Vitamin B9
VitB9
Folate, Tetrahydrofolate(THF), 5,10-methylene THF, 10-formyl THF, 5-formimino THF, 5,10-methylenyl THF, 5-methyl THF
Daily Requirement:
Modified DV:
RDA ?:
Adequate Intake ?:
400
true
DFE/d
DFE/d
Min Deficiency:
Max Toxicity:
Tolerable UL
Animal:Plant Conv:
1000
DFE/d
DFE/d
DFE/d
Date Discovered:
1941
Short Description:
One-carbon transfer reactions for nutrient metabolism and energy production; gene expression; purien and pyrimidine synthesis for DNA and RNA; hematopoiesis. Major Food Sources: Green vegetables = spinach, asparagus, and greens; legumes; fortified grain products. RDA: 400 mcg
Interpretation:
Main sources:
Animal Products: Liver, dairy products, egg yolks
Plant Products: Oranges, Dark leafy vegetables, peanuts & beans
Dietary methyl donors and DNA methylation
• What nutrients are considered methyl donors
Single carbon metabolation pathway, folate, zn, b6, b12, methionine, choline
• Where does DNA methylation normally occur
CpG islands, promoters of genes. folate deficiency has - dutch hunger study - starvation causes problems later in life, first trimester - igf2 dna methylation lack. folate deficiency uracil misincorporation. If folate deficiency, uracil can't turn into thymine. Causes strand breaks, two uracil residues = double strand breaks - bad.
• What is the significance of the agouti mouse experiments
Dietary exposure of your grandma can effect your genotype. Your egg was exposed to that that diet.
• Why are dietary methyl donors important in cancer, what are the mechanisms
If low methyl donors, aberrant methylation, chance for uracil -> cancer
History & Discovery:
1941
Digestion:
Jejunum is the main site of digestion and absorption.
Food folates with many glutamine (3 or 7) need to be broken down by proton-coupled folate transporter PCFT in the membrane of the enterocyte. Then the food folate with one Glu is brought into the enterocyte as either THF or 5,10-methylene-THF, which goes to 5-methyl-THF for transport to the Plasma through multidrug resistant-associated protein (MRP).
Stored in small quantities in liver, kidneys, and spleen for 3-4 months.
Uptake into tissues requires proton-coupled folate transporter (PCFT) or organic anion transporting polypeptides (OATP) B1 and B3.
5-methyl-THF is the main form in blood plasma.
Folate is found as free (33%) or bound to albumin and alpha2-macroglobin (66%)
Absorption and Storage:
AI of folate = 320 mcg/day.
Folic acid from supplements/fortified foods is more bioavailable. This is taken into account for Dietary Folate Equivalents (DFE).
1 DFE = 1 mcg of food folate = 0.5 mcg folic acid from supplement on empty stomach
1 DFE = 1 mcg of food folate = 0.6 mcg folic acid from fortified food (1.7 factor)
Example:
Half cup of avocodo = 60 mcg of folate
Slice of bread = 50 mcg of folic acid * 1.7 = 85 mcg
Folate is degraded by heat, oxidation and UV light.
Overall absorption is 10-90% or 50% on average due to food matrix and inhibitors.
Folate bioavailability of beef liver, lima beans, peas, spinach, mushrooms, collards, orange juice and wheat germ was estimated with a protocol of folate depletion-repletion using growth and liver, serum and erythrocyte folate of weanling male rats. Diets with 125, 250 and 375 micrograms folic acid/kg were standards. Individual foods were incorporated into a folate-free amino acid-based diet alone (250 micrograms folate/kg diet from food) or mixed with folic acid (125 micrograms folate from food + 125 micrograms folic acid) to evaluate folate bioavailability and effects of food matrix. Beef liver and orange juice folates were as available as folic acid, whereas those of wheat germ were less bioavailable. Folates of peas and spinach were also less available than folic acid using liver and serum folate concentrations and total liver folate as response criteria, but they were not lower when based on growth and erythrocyte folate concentrations. Lima bean, mushroom and collard folates were as available as folic acid using four of five response criteria. Folate bioavailability of all foods generally exceeded 70%. All response criteria gave approximately equivalent results, indicating that growth and tissue folate levels are appropriate criteria. No food matrix effects were observed for any food except lima beans. Foods rich in polyglutamyl folates were less bioavailable than those of foods rich in short-chain folates. https://pubmed.ncbi.nlm.nih.gov/2007897/
Folic acid, 5-formyl THF and 5-methyl THF absorbed intact.
Folate in food needs to be converted to tetrahydrofolate (monoglutamate form) by folate hydrolase, which requires Zn.
Jejunum is the main site of digestion and absorption.
Important Pathways:
Folate Appearance
Folate Forms
Folate = tetrahydrofolate (food form) + folic acid (oxidized version, found in supplement form)
Humans can synthesize each individual part but we cannot link pteridine to PABA
One glutamic acid on figure, but typically attached to 3 or 7 glutamic acids in the body and in food which is called a 'glu tail'. 75% of folate exists in this form.
Function of Folate:
One carbon transfer or methyl donor. "Dumping" a methyl on B12 (CH3), which can then be dumped onto homocysteine to be turned into S-adenosyl methionine = central methyl donor which is important for anabolic reactions.
DNA Synthesis
5,10-methyleneTHF reacts with dUMP to create dTMP which can be used for DNA synthesis. Or it can become 5-methylTHF to react with homocysteine to become methionine which can enter the SAM cycle to lead to DNA methylation.
Reactions between Forms of Folate
SAM Cycle
Homocysteine -> Cystathione -> Leads to succinyl CoA, glucose, glycine, Heme
Deficiency Diseases, Detection, Cures:
Red blood cells normally divide, yet this doesn't happen with folate or B12 deficiency.
Deficiency disease:
Common in early 1900's in young. female workers in former British colonies.
Tropical megaloblastic anemia - hyperpigmentation of fingers before treatment of anaemia (A)
Reduction 3 months after treatment (B)
Peripheral blood film shows hypersegmented neutrophils (green arrowheads), macrocytes (blue arrowheads), and a teardrop shaped red blood cell (red arrowhead). (C)
Erythropoiesis: maturation of red blood cells
Hematopoietic stem cell -> Proerythroblast -> Megaloblastic red blood cell due to folate deficiency -> Erythroblasts - two cytosols but no nuclei division (requires carbon donor folate) -> Large immature red blood cells -> Megaloblastic anemia - fewer red blood cells to take up iron -> heme iron deficiency
Recommendation: Take 400 mcg DFE/day 1-3 months before pregnancy and first month to help with embryonic neural tube closure to prevent anencephaly.
Symptoms of Deficiency:
cardiomegaly, tachycardia, shortness of breath
megaloblastic anemia