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Folate and Vitamin B12

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Folate (B9)

  • Folate

    • general term​

    • refers to the reduced form found naturally in foods and tissues

  • Folic acid

    • refers to the oxidized form found in fortified food and supplements​

  • Structure: 3 parts that can be made separately

  • mammals lack the enzyme to join the pteridine ring and PABA

    • why is it considered a vitamin​

  • active form: tetrahydrofolate (THF/THFA)

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Folate Food Sources

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  • breads, flours and cereals have been fortified with folate since 1998 and are now major sources

  • bioavailability depends on sources, forms and other factors

    • most natural folate is in a reduced form​

      • derivative of THF​

  • 37% DRI is produced by hindgut bacteria; 46% of this can be absorbed into colon

Digestion, Absorption, Storage

  • only the monoglutamate form of folate can be absorbed

    • active uptake by reduced folate carrier (RCF); expression up regulated by folate deficiency​

    • folic acid in fortified food is already in monoglutamate form thus more bioavialable

    • passive diffusion accounts for approx. 25% of absorption

    • absorption highest under low pH

  • polyglutamate forms must be hydrolyzed by pteroypolyglutamate conjugases

    • zinc dependent​

      • zinc deficiency impairs digestion and thus absorption of folate​

  • half of total folate storage is in the liver

Folate Functions

  • THF is a coenzyme

    • mitochondria​

    • cytosol

  • accepts one-carbon groups typically generated from amino acid metabolism

  • the resulting THF derivatives serve as donors of one-carbon units in a variety of synthetic reactions

  • 5,10-methylene THF is involved in conversion of glycine to serine

  • 5, 10-methylene THF is needed for pyrimidine synthesis

  • 10-formyl THF is needed for purine synthesis

  • therefore, folate is needed for cell division

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study question: 

  • why do pregnant women need increase folate?

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  • THF is required for histidine metabolsim

  • FIGLU (formiminoglutamate) --> glutamate

  • when folate is deficient, FIGLU builds up

    • basis for assessment​

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Folate Deficiency

  • causes megaloblastic macrocytic anemia

    • immature enlarged RBC, fewer than normal​

    • cell division and maturation is delayed

  • risk factors: 

    • alcoholism​

    • malabsorption

    • certain medications

Folate Toxicity

  • no health risk associated with folate intake from food

    • risk from supplements​

      • digestive problems and insomnia​

    • allergic reactions are possible

    • antifolate medications

  • major concern is that high folic acid deficiency can mask vitamin B12 deficiency

    • Folic acid can cure the f megaloblastic macrocytic anemia caused by vitamin B12 deficiency

    • Folic acid cannot cure neurological damage caused by vitamin B12 deficiency (irreversible)

study question: 

  • how can high folate mask B12 deficiency?

Folate Clinical Application

  • prevention of birth defects such as NTDs

  • related to homocysteine metabolism

    • prevents formation of methionine which: ​

      • —Causes problems with myelin formation

      • —Increases potential for cardiovascular disease

      • —May also play a role in certain cancers and Alzheimer's disease

    • —Elevated folate levels are beneficial to decrease homocysteine in certain populations (i.e., elderly, CVD, inflammatory diseases).

Folate Assessment

  • —Repeated measure of serum/plasma folate levels

    • —RBC folate levels are more reflective of folate status in tissues

  • —FIGLU excretion

    • —Administer histidine load

    • Measure FIGLU 6 hr urine collection

Cobalmin (B12)

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  • Generic term for a group of compounds with a corrin ring

  • the center is an atom of cobalt (Co)

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B12 Food Sources

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  • synthesized by bacteria

  • primarily from animal products

    • concern for vegans 

  • In food, cobalamin is linked to polypeptides

    • ingested cobalamin must first be released from polypeptides​

    • pepsin is required

Digestion, Absorption, Storage

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  1. pepsin releases B12​

  2. R protein binds saliva and gastric juice to protect from bacteria

  3. within small intestine, R protein is digested to release B12

  4. B12 binds to intrinsic factor (IF) to form a complex

  5. B12 binds to a receptor on enterocytes in the ileum and is internalized by endocytosis

study question: 

  • other than a inadequate B12 intake, what else can cause a B12 deficiency?

  • stored in the liver

  • need for vitamin B12 is very small

    • body holds on tightly to stores​

    • can be reutilized via enterohepatic circulation

  • overall average of 50% is absorbed

  • takes a long time to deplete

    • depletion occurs due to decreased HCl and IF​

    • not intake unless a vegetarian

B12 Functions

  • adenosylcobalamin is needed for converting L-methylmalonyl CoA to succinyl CoA

    • intermediate in the TCA cycle​

  • this is a step in fatty acid degradation - important pathway in nerve tissue

  • is distrupted, marks the onset of B12 neuropathy due to increases in methylmalonyl CoA and FAs in neural tissue

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  • vitamin B12 deficiency leads to increased methylmalonyl CoA

    • excreted in urine​

  • methylmalonyl CoA may compete with malonyl CoA for FA synthesis

  • neurological problems

    • lipids in mylenation​

    • myelin turns over rapidly

    • decreased FA synthesis or replacement of FA with methylmalonyl CoA may result in degredation of myelin sheath

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Homocysteine

  • increased homocysteine is toxic to cells

    • especially brain​

      • increased risk of neurological disease​

    • also affects blood vessels

  • associated with increased risk of stroke, CHD, and recently alzheimer's

  • metabolism requires both B12 and folate

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study question: 

  • can this process occur with low folate but adequate vitamin B12? How about vice versa? Why or why not?

Folate and B12 in Methionine Formation

  • synergistic relationship

    • many coenzymes form of folate​

    • vitamin B12 coenzymes helps get the right form of folate by taking the methyl group from it

      • ex. B12 is needed for folate enzyme to work​

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  • When B12 traps CH3 folate in the methyl form:

    • decreased RBC maturation​

    • increased homocysteine

  • methionine is an essential amino acid for transulfuration/remethylation

  • loss of S-adenosylmethionine (SAM) - impared synthesis of

    • creatinine​

    • phospholipids

    • acetylcholine

  • THF

    • decreased folate leads to inadequate CH3 for B12 coenzyme​

      • increases homocysteine​

    • decreased B12 limits or prevents production of methyl-B12 coenzyme

      • therefore trapping folate as 5-methyl THF​

Deficiency

  • Megaloblastic macrocytic anemia

    • same RBC features as seen in folate deficiency​

      • cannot distinguish

    • can be corrected with large doses of folate

  • neuropathy

    • due to demyelination of nerves, probably caused by low methionine levels​

    • does not respond to folate therapy

study questions: 

  • megaloblastic anemia caused by B12 deficiency can be corrected with large doses of folate. Can B12 therapy correct megaloblastic anemia caused by a folate deficiency? why or why not?

  • why does folate therapy work sometimes, but not in other situations?

Toxicity

  • no UL has been established

  • no toxicity or benefit of large doses of vitamin B12 has been reported in people with adequate intake

Folate/B12 Disease Prevention

  • Cardiovascular disease

    • increased homocysteine thought to increase CVD risk​

    • homocysteine leads to increased oxidative stress and lipid peroxidation

    • levels regulated by B12, B6 and folate

      • folate shown to work best at reducing levels​

  • Cancer

    • folate required for synthesis of DNA​

    • decreased availability of folate allows DNA strands to be more easily damaged

    • deficiency of vitamin B12 traps folate (methyl trap) in a form thats unavailable for DNA synthesis

    • both vitamin B12 and folate deficiencies result in decreased methylation reactions

      • B12 deficiency may also lead to DNA damage and altered methylation of DNA​

      • both are risk factors for cancer

  • Alzheimer's

    • moderately increased homocysteine levels, decreased folate and B12 levels have been associated with Alzheimer's disease and vascular dementia​

    • low serum B12 or folate levels associated with a doubling of the risk of developing Alzheimer's disease in elderly men and women

  • Depression

    • observational studies have found as many as 30% participants hospitalized for depression to be deficient in B12

    • vitamin B12 deficient women were twice as likely to be severely depressed as non-deficient women

Assessment

  • serum level is maintained at the expense of tissue concentration - not an accurate indicator

  • measurements of substrates of reactions that require vitamin B12 as coenzymes

    • methylmalonyl CoA​

    • homocysteine

©2023 by Syracuse University Dr.Margaret Voss

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