Vitamin B12: Part 1 – Flashcards

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Pernicious (fatal) Anemia

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- B12 deficiency due to lack of intrinsic factor

 

- Lead to irreversible neurological degeneration of nervous system

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Cobalamin Forms:

1. --CN

2. --OH

3. --NO2

4. --H2O

5. --5'-deoxyadenosyl

6. --CH3

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- Which group is attached to cobalt determines which form B12 is in:

 

1. --CN: cyanocobalamin (most stable synthetic form)

2. --OH: hydroxycobalamin: synthetic

3. --NO2: nitritocobalamin 

4. --H2O: aquocobalamin

5. --5'-deoxyadenosyl (used in body)

6. --CH3: methylcobalamin (used in body)

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Vitamin B12 Absorption: Active

 

(1) Diet

 

 

 

 

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- Naturally occurring B12 in food is bound to protein

 

 

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Vitamin B12 Absorption: Active

 

(2) Stomach

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? = HCl + Pepsin

 

- HCl denatures the protein & then activates pepsin to act on peptide bonds to breakdown the protein, releasing B12 from food

 

- B12 binds to R pros (salivary or from gastric juices)

 

- IF prod by parietal cells

 

 

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Vitamin B12 Absorption: Active

 

(3) SI: Duodenum

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- B12 released from R pros

 

- R pros hydrolyzed by pancreatic proteases

 

- B12 binds IF = B12-IF complex (resistant to pancreatic enzymes)

- B12-IF traverses SI (duodenum --> ileum) and binds to specific receptors on brush border of ileal mucosa

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Vitamin B12 Absorption: Active

 

(4) Enterocyte (ileum)

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- Enterocyte: intestinal absorptive cells

 

- B12-IF absorbed intact via receptor-mediated endocytosis, which requires:

  1. 1. specific receptors w/ pro subunits: receptor-assoc pro (facing into cell) & cubulin(outward)
  2. Ca for binding & neutral pH

- B12-IF now a lysozome ---> brkdwn IF to release B12 (now free to enter portal circulation)

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Vitamin B12 Absorption:

Passive Diffusion

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- occurs when large doses consumed (remaining B12 that can't proceed via active absorption)

 

- location: throughout GI, oral/nasal mucous membranes

 

- rapid process BUT inefficient

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Vitamin B12:

Enterohepatic Circulation

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- Enterohepatic circulation: circulation of biliary acids from the liver, where they are produced and secreted in the bile then move to the SI

 

- B12 secreted into bile: can bind to IF in SI and be reabsorbed in ileum

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Vitamin B12:

Transport

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- Prior to transport across membrane of ileal cells, B12 binds transcobalamin to deliver B12 to cell receptor

 

- Holo-TC (bound to B12) complex taken up by cells

  • biologically active form; binds 20% total plasma

- Haptocorrin (HC): tissues don't take up this form

  • binds 80% plasma B12 
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Cellular Uptake
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- Most tissues contain: holotoranscobalamin receptors (Holo-TC) = evidence that TC is primary B12 delivery pro

 

 - B12-holoTC taken into cells via endocytosis & then fused w/ (enter) acidic lysosomes

 

- TC degraded, B12 released

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Storage & Excretion
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- 2-3 mg (large) stored in body-> primarily in liver

 

- Reabsorption from bile essential 

 

- Excretion:

  • Bile (major, via feces)
  • Urine

 

 

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B12 Pathway:

Remethylation of homocysteine

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- occur in cytoplasm; 2 parts

 

1. 5-methyl-THF + cobalamin(I)--MS--> THF + methylcobalamin (+3 form)

 

2. methylcobalamin (+3) + homocysteine --MS--> cobalamin(1) + Met

 

 

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B12 as Reactive Species
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- Every 200-2000 turnovers (in Hcy->Met), B12 undergoes oxidation

  • cobalamin(I) ---> cobalamin(II) = inactive

 

- cobalamin(II) --MS reductase--> cobalamin(I)

 

- needs to be cobalamin(I) to be converted back to cobalamin(III) = active form 

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Folate Methyl Trap &

B12 deficiency

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- Formation of 5-methyl-THF is irreversible

 

- B12 needed to convert 5-methyl-THF to THF

 

- B12 deficiency = can't regenerate THF which is needed to for 5,10methyleneTHF for DNA synthesis

 

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Masking B12 deficiency
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- Macrocytic anemia (^MCV, low #RBC, Hb) occurs w/ B12 and folate deficiency

 

- Assume folate def & treat w/ folic acid = reverse anemia

 

- BUT: if actually B12 deficiency, neuropathy will still result causing spinal degeneration

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B12 Pathway:

L-methylmalonyl-CoA --->

succinyl CoA

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- occurs in mitochondria

- L-methylmalonyl CoA--> succinyl CoA

  • intermediate step btw propionate --> succinate
  • propionyl CoA prod via: odd chain FA oxidation & catabolism ketogenic aa

- enz: methylmalonyl CoA mutase

  • 5'deoxyadenosylcobalamin dependent 
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B12 Deficiency:

Effect on M-CoA-Reductase

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- methylmalonyl CoA reductase impaired causing:

     - methylmalonyl CoA ---> methylmalonic acid (MMA)

 

- ^MMA = useful dx for B12 def

 

 

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