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Endocrine Exam 2 > 30 - Folic Acid and B12 Metabolism > Flashcards

30 - Folic Acid and B12 Metabolism Flashcards

1
Q

What is the dietary source of folic acid?

A
  • Green leafy vegetables (“foliage”)
  • Spinach, lettuce, broccoli
  • Liver

Note that folic acid is water soluble, so if you boil it too long, it will be removed from the vegetables

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2
Q

What form is folic acid typically found as?

A

Folate polyglutamates

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3
Q

What is the functional form of folic acid in the body?

A

The functional form of folate in the body is tetrahydrofolate (THF)

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4
Q

How is THF formed?

A

THF is formed from folate by the action of the enzyme dihydrofolate reductase

Dihydrofolate reductase coverts folate to dihydrofolate and converts dihydrofolate to THF

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5
Q

Why is dihydrofolate reductase relevant pharmacologically?

A

Dihydrofolate reductase is an important chemotherapy drug target

Drug: Methotrexate

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6
Q

Describe the action of methotrexate

A
  • folate analog
  • inhibitor of dihydrofolate reductase
  • prevents generation of THF
  • has an antiproliferative effects
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7
Q

Why are THF derivatives important?

A
  • THF derivatives function as intermediates in biochemical reactions involving the transfer of one carbon groups
  • The one carbon groups attached to THF are referred to as the one-carbon pool
  • While they are bound to THF, the one carbon groups can be oxidized and reduced
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8
Q

What is a major source of one-carbon groups for the one-carbon pool?

A

The source of the majority of carbon in the one carbon pool is the reaction catalyzed by serine hydroxymethyltransferase

Serine + THF Glycine + N5,N10-methylene THF + H2O

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9
Q

Describe the absorption of dietary folate into intestinal epithelial cells

A

The polyglutamate form of folic acid is hydrolyzed by the brush border of the intestinal epithelial cell and folate enters the cell in the monoglutamate form of folic acid

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10
Q

What happens once the monoglutamate form of folic acid has entered the intestinal epithelial cells?

A
  • The monoglutamate form of folic acid is reduced and methylated once in the intestinal epithelial cell
  • This leaves us with N5-methyl THF (monoglutamate), which is the form that enters the blood ***
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11
Q

Describe the uptake of folate from the blood into cells throughout the body

A
  • Receptor-mediated endocytosis allows for the uptake of folate from the blood into cells throughout the body
  • Receptors have high affinity for folate monoglutamates***
  • N5-methyl THF monoglutamate is most abundant form in circulation
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12
Q

What happens to the intracellular folate in cells throughout the body?

A
  • Intracellular folate is rapidly metabolized
  • Polyglutamate is added
  • This adds a negative charge and makes it hard for folate to leave
  • This is a mechanism of folate retention
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13
Q

What is the most important metabolic process that requires folate?

A
  • The most important of these reactions from a clinical standpoint is the reaction catalyzed by thymidylate synthase, which converts dUMP (deoxyuridine-5’-monophosphate) to dTMP (deoxythymidine-5’-monophosphate)
  • This reaction is an essential step in the synthesis of DNA
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14
Q

Describe the structure and properties of vitamin B12 (cyanocobalamin)

A
  • B12 has a complex structure
  • It is ONLY synthesized by certain bacteria ***
  • The best dietary sources of B12 are liver, kidney, other meats, dairy products, shellfish
  • Plants do NOT supply B12 ***
  • Unless foods are fortified or contaminated with bacteria and soil, plant products will not supply you with B12
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15
Q

What are the four cobalamins in human metabolism?

A
  • cyanocobalamin
  • hydroxycobalamin
  • adenosylcobalamin***
  • methylcobalamin***

All of these have a slight modification

The last two are BIOLOGICALLY active, meaning that reactions in the body use these forms of B12

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16
Q

Describe the path of vitamin B12 in the stomach and duodenum

A
  • Dietary vitamin B12 is released from food in the presence of gastric acid and pepsin
  • Binds to R proteins in the stomach and forms a complex
    Complex enters duodenum where it is digested and B12 is freed
  • The freed B12 rapidly binds to intrinsic factor which is produced by the parietal cells of the stomach
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17
Q

What happens once B12 reaches the ileum?

A

ABSORPTION

  • Once B12 and intrinsic factor reach the ileum, the compound is taken up into cells via receptor-mediated endocytosis
  • B12 is freed and it passes into the cytoplasm and is released into the circulation via transcobalmin transport protein
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18
Q

Describe the storage of B12

A

Vitamin B12 is stored mainly in the liver and, to a certain extent, the kidneys

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19
Q

What happens to the intrinsic factor and receptor?

A

Other components

  • Intrinsic factor is degraded
  • Receptor is recycled
20
Q

Describe pernicious anemia

A
  • A disorder characterized by a lack of ability to absorb vitamin B12 from the ileum
  • It is an autoimmune disease that results in gastric atrophy
  • No intrinsic factor is therefore produced, so there is no way for high affinity absorption to occur
21
Q

How were patients treated in the past? How are they treated now?

A

Past
- Prior to the discovery of vitamin B12, anemic patients were instructed to eat 1/4 to 1/2 lb of beef liver per day

Now
- Intramuscular injection or 1 mg/day oral dose

22
Q

Describe the uptake of B12 from the blood into cells throughout the body

A
  • Once the transcobalmin-B12 complex is in the blood stream, it is taken up by cells again via receptor-mediated endocytosis
  • Most cells don’t store B12, so it ends up leaving the cell readily and most of the B12 in your body is in the circulation
23
Q

What is haptocorrin?

A

Although binding to TC is required for uptake of vitamin B12 by cells, the majority of the vitamin in the circulation is actually bound to proteins known collectively as haptocorrins

24
Q

Describe the role of haptocorrin in B12 processing

A
  • Binding of B12 to TC is required for uptake into cells
  • BUT most B12 in circulation is bound to haptocorrin
  • Haptocorrin/ B12 complexes are taken up by the liver
25
Q

Describe the enterohepatic B12 cycle –> In the LIVER

A
  • Haptocorrin is degraded and B12 secreted into bile
  • B12 binds to haptocorrin again
  • Haptocorrin/ B12 complexes digested in duodenum
  • B12 binds intrinsic factor
    reabsorbed in ileum

This is a process of RECYCLING
- Haptocorrins form a circulating store of B12

26
Q

What is the Schilling test?

A
  • A test to determine the cause of B12 deficiency
  • No longer available in the US
  • Still talked about in literature
  • It measures the patients ability to absorb B12
27
Q

What is the first part of the Schilling test?

A

Part 1

  • Give an oral load of radioactive B12
  • Then give an injection of non-radioactive B12 to saturate circulating B12-binding proteins
  • 24 hr urine collection started
  • In normal individuals, they should excrete at least 7% of radioactivity within 24 hr
  • If that happens, then the B12 has been absorbed
28
Q

What is the second part of the Schilling test?

A

Part 2

  • oral load of radioactive B12
  • oral load of purified intrinsic factor
  • proceed as for part 1
29
Q

How do you interpret the findings of the Schilling test?

A

Abnormal part 1, normal part 2

  • Pernicious anema
  • The problem is intrinsic factor
  • There is a problem with B12 absorption that is fixed with intrinsic factor replacement

Abnormal part 1 AND 2

  • Defect in B12
  • Absorption independent of intrinsic factor production
  • E.g. defect in TCII production, TCII receptor, etc.
30
Q

What is a metabolic process requiring vitamin B12?

A
  • Propionyl-CoA metabolism

- Methylmalonyl-CoA mutase requires adenosylcobalamin

31
Q

What happens when there is a deficiency of B12?

A

Deficiency of B12

  • Conversion of L-methylmalonyl-CoA to succinyl-CoA inhibited
  • L-methylmalonyl-CoA accumulates ***
  • Hydrolysis of this compound yields methylmalonic acid
  • Organic acidemia results
32
Q

What is another metabolic process requiring vitamin B12?

A

Homocysteine metabolism

  • Methionine synthase converts homocysteine to methionine
  • Concomitantly, THF regenerated from N5-methyl THF
  • This is the ONLY mechanism in the body that can make THF from N5-methyl THF
33
Q

What is the methyl trap hypothesis of folate deficiency?

A

Folate deficiency

  • only the methionine synthase reaction can convert N5-methyl THF back to THF
  • lack of B12 prevents synthesis of methylcobalamin
  • lack of methylcobalamin blocks methionine synthase reaction
  • folate becomes ‘trapped’ in N5-methyl THF form
  • Functional folate deficiency arises***
  • may have enough folate in diet but not enough folate in the correct oxidation state inside cells
34
Q

What are the neurological consequences of vitamin B12 deficiency?

A

Vitamin B12 deficiency results in demyelination

35
Q

What is the mechanism of vitamin B12 deficiency?

A
  • Failure of methionine synthase reaction occurs
  • Some patients undergoing demyelination due to lack of B12 have shown improvement upon methionine administration
  • Mechanism unclear
  • possibly related to lack of S-adenosylmethionine
  • Inability to correctly methylate key substrates?
36
Q

Describe a functional folate deficiency

A
  • Vitamin B12 deficiency leads to functional folate deficiency
  • accumulation of N5-methyl THF ***
37
Q

Describe an actual folate deficiency

A

Dietary insufficiency may lead to actual folate deficiency

38
Q

What happens in both cases of folate deficiency?

A
  • thymidine synthesis blocked
    • thymidylate synthase requires N5,N10-methylene THF
  • purine synthesis blocked
    - two steps require N10-formyl THF

Overall, DNA SYNTHESIS IS PREVENTED ***

39
Q

Describe the development of megoblastic anemia

A
  • Thymidylate synthase is an important enzyme which is now missing
  • A lot of dUTP is available but no dTTP is around
  • The cells decide to use dUTP to make DNA instead
  • This leads to cells which can grow, but cannot divide
  • They become “megoblastic”
  • Eventually this leads to DNA fragmentation and cell death
  • This is most obvious in rapidly-dividing cells
40
Q

What are some scenarios in which folate needs are increased?

A
  • pregnancy
  • lactation
  • growth
  • chronic hemolytic anemia
41
Q

What are some common situations we see folate deficiency in?

A
  • alcoholism
  • old age
  • poverty
  • celiac disease/tropical sprue/other conditions of malabsorption
42
Q

What are some scenarios in which B12 needs are increased?

A
  • pregnancy

- periods of growth

43
Q

What are some common situations we see B12 deficiency in?

A
  • strict vegans (who shun supplements/fortified foods)
  • pernicious anemia
  • celiac disease/tropical sprue/impaired absorption
  • gastric acid insufficiency
  • ileitis/resection of the ileum
  • fish tapeworm infestation
  • competing intestinal flora
44
Q

What is a potential cause or acute amplification of megoblastic anemia?

A

Nitrous oxide ***

45
Q

Describe a case study of nitrous oxide induced acute megoblastic anemia

A
  • 8 month-old boy hospitalized with fever, lethargy, athetoid movements
  • Surgery 6 days prior to admission with inhaled nitrous oxide anesthesia
  • On day 3 of hospitalization
    pancytopenia develops
    megaloblastic abnormalities in bone marrow, methylmalonic aciduria,
    hyperhomocysteinemia
  • Patient is found to have a profound cobalamin deficiency
    and normal folate levels
46
Q

What caused this acute attack?

A
  • Mother was B12-deficient
  • B12-deficient intrauterine environment
  • B12-deficient breast milk
  • Child likely would develop chronic megaloblastic anemia

Why the acute course?
- Nitrous oxide destroys methylcobalamin ***

Endocrine Exam 2 (18 decks)

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