Folate

Question 1

folate terminology

Answer 1

Folate = food form that is a family of compounds with 1 to 9
Glu [mostly 3 to 8]
when Glu >1, call these polyglutamate forms
this is the way folate is found in cells

Question 2

folic acid terminology

Answer 2

Folic acid = synthetic molecule with 1 Glu
also referred to as the monoglutamate form
is added to foods therefore called “synthetic” (although
some is found naturally)
is the fortification/supplementation form

Question 3

coenzyme form of folate

Answer 3

tetrahydrofolate THF

Question 4

2 steps of absorption that requires mono-Glu

Answer 4

absorption in GI at BBM
cell entry/exit, once in cell add Glu to make folate and keep inside cell

Question 5

folate absorption/bioavailability

Answer 5

enzyme conjugase remove all the Glu except 1 ( to digest folate to folic acid)
requires Zn

bioavail of food folate limited if low conjugase activity bc of Zn def
efficiency of conjugase not 100% - supplemental folic acid is more available than folate

Question 6

DFE

Answer 6

dietary folate equivalents
1mcg folate = 1 DFE
1 mcg folic acid = 1.7 DFE w food
1mcg folic acid = 2 DFE w/out food

Question 7

4 functions of folate

Answer 7

1. all bc of a 1 carbon transfer
2. aa and choline metab
3. gene expression
4. purine and pyrimidine synthesis/ nucleotide metab - DNA and RNA synthesis

Question 8

aa and choline metabolism reactions

Answer 8

serine and glycine interconversion

choline degradation

histidine degradation

methionine and S-adenosyl M synthesis (SAM)

Question 9

coenzyme role of folate, how its made, transport

Answer 9

THF
1) folic + 2hydrogen = dihydrofolate (DHF)
2) DHF + 2Hydrogen = THF (uses NADPH + H+ as donor)

folate exits enterocyte as methyl THF (mono-Glu) most folate is taken up by liver “stored in coenzyme form”

Question 10

folate metabolism pathway

Answer 10

1. cobalamin bound to methionine synthase, picks up methyl group on 5-methyl THF = THF + methylcobalamin
2. methylcobalamin (methionine synthase) donates methyl group to HCY = methionine + reforms cobalamin
3. THF reconverted to 5-methyl THF: serine hydroxymethyl transferase = 5, 10 methylene THF, methylene THF reductase converts 5, 10 methylene THF to 5-methyl THF, repeats cycle

Question 11

normal folate levels means that folate will enter cell as

Answer 11

5 methyl THF

Question 12

excess dietary intake of folate means folate will enter cell as

Answer 12

folate interconverts to DHF

DHF can convert to THF

OR

converts to 5, 10 methyl THF, used in dUMP->dTMP->dTTP-> DNA SYNTHESIS

Question 13

methionine synthase role

Answer 13

need free THF, removes methyl to make THF, donates to B12 which then donates to HCY to = MET

if B12 low/def this doesn’t happen and methyl is trapped in cell and other folate reactions can’t take place (HCY->MET)

Question 14

what is methyl trap

Answer 14

prevents (reduces) folate functions unless one consumes excess folate
If ingesting a lot of dietary folate, cell THF can be obtained from folate rather than methyl-folate
The “methyl trap” of B12 deficiency can be overcome with ingesting large amounts of folate, and symptoms of folate deficiency disappear except buildup of HCY; however, this does not cure B12 deficiency

Question 15

B12 def and excess folate

Answer 15

both functions decrease
Main symptoms of folate def: megaloblastic anemia bc of DNA impairment

only function effected is HCY to MET
- no anemia, B12 def symptoms DO occur

*UL for folate bc of masking

Question 16

primary folate def cause

Answer 16

lack of folate in diet

Question 17

folate food sources

Answer 17

green veg (spinach), legumes, mushrooms, liver, tea, beer, citrus fruit

Question 18

folate fortification

Answer 18

can higher than usa for white flour
can later allowed whole wheat flour to be fortified and pasta, not mandatory, whole GRAIN not fortified

Question 19

RDA folate

Answer 19

400 DFE
based on maintaining RBC folate levels, plasma folates and plasma HCY in normal range

Question 20

secondary folate def

Answer 20

drugs interfere: alcohol, anticonvulsants, anti-cancer, and prevent folate use (cancer one is intentional tho to prevent tumor DNA growth)

B12 def = methyl trap, has apparent folate def bc of lack of B12, adding excess folic overcomes folate def but B12 def continues

Question 21

folate storage

Answer 21

half the body’s folate is in the liver, bound to cell proteins

Question 22

3 problems of folate def

Answer 22

1. megaloblastic anemia
2. neural tube defects
3. Heart disease, dementia, cancer

Question 23

megaloblastic anemia mechanism

Answer 23

RBC most rapidly dividing cell, can detect need for DNA synthesis

dUMP, transfer methylene-THF + Serine = THF-methylene + GLY

THF methylene + /dUMP -> dTMP = DNA

Hb, Fe low, reduce oxygen carrying capacity of blood

Question 24

neural tube defects mechanism

Answer 24

lack of folate in developing fetus spina bifida

malform of embryonic neural tube
public health success story, decrease 50% of NTDs

fortfied flour about 100mcg/day

Question 25

folate and heart disease, dementia, cancer

Answer 25

for every 5mcmol/L increase HCY = 30 or 40% increase risk of heart disease no benefit if already had heart attack, longer term ingestion benefit, stroke protection seen w folic fortification cognitive benefits: slow dementia in countries where no fortification cancer prevention: folate prior to cancer onset prevent, after might greaten cancer progression bc hypermethylation of DNA possible = why fortification so controversial

Question 26

test of folate status

Answer 26

1. serum levels: measure transport, good measure but tends to rise quickly w ingestion, most North americans have lots in diet bc of fortification 2. RBC folate levels: better bc assess use at tissue level 3. functional: abnormal metabolite- formiminoglutamate in urine 4. high plasma HCY if poor folate status= reflects folate's role *several vits can do this so not specific, most elevated plasma HCY prior to fortification due to low folate but now usually B12 def

Question 27

UL folate

Answer 27

1mg for supplements and fortified, not foods 1000 mcg = 1700 DFEs high UF bc neurological effects of B12 def when masked and uncertain of large folate intakes