*B9

*Helps body make healthy new cells

*Important for women who may get pregnant

*Folic acid is the term used to refer to the oxidized form of the vitamin

*Folate: reduced form

*Discovery of folate and B12: bc megoblastic anemia

*Folate and B12: necessary for formation of normal RBCs and synthesis of DNA

Structure of Folate

*Mushrooms, green vegetables (spinach, cabbage, broccoli, brussels sprouts), legumes (lima and kidney beans), fruits (oranges and strawberries), and liver

*Lentils, spinach, blackbeans, sunflower seeds

*Higher in raw foods [bc heat liable]

*In foods, primarily as 7,8 dihydrofolate (polyglutamates)

*Folate fortification of flours, grains, cereals help prevent neural tube defects

*In supplements and in fortified foods, as folic acid (the most oxidized and stable form)

*Bacterial flora in distal ileum and in colon produce folate

*Food folate bioavailability can vary from 10% - 98%

*Folate bioavailability from a mixed ~50%

*Processing, food prep and cooking = major losses of food folate

-Water used for cooking leaches folate

-Heating

-Oxidative conditions

*Folate added to foods (supplement and fortification) = 85% available

*Folate taken while fasting = ~100% available

*Due to the diff, folate equivalents are used in RDA

*Polyglutamate forms in foods must be hydrolyzed to the monoglutamate form

*Chronic alcohol intake and conjugase inhibitors (in legumes, lentils, cabbages, and orange) can impair conjugase (hydrolase) activity

*Decrease digestion of polyglutamate = decrease folate absorption

*Folic acid in fortified foods doesn't need to be hydrolyzed bc it's already in the monoglut form

*Mostly jejunum

*Active transport at low concentrations

-Na+-dep, carrier-mediated

-Folate binding proteins

-Folate transporters

*Passive diffusion at high concentrations (pharmaceutical doses)

*Folate across the basolateral membrane to enter the blood is mostly carrier dependent

*Folate is found mostly as 5-methyl THF in portal circulation in monoflut forms or as oxidized folate

*Uptake into liver is carrier mediated by folate receptors

-Metabolized to polygluts and retained

-Released into blood as 5-methyl THF

-Secreted into bile [where none is lost, reabsorbed, recycled in SI]

*We cann't transport polygluts that are 1/ >2 gluts

*Glutamates are added one at a time onto THF by folylpolyglutamate synthetase for conversion to 5-methyl THF and 10-formyl THF (3-9 gluts)

-Polyglut form traps folate in cell

-Better substrate for folate-dep enzymes than the monoglut form

*Before release into systemic blood, glutamate residues will be removed from polyglutamate by hydrolases

*In blood, folate found as monoglut (THF, 5-methyl THF, and 10-formyl THF)

-2/3 of folate is bound to FBPs and 1/3 as free folate

Interconversions of coenzyme forms of THF

Folate - Transport

*[Folate in RBCs] > [Folate in the plasma]

*RBC folate is only attained during erythropoeiesis

*RBC folate is used as an index of longer-term folate status

*Folate in RBCs don't come out

*Liver stoes 1/2 of body's folate

*Polyglut forms of THF and 5-methyl THF = main storage forms

*Folate is found in cytoplasm and mitochondria of cells

-Coenzyme to accept and donate one-C units

*When the supply of dietary folate is limited, availability of folate to active tissues is carefully regulated through changes in the rate of polyglut synthesis

*The less active tissues return monoglut to the liver and redistribute them to active tissues

*Excreted mostly as folate metabolites in both urine and feces

*Within kidney, high-affinity folate binding proteins resorb folate

*Folate is secreted by liver into the bile

*Most of them are reabsorbed, enter hepatic recirculation (liver-gall bladder-si), so fecal loss is minimal

**1-Carbon metabolism

*Amino acid metabolism:

-Histidine catabolism

-Interconversion of Serine and Glycine

-Methionine regeneration from homocysteine

*Purine and pyrimidine synthesis:

-Important in DNA and RNA synthesis

*Serine is a major source of one-C units for use in folate rxns

*The conversion of Gly to Ser is reversible

Methionine from Homocysteine

*Vit B12 deficiency causes a metabolic folate def

*B12 is needed to accept the methyl group from 5-methyl THF

*Without B12, folate gets trapped as 5-methyl-THF

*Other forms of active folate are reduced bc most us THF tied up as 5-methyl THF

*The involvement of folate in purine and pyrimidine synthesis: essential for cell division

*During DNA replication before the cell mitosis, pyrimidines (cytosine and thymine) and purines (Adening and guanine) are required

*RDA Men/Women: 400ug/d

*The diff in bioavailability of folate has led to the use of Dietary Folate Equivalents (DFE)

-Folate trapped in food

-Instability of various THF forms in intestinal tract

-Removal of GLUs in food folates not complete

-Individual variations

*1 DFE = 1ug of food folate

*0.6ug of folic acid from fortified food or supplement

*0.5ug of synthetic folate supplement taken on empty stomach

*Bioavailability: supplemental folic acid on empty stomach > folic acid fortified in food

*If a mix of food folate and folic acid fortified food has been consumed then:

*DFE = ug food folate + (1.7 x ug folic acid)

-Food folate is ~50% bioavailable

-Folic acid taken with food is ~85% bioavailable [1.7x (=10fol/6folic acid) more available than food folate]

-Folic acid taken in fasting conditions is ~100% bioavailable [2x (=10folate/5synthetic folate) more available than food folate]

*Plasma, serum, or RBC folate levels

*FIGLU (N-formiminoglutamate) urinary excretion

-Formed during catabolism of histidine, needs THF to completely breakdown

-Given oral histidine and measure FIGLU excretion in the urine

-Folate deficiency = FIGLU excretion increases bc no folate to break it down

*[Plasma homocysteine]: a functional marker of folate and B12 deficiencies

*Deoxyuridine suppression test: measures the availability of folate for thymidine synthesis

*Anemia, fatigue, paleness, irritability, shortness of breath, dizziness

*A severe deficiency may result in depression, dementia, peripheral neuropathy, megaloblastic anemia, hyperhomocysteinemia

*Deficiency also associated with increased cancer risk and neural tube defects

*Who is at risk?

-Chronic alcohol abusers, elderly, pregnant women, ppl on anticonvulsant meds

*Low plasma folate = low RBC folate = Megaloblastic anemia

*The release into circulation of RBCs that are fewer than normal and large and immature

*Why larger RBCs?

-Abnormal DNA synthesis and failure of blood cells to divide properly + continued formation of RNA

-Amount of RNA becomes greater than normal which leads to excess production of cytoplasmic constituents (including Hgb)

*Can also be caused by B12 def

*If caused by folate def, supplement with folic acid

*Important to determine cause of megaloblastic anemia b4 treatment

*Folate supplementation can "mask" the more serious consequences of B12 def by relieving the anemia w/o addressing entire def

*Serious, irreversible neurological damage may result if the vit B12-requireing pathways are not corrected

*Heart disease

-Hyperhomocysteinemia: def in vit B6, folate, or B12

*Cancer

-Low [blood folate] is associated with risk of cancer

-Folate is needed for DNA synthesis and repair

*Methotrexate is used to treat cancer: competes with DHFR which in turn inhibits the conversion of DHF to THF w/h is required for the synthesis of DNA

-Since cancer cells are rapidly dividing they are rapidly synthesizing DNA

*NT is the part of the fetus that becomes the spinal cord and the brain

*NTDs: birth defects occurring in the brain or spinal cord- the most common of all serious birth defects

*Adequate folate intake during the periconceptual period, the time just before and just after a woman becomes pregnant, reduces the risk of NTDs

*Spina bifida: opening in bones in spine, but no spinal cord damage

*All women of childbearing age should consume 400ug folic acid/d

*These birth defects of the spine and brain occur before most women know they are pregnant

*Foods made from enriched flour, many breakfast cereals, multivitamins

*National Birth Defects Prevention Study:

*How a woman's intake of micronutrients and the way in which her body uses folic acid may affec risk of heart defects

*How much women know about folic acid, NTD and other defects

*US-China Collaborative Project:

*Effect of 400ug folic acid before and during early pregnancy prevents NTDs

*Mothers took 400ug folic acid = decrease risk of NTD

*NHANES:

*Look at population's folic acid intake and [blood folate]

*2.7% of adults consumed >  the UL of folic acid

*By 3 major folic acid intake sources- enriched cereal grain products, ready-to-eat cereals, and supplements

*Rare

*UL: Men/Women: 1000ug/d in supplements

*The UL applies to syntheti forms of folate obtained from supplements and fortified foods

*Insomnia, irritability, gastrointestinal probs

*The various forms of folate differ based on redox state, number of Glu residues, and the one-carbon constituent

*Primary active form = polyglutamated THF

*Folate plays a role in AA metabolism, hematopoiesis, and DNA synthesis

*Folate intake is critical in the periconceptual period

*Folate supplementation can mask vit B12 def

*Folate may play a role in preventing some types of cancer and heart disease