Remethylation Cycle:
- Folate (specifically 5-methyltetrahydrofolate) is required for the conversion of homocysteine to methionine.
- This reaction is catalyzed by methionine synthase and requires Vitamin B12 (methylcobalamin) as a cofactor.
- This process regenerates tetrahydrofolate from 5-methyltetrahydrofolate.
Clinical Significance: In the absence of folate (or B12), homocysteine accumulates, leading to hyperhomocysteinemia, which is a risk factor for vascular disease,.

Folate is essential for the maturation of red blood cells.
It works in conjunction with Vitamin B12 to facilitate normal erythropoiesis.
Deficiency hinders erythropoiesis, causing the release of large, immature red blood cells (megaloblastic anemia),.
The deficiency affects the tissues with the fastest rate of cell replacement first, notably the bone marrow.

Folate regulates neurulation and neural tube closure during the critical first 4 weeks of pregnancy.
It is vital for central nervous system (CNS) development during embryogenesis.
Adequate maternal status during this "critical window" is necessary to prevent neural tube defects (NTDs) such as spina bifida and anencephaly,.
Folate acts as a gene activator and informational molecule that triggers developmental programs.

Folate is categorized as a "smart nutrient" or "super nutrient" that promotes brain growth and function,.
Cerebral folate deficiency (a condition where folate transport into the brain is blocked) leads to severe neurologic deterioration, including microcephaly, developmental delay, ataxia, and seizures.
It is involved in the synthesis of neurotransmitters.

There is a close metabolic relationship between folate and Vitamin B12.
The conversion of homocysteine to methionine helps in folate regeneration (Homocysteine + N5-methyltetrahydrofolate -> Methionine + Folate).
In the absence of Vitamin B12 (cobalamin), folate gets "trapped" as 5-methyltetrahydrofolate and cannot be utilized for DNA/RNA synthesis.
This functional folate deficiency leads to megaloblastic anemia indistinguishable from primary folate deficiency,.
Therapeutic Implication: Treating megaloblastic anemia with folic acid alone when the underlying cause is B12 deficiency can correct the anemia but allows neurological damage (subacute combined degeneration) to progress irreversibly,.

Plant Sources: Dark green leafy vegetables (spinach, lettuce, mustard greens), beans, legumes (peas), broccoli, sprouts, and sunflower seeds,,.
Fruit Sources: Citrus fruits (oranges, lemons), melons, bananas, and papaya,,.
Animal Sources: Liver is a good source,.
Fortified Foods: Enriched cereals, wheat flour, and bread products,.
Stability: Folate is heat-labile; much of it can be lost during cooking or prolonged storage. Repeated washing of vegetables in large amounts of water can also lead to loss.

Increased Requirements: Periods of rapid growth (infancy, adolescence), pregnancy, and lactation,.
Malabsorption: Celiac disease, inflammatory bowel disease, short bowel syndrome, and chronic gastrointestinal infections.
Drugs:
- Anticonvulsants (phenytoin, phenobarbital, carbamazepine) increase hepatic catabolism of folate,.
- Methotrexate acts as a folate antagonist.
Hemolytic Anemia: Conditions like sickle cell anemia increase bone marrow erythropoiesis, raising folate demand.
Genetic Disorders: Hereditary folate malabsorption (PCFT gene mutation) and inborn errors of metabolism.

Hematological: Megaloblastic anemia (macrocytosis, hypersegmented neutrophils) and pancytopenia,.
Gastrointestinal: Glossitis, diarrhea, and oral ulcerations,.
Developmental: Growth stunting and neural tube defects in the fetus.
Dermatological: Knuckle and periungual pigmentation (similar to B12 deficiency).
Other: Hyperhomocysteinemia.

Periconceptional Supplementation: All women capable of becoming pregnant should consume 400-800 µg of folic acid daily starting at least 1 month before conception and continuing through the first 2-3 months of pregnancy to prevent NTDs,.
Recurrence Prevention: Women with a previous child with an NTD require a higher dose (4 mg/day).
Anemia Prophylaxis: Folic acid (usually 100 mg) is combined with iron (20 mg elemental) for anemia prophylaxis in children,.
Adolescent Health: Weekly iron and folic acid supplementation is recommended to reduce future anemia prevalence and improve pregnancy outcomes.
Therapeutic Dose: Treatment of deficiency involves 0.5–5 mg/day orally for 3–4 weeks or until hematologic response occurs, followed by maintenance,.