Vitamin B12 (4 questions) Flashcards
What are the coenzyme forms of Vitamin B12?
Methylcobalamin
5-deoxyadenoslycobalamin
Food Sources of B12
- Clams
- Liver
- Fortified yeasts
…Seafood, Fish (salmon, trout, tuna, haddock)
…Beef
…Dairy
Not naturally found in plant-based foods (these are fortified)
R BINDER
Secreted into saliva into the mouth
Low pH environment in the stomach favors the binding of cobalamin to R Binder
No action until it binds with cobalamin into the stomach, after pepsin frees B12 from food
Once in the duodenum, biliary and pancreatic secretions degrade R Binder and cobalamin binds with IF
PEPSIN
Gastric pepsin releases the food-bound cobalamin in the stomach by breaking down the protein and any food that B12 is a part of
B12 Absorption - - What is in the stomach?
Mix of:
-Cobalamin (free form due to pepsin)
-R-Binder
-IF (secreted by parietal cells)
-B12-R Binder Complex (due to HCl acid)
The low pH of the stomach (caused by HCl acid) favors what?
FAVORS the binding of B12 to R-Binder in the stomach
IF
Secreted in the stomach by the parietal cells
It is along for the ride, until it reaches the duodenum, and will bind to cobalamin, which will move to the ileum
It can bind to cobalamin because biliary and pancreatic secretions degrade R-Binder
B12 Absorption - - What happens in the duodenum?
Biliary and pancreatic secretions degrade R-Binder protein, allowing cobalamin to bind to IF, and move to the ileum
IF-B12 Cobalamin Complex
Taken up directly into the ileal mucosal cells, through endocytosis, and brought into the cytoplasm, and makes its way to the lysosome
It is split in the lysosome
Where does cobalamin-IF complex split?
In the lysosome of the ileal mucosal cells
B12 Absorption - - What happens in the lysosome?
IF-Cobalamin complex is split
Cobalamin is bound to TCII (transcobalamin II; a binding protein)
and exits the enterocyte, and enters systemic circulation
How much B12 can be passively absorbed?
About 2%
At what oral dose does B12 absorption decrease? Why?
Above 0.25 micrograms
The cubilin-amnionless receptors can become saturated, and excess B12 is secreted in the urine
(T/F) B12 is excreted in bile. Explain.
TRUE
Bile is synthesized in the liver, taken to the GB, then secreted into the S.I.
a) Bile helps w/ digestion and absorption of lipids
b) Some B12 are part of bile acids and bile salts
Bile can be reabsorbed in the S.I. (including the B12 w/in the bile). This process is the exact same in the ileum. AKA IF is required.
Enterohepatic circulation
B12 is excreted in bile but can bind IF in the duodenum and be reabsorbed in the ileum.
TCII
Transcobalamin II; binding protein, that binds to cobalamin in the lysosome and then goes to portal circulation, then systemic circulation
Portal Circulation
The circulation of nutrient-rich blood between the gut and the liver
What are the 2 receptors for cobalamin-TCII complex?
(on peripheral tissues in systemic circulation)
- Holo-TCII Receptor
- Megalin
Expressed on peripheral tissues
Responsible for bringing the cobalamin-TCII complex into the cell
Once in the cytoplasm (of peripheral tissues), cobalamin is converted to what?
Methylcobalamin (coenzyme form)
To be used for homocysteine metabolism
In the mitochondria (of peripheral tissues), cobalamin is converted to what?
5-deoxyadenosylcobalamin (coenzyme form)
It is used for propionyl-Coa metabolism
In a healthy adult, how much cobalamin is stored?
About 2,500 micrograms (2-3 mg)
What is the distribution and where is cobalamin stored
50% in the LIVER
30% in MUSCLE
20% in pituitary glands, bones, kidney, heart, brain, spleen
(T/F) A lot of B12 is lost daily.
FALSE - only about 1 microgram a day (very, very low) due to B12 recycling via enterohepatic recirculation
How long would it take to see clinical signs of deficiency, in a normal healthy adult?
About 2-5 years
Resulting from a complete loss of IF
Seen in the elderly population
What is the primary function of methylcobalamin?
Needed for methionine and homocysteine metabolism
Methionine Synthase
This enzyme binds cobalamin
Takes a methyl group from 5-methyltetrahydrofolate (THF) and transfer it to cobalamin, becoming methylcobalamin
Thus converting 5-methylTHF —> THF
How is homocysteine created?
Methylcobalamin still attached to methionine synthase is going to transfer that methyl group to homocysteine
This creates/synthesizes methionine
Methionine
Very important AA because it is converted to SAM (S-adenosylmethionine)
S-adenosylmethionine
SAM
Able to transfer its methyl group to DNA and other proteins
-these thousands of proteins are activated when they receive a methyl group
-this creates SAH
S-adenosylhomocysteine
SAH
Generated when SAM transfers methyl group to DNA and other proteins
SAH is converted to homocysteine
Homocysteine
“Bad Guy”
Higher homocysteine is associated with increased risk of CVD, including venous thrombosis, atherosclerosis, high BP, CAD, and stroke
–aka needs to be kept in check
High homocysteine levels are a good indicator if someone has low B12, or folate, or even B6
If more methionine is not needed, what happens?
Homocysteine can be metabolized ——————————–> Cysathionine
Cystathionine Synthase (PLP dependent; coE of B6)
Explain how homocysteine can be converted back to methionine
The reaction requires the methyl group from folate to be transferred over to cobalamin, creating methylcobalamin. Then methylcobalamin is going to give its methyl group to homocysteine, therefore synthesizing methionine
What is the function of coE form 5-deoxyadenosylcobalamin?
It is going to act as a cofactor for the enzyme, methylmalonyl-CoA mutase
-It is the sole function of this coE.
Propionyl-CoA
a 3-carbon FA that comes from the odd-chain FA metabolism (aka: the 3 carbons leftover from beta-oxidation)
OR it can come from BCAA metabolism
Why is MMA bad?
MMA = D-methylmalonic acid
associated with destabilizing myelin, and promoting the formation of deformed or highly destabilized myelin
Myelin
the insulating layer or that sheath that covers nerve cells
helps to transmit the electric impulses (messages) through the nerve, from one nerve cell to another
MMA build-up is going to potentially cause….what?
Nerve damage; reduced cognition
Been shown that it can inhibit complex II of the ETC, and therefore can cause problems with oxidative phosphorylation (which can result in not having enough biosynthesis of ATP)
High blood levels of MMA and low B12 markers, would indicate what?
CoE. B12 deficiency of 5-deoxyadenosylcobalamin
Megaloblastic Anemia
Frank B12 deficiency
appears as multi-lobular/hyper-segmented neutrophils and oval shaped RBCs
What population is at increased risk of B12 deficiency? Why?
Elderly
Gastritis (acute or chronic)
—Autoimmune gastritis
—H. Pylori infection
Not from lower intakes of B12 except for long-term vegans
Autoimmune Gastritis
Antibodiesin the stomach that attack parietal cells
Major inflammation prevents those cells from secreting HCl acid, pepsin, and other digestive enzymes
H. Pylori infection
Bacteria that invade the stomach lining, causing inflammation, blocking secretion of those enzymes that are needed to lower the pH and breakdown food
What are secondary deficiency clinical manifestations of B12?
Neurological changes (dementia, confusion symptoms)
Due to build-up of MMA and destabilization of myelin
Multi-lobular and oval shaped RBCs indicate, what?
Megaloblastic anemia (B12 deficiency)
How does roux-en-Y gastric bypass cause B12 deficiency?
Combination of decreased intake
Lack of IF
Reduced gastric acid
Impaired absorption due to bypass of proximal S.I.
What are other subclinical cobalamin deficiency symptoms or clinical manifestations?
Any 2 or more:
—Increased MMA
—Increased plasma homocysteine
—Decreased [cobalamin]
—Decreased [holotranscobalamin II]
Individuals s/p RYGB are at increased risk for these.
Not all will be present with frank megaloblastic anemia
How is B12 assessed?
No gold standard
Will run a panel for all water-soluble vitamins
Use SERUM COBALAMIN (~200-250 ng/L for deficiency)
–Holo-TC II assay
–Serum MMA (indicates B12 deficiency ALONE, if high)
–Serum homocysteine (could be confounded by folate status)
There is no official upper limit
