Vitamin B12: Part 1 Flashcard

 

Pernicious (fatal) Anemia

– B12 deficiency due to lack of intrinsic factor

 

– Lead to irreversible neurological degeneration of nervous system

Cobalamin Forms:

1. –CN

2. –OH

3. –NO2

4. –H2O

5. –5′-deoxyadenosyl

6. –CH3

– 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)

Vitamin B12 Absorption: Active

 

(1) Diet

 

 

 

 

– Naturally occurring B12 in food is bound to protein

 

 

Vitamin B12 Absorption: Active

 

(2) Stomach

? = 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

 

 

Vitamin B12 Absorption: Active

 

(3) SI: Duodenum

– 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

Vitamin B12 Absorption: Active

 

(4) Enterocyte (ileum)

– 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)

Vitamin B12 Absorption:

Passive Diffusion

– 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

Vitamin B12:

Enterohepatic Circulation

– 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

Vitamin B12:

Transport

– 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 

Cellular Uptake

– 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

Storage & Excretion

– 2-3 mg (large) stored in body-> primarily in liver

 

– Reabsorption from bile essential 

 

– Excretion:

  • Bile (major, via feces)
  • Urine

 

 

B12 Pathway:

Remethylation of homocysteine

– occur in cytoplasm; 2 parts

 

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

 

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

 

 

B12 as Reactive Species

– 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 

Folate Methyl Trap &

B12 deficiency

– 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

 

Masking B12 deficiency

– 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

B12 Pathway:

L-methylmalonyl-CoA —>

succinyl CoA

– 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 

B12 Deficiency:

Effect on M-CoA-Reductase

– methylmalonyl CoA reductase impaired causing:

     – methylmalonyl CoA —> methylmalonic acid (MMA)

 

– ^MMA = useful dx for B12 def

 

 

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