Cobalamin, methylcobalamin, adenosylcobalamin
Adequate Intake ?:
Nutrient metabolism; energy production; hematopoiesis. Megaloblastic anemia, degeneration of peripheral nerves. Major Food Sources: Animal products, meat, fish, shellfish, poultry, milk. RDA: 2.4 mcg
Difficult to absorb - requires IF / R Protein
Comes only from animal products
Likely deficient in vegans and animal-avoiding omnivores.
Just 2.4 mcg is required per day, but the liver stores 3-5 years worth of Vitamin B12.
Involved in taking methyl group from folate and putting it on homocysteine to run the SAM cycle.
Also involved as adenosylcobalamin in the mitochrondria
History & Discovery:
Subacute combined degeneration of the spinal cord (SACD) was linked to pernicious anemia by Putnam, Lichtheim, and Dana in the 1890s.
Pernicious anemia is a type of Vitamin B12 anemia, caused by either an absence of an Intrinsic Factor (protein secreted by parietal cells that bind to B12) or an Extrinsic Factor (Vitamin B12). The body can't make enough healthy red blood cells due to a Vitamin B12 Deficiency.
William B. Castle discovered an intrinsic factor in the gut mucosa in the 1920s later called the Castle Factor.
Parietal cells -> secrete -> Intrinsic factor. HCL needed for absorption of IRON. IF needed for absorption of Vitamin B12.
Karl Folkers, a scientist at Merck, discovered the mysterious "extrinsic factor" in liver in 1947, which was the final B-vitamin to be discovered.
Animal foods consumed and Vitamin B12 released in the highly acidic environment of the stomach and with the help of pepsin.
Vitamin B12 binds to R proteins found in saliva and gastric juice to form a B12R protein complex travels from the stomach to the duodenum.
The duodenum is alkaline and the R protein is broken down to release Vitamin B12 which then forms a complex with intrinsic factor (IF) which was made by parietal cells.
The complex travels through the jejunum to the ileum.
Within the ileum, vitamin B12-IF complex binds to a specific intestinal cell receptor for endocytosis using multidrug protein carrier 1 (MRP-1).
About 0.1% (2 mcg) of vitamin B12 is excreted through the bile. However, most (about 75%) is reabsorbed in the ileum after binding to intrinsic factor in the proximal small intestine.
About 0.25 mcg of the vitamin is excreted daily in the urine.
Absorption and Storage:
Vitamin B12 = antipernicious anemia factor = animal/liver factor = extrinsic factor of Castle = cobalamin
Cobalamin = 4 pyrolle rings + 1 cobalt + 1 PO4 group (Phosphorus + 4 oxygen)
Cyanocobalamin = Cobalamin + CN (Cyanide) = supplemental form
Hydroxycobalamin = Cobalamin + OH (Hydroxide ion) = common food form in eggs
Methylcobalamin = Cobalamin + Me (methyl) = common in meats
Adenosylcobalamin = Cobalamin + Ado (Adenosyl) = common in meats
B12 dissociates from IF and binds to Transcobalamin (TC) II in the liver for long term storage.
HoloTCII = TCII bound to methylcobalamin (60-80%) or adenosylcobalamin (20%) and circulates in the blood for transport toward peripheral tissues.
HoloTCII binds to receptors -- TCII receptor enters cells by endocytosis with subsequent fusion to lysosomes that provide for proteolytic degradation of TCII and release of the vitamin within the cell cytosol.
Cycles back: Haptocorrin (protein from white blood cells) helps transport B12 from tissue to liver.
Overall absorption of Vitamin B12 is about 50%
Peaks after 2-3 hours in blood.
Liver stores 2-4 mg.
Enterohepatic recirculation provides about 3-8 mcg per day.
Folate donates a methyl to cobalamin for remethylation of cobalamin to methylcobalamin. Besides folate and Vitamin B12, betaine can also provide for the remethylation of homocysteine.
Dimethyl-glycine catabolism results in the donation of a methyl group to a THF forming 5-methyl-THF. It's a cycle!
5-methyl THF (folate) + Cobalamin -> THF + Methylcobalamin
Methylcobalamin + Homocysteine + Methionine synthase = Methionine
Methionine -> S-adenosyl methionine (SAM) -> S-adenosyl homocysteine (SAH) -> Homocysteine
Homocysteine -> Cystathionine synthase--PLP dependent = Cystathionine
Homocysteine + Betaine + Betainehomocysteir methyltransferase (BHMT) = Methionine + Dimethyl glycine
Methylmalonyl-CoA + Adenosyl-B12 + Methylmalonyl-CoA mutase = Succinyl-CoA -> TCA Cycle
Odd-chain FAs C15:0 Pentadecanoic acid, C17:0 Heptadecanoic acid, C23:0 Triconanoic Acid - enter B-oxidation and eventually get a three carbon called propionyl-CoA -> Propionyl-CoA carboxylase + Biotin (carrying CO2) = Methylmalonyl-CoA which requires B12 to become Succinyl-CoA
Methylmalonyl-Coa without Adenosyl-B12 -> Methylmalonic acid (marker of B12 deficiency)
Deficiency Diseases, Detection, Cures:
Normally undectable in urine, but if you have B12 deficiency...
Normal serum methylmalonic acid = 280 nmol/L, this will rise several fold.
Homocysteine >20 umol/L in the absence of folate and PLP deficiency = B12 deficiency
HoloTCII <25-75 pmol/L
Causes of Deficiency
Inadequate intake - Strict vegan, elderly, malnourished
Too high gastric pH (alkaline) due to diminished HCL production by parietal cells because of inflammation
Insufficient intrinsic factor because of atrophic gastritis (inflammation of gastric cells) or pernicious anemia
Zollinger-Ellison syndrome lowering pH in duodenum = impaired release of protein R. It needs to be released from R in the duodenum and lower pH impairs this.
Celiac or Crohn's Disease, which impairs absorptive surface.
Ileal resection, bypass surgery
Pancreas = chronic pancreatitis
Bacteria = prolonged antibiotics use
Competition = parasitic infection, tapeworms
Drugs - metformin (reduced absorption) PPIs(bacterial overgrowth)
Symptoms of Deficiency
Cardiomegaly, tachycardia, Shortness of breath
Changes in reflexes
Nervous system - general effects
Recommended Reading: What if it's B12?