B12 (cobalamin) (mine)

B12 names (3)

Cyanocobalamin

methylcobalamin

5-deoxyadenosylcolbalamin

B12 most critical forms

critical: methylcobalamin & 5-deoxyadenosylcolbalamin

B12 structure

Macrocyclic rings made w/ 4 pyrrole rings, linked w/ colbalt

B12 is synthesized exclusively by

bacteria, fungi, algae

B12 plays a role in (2)

- maintenance of myelin sheath

- Folate metabolism

How can B12 enter the citric acid cycle (TCA)?

rearrange 3-carbon chain FA's

Cobalamin w/ a -CN group attached results in

cyanocobalamin

Cobalamin w/ a -OH group attached

Hydroxycobalamin

Cobalamin w/ a -H2O group attached

aquocobalamin

Cobalamin w/ a -NO2 group attached

Nitritocobalamin

Cobalamin w/ a -CH3 group attached

Methylcobalamin

what is a major issue with absorption of B12?

bioavailability 

B12 bioavailability is impaired by

high doses of vit C

Major destruction of B12 in the presence of... (4)

ascorbate

folate

Fe

Gastric juices

salivary glands produce what

R-protein

where is B12 released from food and how?

in the stomach due to the acidic environment and pepsin

After food goes through digestion, B12 binds to ____ found in ___ & ____ to form _____

R-proteins

saliva & gastric juices

B12*R-protein complex

where is R protein found

saliva and gastric juices 

made by salivary glands

the binding of B12 and R protein forms

B12-Rprotein complex

B12*R-protein complex travels from the...

stomach to the duodenum

what environment in the duodenum is the R protein digested & releases B12

alkaline

what enzyme releases R-protein from B12?

trypsin

In the duodenum, B12 binds & forms a complex w/ ____

IF (intrinsic factor)

IF is made by _____

gastric parietal cells

what does B12 binding to IF form?

to form the B12-IF complex

B12*IF complex travels through the ___ to the ___

jejunum and ileum

what occurs to B12-IF complex in ileum

B12 is absorbed via binding with receptor called cumbam complex

this process is facilitated by

calcium

cubam complex composed of

cubulin & amnionless, megalin)

After binding of B12-IF complex to receptor, appearance in the blood has a delay period of ___ and peak levels at are attained at___

4hrs

peak at 8hrs

what results in lack of IF production (like what would cause a lack of IF)

destruction of parietal cells

what does destruction of parietal cells lead to?

leads to B12 malabsorption & pernicious anemia

difference between megaloblastic and pernicious anemia 

• Macrocytic anemia = lack of folate or B12 intake

• Pernicous anemia= lack of IF production

In older adults, malabsorption may result in....

inability to release food bound cobalamin

what is zollinger ellison syndrome

tumors associated w/ beta cells of pancreas

zollinger ellison syndrome what does it result in

results in overactivity of parietal cells (because of lack of bicarbonate secreted form pancreas), increasing acidity in SI & impair B12 release from R-protein

if R protein and B12 cannot separate…

B12 cannot be absorbed properly (because it cannot bind to IF —> cannot be absorbed through receptor)

absorption occurs through

active transport

absorption at high concentrations occurs through

passive diffusion

rate of absorption at low concentrations is

as high as 80%

rate of absorption at high concentrations is

as low as 3%

B12 binds too what carrier proteins

transcobalamins (I, II, III)

about ___% of B12 is bound to what carrier protein as a circulating storage form

80%

TCI (TC one)

major transporter to tissue & %

TCII (20-30%)

TCIII function

return cobalamin from peripheral tissues back to the liver

what is the major form of B12 in the blood

60-80% methylcobalamin

what form is found up to 20% in plasma?

adenosylcobalamin

what are the other 2 forms found in the blood (very tiny amounts)

cyanocobalamin & hydroxocobalamin

even if digestion and absorption is working, what could occur that will impact B12 

genetic mutation that impact transporter 

what genetic mutation may occur? what does it affect?

insertion of arginine for proline, which diminishes transport capacity of TCII

the genetic mutation is found in ____% of the population

20% of population

how does the genetic mutation with TCII affect compounds of the blood (2)

results in low serum B12 & high homocysteine in blood

tissue uptake of B12 is _________ dependent

receptor

tissue uptake of B12 is dependent with what receptors?

TCII receptors (bind to TCII-B12) and non-specific receptors (that bind to TCI-B12)

these receptors bind to what

TCII-B12 complex

Upon binding to receptor, B12 enters cells via ____ & ___ for _____

endocytosis AND fusion to lysosomes for degradation of TCII

what facilitates transport within cell organelles

chaperones & other transport proteins

storage of B12 is similar to 

fat-sol vitamins 

how much B12 is stored and length of storage

stored in larger quantities and retained for long periods of time (very low turnover rate)

how long before deficiency can arise

3-5 years

B12 is mainly store in ___, lesser amounts in the __

liver

muscle, bone, heart, brain etc.

primary form stored in the liver

adenosylcobalamin (70%)

main form associated w/ blood

methylcobalamin

What is required for the synthesis of methylcobalamin? (what pathway)

Homocysteine metabolism

what are the functions of B12?

• homocysteine metabolism 

• adenosylcobalamin helps convert methylmalonyl CoA to succinyl CoA (citric acid cycle).

• Two specific reactions catalyzed by mutase enzymes in the mitochondria requiring adenosylcobalamin are (methylmalonyl CoA mutase and leucine aminomutase)

how is methylcobalamin made (process)

cobalamin is converted into methylcobalamin in homocysteine metabolism 

what is the enzyme in this reaction?

methionine synthase

what other vitamin is involved in this process?

folate (5-methyl THF and THF)

when converving cobalamin to methylcobalamin, what occurs (enzyme, coenzyme)

reaction: cobalamin —> methylcobalamin

enzyme: methionine synthase

cofactors: 5-methyl THF —> THF 

how does homocystine become methionine

reaction: homocysteine—> methionine

enzyme: methionine synthase 

coenzyme: methylcobalamin —> cobalamin

What does adenosylcobalamin convert?

Methylmalonyl CoA to succinyl CoA

what form of B12 helps convert methylmalonyl CoA to succinyl CoA? 

adenosylcobalamin

what does adenosylcobalamin do? (regarding reaction)

it oxidizes methylmalonyl CoA

methylmalonyl CoA requires what enzyme to become succinyl CoA?

methylmalonyl CoA mutase (requires x2 units of 5'deozyadenosyl cobalamin)

if B12 is not available, what occurs to methylmalonyl coA?

it becomes methylmalonic acid (loses CO2

Where do reactions catalyzed by mutase enzymes requiring adenosylcobalamin occur within the cell?

In mitochondria

mutase enzymes requiring adenosylcobalamin are (2)

methylmalonyl Coa mutase & leucine aminomutase

what is associated w/ B12 deficiency (think symptom,effect)

neuropathy

how does B12 deficiency lead to neuropathy?

because it causes degradation of the myelin sheath (related to lack of methionine and availability of s-adenosylmethionine (SAM)

what is essential for maintenance of myelin sheath

SAM

excretion of B12 requires

little to no degradation prior

0.1%/d turnover (very little)

excretion of B12 occurs primarily through 

bile & fecal

therapy for ineffective absorption (3)

monthly injections

B12 nasal gel

megadoses (allow for passive diffusion)

B12 is primality synthesized by

 bacteria, fungi and algae

B12 is stored primarily in the

liver

food sources

animal products

organ meat (mainly liver)

seafood

eggs

hot dogs

milk

RDA (adults, elderly, pregnancy, lactation)

2.4ug/d adults & elderly

2.6ug/d pregnancy

lactatio2.8ug/dn

non-toxic; intake tends to exceed RDA

Deficiency of B12 is associated with what disease

pernicious anemia (megablastic/macrocytic)

pernicious anemia is characterized by

lack of IF

symptoms of pernicious anemia (4)

• Nerve degeneration, weakness

• Tingling/numbness in the extremities (parasthesia)

• Paralysis and death

• looks like folate deficiency

deficiency usually occurs due to

decreased absorption

deficiency treatment

monthly IM injections

what in elderly population can lead to B12 deficiency?

achlorhydria (lack of HCL in stomach)

Assessment is based on 

Serum B12 concentrations

what is gold standard to determine problems with B12 absorption

Schilling test (finds absorption prob)

used to determine problems of vitamin B12 absorption related to IF insufficiency.

what compounds can be assessed to see issues wth B12 (serum and urine)

• Serum methylmalonyl CoA or methylmalonic acid & homocysteine

• Urinary methylmalonic acid

MMA and homocysteine

what other test may be used?

Doxyuridine (thymidine synthesis) supression test