Folate

FOLATE

Megaloblastic anemia research in 1870s-1880s discovered folate and B12's role, eating liver shown to cure the disease.

Folate is the reduced form of the vitamin (found in foods, tissues).
Folic acid is the oxidized form (not in foods, but used in supplements).

Sources:

Liver 200 ug/3-oz
85% bioavailable

Digestion, Absorption, Transport, Storage

Folic acid (fortified, supplements) does not require digestion = monoglutamate form.
Folate (foods) does = polyglutamate.

• Hydrolysis or deconjugation performed by 2 gamma-glutamyl carboxylpeptidases to convert to monoglutamate forms.
• Zinc deficiency and more acidic small intestinal pH (eg pancreatic insufficiency of bicarbonate release) diminish enzyme activity
• Alcohol ingestion and inhibitors in foods (eg legumes, lentils, cabbage, oranges) also limit enzyme activity

Transporter into intestinal cells = PROTON-COUPLED FOLATE TRANSPORTER (PCFT)

• Vitamin D and Retinoic acid influence PCFT gene expression
• Hereditary folate malabsorption from mutations in PCFT gene
• Overall absorption = 50%

In the intestinal cell:

• Folic acid and Folate are reduced to DIHYDROFOLATE (DHF) and then to THF
• Occurs via action of NADPH-dependant DIHYDROFOLATE REDUCTASE
• Folate binding proteins transport folate into portal blood as FOLATE and 5-methyl THF (all forms are monoglutamates, NOT poly).

Uptake into the liver and other tissues:

• Carrier mediated, delivered by REDUCED FOLATE CARRIERS (RFC).
• FOLYPOLYGLUTAMATE SYNTHESTASE catalyzes the ATP dependant addition of glutamates and traps folate within LIVER CELLS

In  systemic blood;

• 1/3 free, 2/3 bound to protein
• Major forms: THF, 5-methyl THF, 10-formyl THF
• Plasma [ ] = 3-20 ug/L
• More folate in RBC than plasma, enters RBCs during erythropoeisis.
• RBC folate = longer term folate status (2-3 months)

Body Stores:

• 7-30 mg
• 1/2 in liver
• Major storage forms: polyglutamate of THF and 5-methyl THF

FUNCTIONS AND MECHANISMS OF ACTION

The THF DERIVATIVES:

• Found in mitochondria, cytosol, nucleus
• Serve as donors of single or one-carbon groups in reactions
• Reaction involve:
• Metabolism of several nutrients:
• Choline
• Amino Acids
• Purine and Pyrimidine production
• Thus, folate critical for DNA synthesis and repair
• Impacts on cell division
• Carrier of methyl groups
• Impacts gene expression

Genetic polymorphisms

• 50 mutations have been identified in METHYLENE THF REDUCTASE (MTHFR)
• An FAD-dependant enzyme converts 5,10 methylene THF to 5-methyl THF

1. AMINO ACID AND CHOLINE METABOLISM
1. Serine and Glycine Degradation
2. Choline Degredation
3. Histidine Degredation
4. Methionine and SAM Synthesis

1. GENE EXPRESSION
2. PURINE AND PYRIMIDINE SYNTHESIS / NUCLEOTIDE METABOLISM

INTERACTIONS

Methyl-Folate Trap

Homocysteinemia >11 umol/L due to deficiency in folate, B12 or B6

METABOLISM AND EXCRETION

Urine = Feces > Bile

RDA

400 ug/d, 600/d with pregnancy

DEFICIENCY

1-2 months of deficient diet ~ reduced serum levels, high homocysteine

3-4 months ~ reduced RBC folate

4-5 months ~ megaloblasts

RX: 1-5 ug folate daily

TOXICITY

TUL 1,000 ug or 1 mg 

ASSESSMENT

Serum < 3 ug/L

RBC < 140

FIGLU excretion

Deoxyuridine suppression test

Homocysteine levels