Folate

folic acid

reduced, synthetic form of the vitamin used in supplements and fortified foods

folate

oxidized, naturally occurring form of the vitamin found in foods and biological tissues

tetrahydrofolate (THF)

active coenzyme form

monoglutamate form

very stable, requires no digestion, and is readily absorbed; the form found in synthetic sources

polyglutamate form

form found in nature, requires digestion prior to absorption

describe the digestion of the polyglutamate form of folate

folate hydrolase breaks the polyglutamate form of folate down into the monoglutamate form and a glutamate chain

this process occurs mainly in the small intestine, as folate hydrolase require an alkaline environment

How can zinc deficiency affect folate levels?

folate hydrolase are zinc-dependent, so a zinc deficiency reduces folate digestion

proton coupled folate transporter (PCFT)

main transporter of mono glutamate folate into the intestinal cells in the jejunum and duodenum, but it requires an acid pH (between 5.5-6)

Multi-drug resistant-associated protein 3 (MRP3)

transporter that transports folate across the basolateral membrane into portal blood

reduced folate carrier (RFC)

absorbs bacterially produced folate in the colon

What can reduce folate hydrogenase activity?

folate hydrogenase inhibitors in certain foods (like legumes, lentils, cabbage, and oranges), oral contraceptives, chronic alcohol consumption, zinc deficiency, suboptimal lumen pH

What can reduce folate bioavailability?

Vitamin A and D deficiency, trauma, bypass surgery, IBS, and celiac disease

5 methyl THF

major form of folate found in systemic blood and cerebral spinal fluid

How is folate transported?

either freely or bound to proteins (albumin)

What happens to folate inside of cells?

the monoglutamate form of folate is taken up by the body cells and glutamates are added back to create polyglutamate folate, which traps folate inside of cells, prevents degradation, and enables storage

Where is folate stored in the body?

primarily in the liver but also in RBCs

Describe folate excretion

only a small amount is secreted in the urine and feces because the human body has an efficient enterohepatic recirculation that almost completely reabsorbs it

folate function

essential for cell division, carries methyl units in methylation reactions

Describe how 5 methyl THF can be converted to methionine

5 Methyl THF donates a methyl to cobalamin to create methylcobalamin

Methylcobalamin donates a methy to homocysteine using the methane synthase enzyme to create methionine, an amino acid

Describe how THF can be converted back to 5 methyl THF

THF can be converted to 5,10 methylene THF, and methylene THF reductase (MTHFR) coverts 5,10 methylene THF back to 5 methyl THF

Why are high levels of homocysteine dangerous?

for every 5umol/L increase in serum homocyteine levels, heart disease risk increases by 20-30%

How can homocysteine be converted to cysteine?

Cystathione synthase, which is PLP (vitamin B6) dependent, converts homocysteine to cystationine, and then the cysteine

methyl folate trap

caused by a lack of vitamin B12, which traps 5 methyl THF, lowering THF, methylcobalamin, methionine, and SAM and increasing homocysteine levels (since it can’t be converted to methionine)

consequences of the methyl folate trap

hyperhomocyteinemia, which increases CVD risk

impaired DNA methylation, DNA synthesis, and cell division which can impair gene expression and blood formation (causing anemia), along with other rapidly dividing cells

How is methionine converted to homocysteine?

Methionine is converted to SAM (s-adenosyl methionine) but methionine adenosyl transferase. Then SAM is converted to S-adenosyl homocysteine after donating a methyl group. Finally, the adenosine is removed to create homocysteine again

SAM (s-adenosyl methionine)

essential methyl donor in methylation reactions, including DNA methylation that impacts gene expression

What level of folate supplementation can increase cancer risk and mortality?

2.5x folate recommendation

Dietary sources of folate

lentils and legumes, beans, vegetables, liver, certain fruits and juices

How does heat and processing affect folate content in food?

folate content is reduced by 50-80% by food processing, preparation, heat, and exposure to UV light

spina bifida

opening in the spinal cord

anencephaly

absence of major portions of the brain

How much folic acid is added to fortified products?

140ug/100g of product

Why do we use DFE (dietary folate equivalent) for folate recommendations?

DFEs account for the higher bioavailability of folic acid consumed from supplements and fortified foods versus natural folate in food

How to calculate DFEs?

Method 1: 1 DFE=1.0ug natural food folate, 0.6ug folic acid from fortified foods or supplements taken with food, 0.5ug folic acid from supplements taken without food

Method 2: Total DFE=ug natural food folate + (1.7xug folic acid)

RDA for folate

Men and Women >14: 400DFE/day

Pregnancy: 600 DFE/day

Lactation: 500 DFE/day

UL for folate

1000ug/day

only applies to synthetic folic acid obtained from foods and supplements

What is the UL for folate based on?

the ability of folate to mask an underlying B12 deficiency

People at risk of a folate deficiency

alcoholics, pregnant women, women of childbearing age, malabsorption disorders, poor/weight loss diet, MTHFR polymorphism, nutrient deficiency, some medications

megablastic macrocytic anemia

RBCs are fewer, larger, and abnormally nucleated (immature), with decreased O2 carrying capacity

MTHFR mutation

caused by a mutation in 1 nucleotide (changed alanine to valine) which reduces enzyme activity and stability

higher prevalence in the hispanic population, and people with this mutation could benefit from 5-methyl/THF supplementation

How can FIGLU be used to to measure folate levels?

THF formininotranserase transfers the forminino group from FIGLU to THF to form 5-formimino THF and glutamate. Without sufficient folate, FIGLU is excreted in the urine