The B12 vitamin (also called cobalamain) is a member of vitamin B group.
It is normally involved in the metabolism of every cell of the human body, especially affecting DNA synthesis and regulation, but also fatty acid synthesis and energy production.
The discovery of vitamin B(12), the elucidation of its role in metabolism, and the effects and treatment of its deficiency occurred in distinct phases over more than 100 years, and it was the subject of two separate Nobel Prizes.The vitamin was isolated by two groups simultaneously and was crystallized and characterized in the laboratory of Dorothy Hodgkin in 1956, contributing to her Nobel Prize in 1964. Vitamin B(12) is still the subject of intense research and, in particular, its role in preventing these irreversible neurological lesions remains unclear.
The discovery of vitamin B(12). 2012
STRUCTURE
Cobalamin is a water soluble compound. It has corrinico ring, formed by 4 pyrrole rings and 3 methine bridges. In the centre there is a cobalt atom coordinated by 4 nitrogen atoms of the pyrroles. Cobalt has also 2 coordination links, which are perpendicular to the ring level: one with a 5,6 dimethylbenzimidale, which is bound to a ribose 3-phosphate; the second one with different R groups, which can be:
- Hydrocyanic acid -CN ( cyanocobalamin )
- hydroxyl -OH ( hydroxocobalamin )
- methyl group -CH3 ( methylcobalamin )
- 5-deoxyadenosyl ( adenosylcobalamin ).
INTAKE
We are not able to synthesize it, so it is necessary to take it with food. You can mainly find it in meat, fish, eggs, milk and dairy products. The daily requirements of the cobalamin is between 2 and 6 mg and you can easily get it with a normal eating. Severe deficiency of this vitamin caused by insufficient foodstuff ingestion is rare and can occur in vegans or old people, which have also intake problems.
The B12 intake requires 4 different types of binding proteins.
In the gastric lumen, the cobalamin is bound with salivary haptocorrine; when the acid chime enters in the duodenum, this protein is hydrolyzed by some pancreatic proteases, releasing free cobalamin; then it is bound by Castle intrinsic factor, produced by gastric parietal cells. Linked with the intrinsic factor, the cobalamin arrives at the distal ileum, where the intestinal cells have the specific receptor, called cubilin, for this complex. The intake size is determined by the number of receptor.
The cobalamin/intrinsic factor/ cubilin/ megalina (associated to cubilin) complex is carried in enterocytes with a endocytosis process.
In the endosomes occurs the complex dissociation: cubilin/megalina returns to plasmatic membrane and the cobalamin/ intrinsic factor goes to lysosome, where the intrinsic factor is disrupted by lysosomal enzymes. The B12 vitamin instead goes out from lysosome and enterocyte and carries in the bloodstream bound to transcobalamin II.
METABOLISM
The metabolically active forms are methylcobalamin and 5'-deoxyadenosylcobalamina.
The 5'-deoxyadenosylcobalamina is involved in the isomerization of methylmalonyl-CoA in succynil-CoA, reaction catalyzed by the methylmalonyl-CoA mutase enzyme, and in the synthesis of 2-deoxyribonucleotide.
This reaction happens during the amino acids valine, methionine and isoleucine catabolism and it is catalyzed by the methylmalonylCoa mutase enzyme. This enzyme needs the B12 cobalamin and transfers a substituent to a carbon atom close to it. The reaction is radical with homolytic breakage and the coenzyme B12 acts as electron acceptors.
A deficiency of vitamin B12 leads to the failure of the enzyme and accumulation of methylmalonylCoA, with consequent inhibition of the synthesis of fatty acids; this because the enzyme fatty acid synthase uses the malonylCoa, but the methylmalonylCoA competes with the latter and it is preferred because it's at higher concentration. This implies that it is impossible to condense the malonylCoA to acetylCoA; then the production of fatty acids reduces. The main organ affected is the nervous system, with deterioration of the myelin sheath (formed by oligodendrocytes, which consists of membrane lipid complex formed by fatty acids).
The methylcobalamin
It is involved in the metabolism of methionine: methionine is converted to S-adenosyl methionine, which is transformed first into S-adenosyl homocysteine, losing a methyl, and then in homocysteine, losing adenosine. Homocysteine can then be converted back to methionine through methionine synthase enzyme and this reaction requires two cofactors: methylcobalamin and tetrahydrofolate. The methionine synthase enzyme catalyzes the addition of a methyl group to reform the methionine. The methyl group is donated by methylcobalamin, which in turn receives the methyl by the N5metylTHF.
DEFICIENCY
Deficiency of B12 vitamin is generally due to an insufficient intake and can be the consequence of:
- Deficiency of intrinsic factor caused by gastric surgery resection, used to reduce obesity or to treat gastric ulcers and malignances tumors.
- Inborn deficiency, caused by a mutation of GIF gene, situated in chromosome 11, that encodes for intrinsic factor. It is a rare condition.
- Deficiency of intrinsic factor due to atrophic gastritis: the gastric mucosal cells are chronically inflamed and there is a progressive decrement of glandular component.
- Ileostomy: the surgical removal of a part of the small intestine (in the last portion of the small intestine the cobalamin is absorbed).
- Crohn’s desease, an autoimmune disorder, that causes inflammation in bowel.
- Disorder of the normal bacterial flora
- Achlorhydria: hydrochloric acid lack in the gastric lumen, caused by assumption of pump protonic inhibitors, like drugs used in the treatment of peptic ulcers and gastric reflux.
- Assumption of metformin, an oral antidiabetic drug that can interfere with the intake of cobalamin.
A deficiency of vitamin B12 leads to the failure of the methylmalonyl-Coa mutase enzyme and accumulation of methylmalonylCoA, with consequent inhibition of the synthesis of fatty acids; this occur because the enzyme fatty acid synthase uses the malonylCoa, but the methylmalonylCoA competes with the latter and is used because at higher concentration. This implies that it is impossible to condense the malonylCoA to acetylCoA; then the production of fatty acids reduces. The main organ affected is the nervous system, with deterioration of the myelin sheath (formed by oligodendrocytes, which consists of membrane lipid complex formed by fatty acids).The nervous system can be also affected by a 'subclinical' form of B(12) deficiency, particularly within the elderly. This is often associated with cognitive impairment and dementia, including Alzheimer's disease, neurodegenerative disorders including vascular dementia, Parkinson's disease and multiple sclerosis. These conditions are all associated with chronic neuro-inflammation and oxidative stress.
Vitamin B(12) in neurology and ageing; Clinical and genetic aspects. 2012
Besides In case of vitamin B12 deficiency and in case of folate deficiency, there is a reduction of the activity of the methionine synthase enzyme; if this reaction does not take place, it locks the transformation of methyltetrahydrofolate to tetrahydrofolate, resulting in the accumulation of the first compound. The decrease of tetrahydrofolate and its derivative methylenetetrahydrofolate determines a block of enzymes that requires these two compounds. This leads to a dysfunction of the metabolic pathways producing purines and deoxyitimidina monophosphate, resulting in damage to DNA. The cells are those most affected in rapid removal and synthesis, especially red blood cells.
A deficiency of these cofactors is the basis of the anemie megaloblastic in which red blood cells have large size, equal to 12-13 microns (compared to 5-6 uM), and are also precursors of large dimensions. Let's say that the number of red blood cells is usually 4 ½ million-5 million; in this type of anemia the red blood cells is reduced about 3 million red blood cells.
Vegetarians are more prone to vitamin B12 deficiency, in fact, studies show that the prevalence of this deficiency in these individuals is greater. Higher rates of deficiency were reported among vegans compared with vegetarians and among individuals who had adhered to a vegetarian diet since birth compared with those who had adopted such a diet later in life.
How prevalent is vitamin B(12) deficiency among vegetarians?, 2012
PERNICIOUS ANEMIA
Pernicious anemia means anemia "dangerous" and megaloblastic anemia caused by B12 deficiency. In the past this type of anemia could result in death. A remedy was to eat raw liver of these individuals, in order to compensate for this deficiency.
The megaloblastic anemias due to a deficiency of B12 or folate are characterized by an altered DNA synthesis, hence the failure erythropoiesis and by the presence of blood cells (so adult cells) and precursor cells (in the bone), which appear morphologically large, large dimensions. These cells, especially at the level of the precursors in the bone, fail to mature and are unable to divide, then struggle to release circulating reticulocytes and red blood cells.
Both these red blood cells and these precursors undergo very often to death.
Thus, there is a defective maturation of the nucleus of precursor cells; this defective maturation of DNA replication will result in a delay and a block cell division. This does not affect the RNA.
Then there is a maturation of the cytoplasm and everything related to protein synthesis works well, what does not work is the division of DNA, and this will result in a +nucleus-cytoplasm asynchrony.
Then this cell grows and increases in size but there is no cell division, because the DNA can’t replicate.
The consequences will be an insufficient erythropoiesis and these large precursors undergo death, to self hemolysis or apoptosis. This will result in a reduction of the precursors; so will be produced megaloblasts and megalocytes, which are large cells that cannot pass into the blood vessels so they are deleted from bloodstream faster.
But the lack of vitamin B12 affects not only the precursor cells of red blood cells: it is a deficiency that affects all the cells of high proliferative activity. It will also cover the destruction of precursors of granulocytes, and the destruction of all cells that have a high mitotic activity. It means not only anemia but also other signs such as leukopenia and thrombocytopenia. All cells will be damaged, also in other tissues, it will then have more clinical signs that characterize this type of anemia.
So erythropoiesis will be reduced: in normal conditions there is a physiological death of the precursors of 10% and in deficiency of vitamin B12 or folic acid death precursors can also get to reach 90%. The individual will be deficient in red blood cells and can also get into death.
Pernicious anemia is also characterized by neurological deficiencies due to the alteration of the myelin sheath.
Although anemia appears in both deficiencies, it is necessary to make a differential diagnosis because the administration of folic acid does not allow to treat the neurological symptoms, if the anemia was caused by cobalamin deficiency which may then become irreversible. It was also seen that the intake of high amounts of vitamin C (> 1 g) may, over time, generate cobalamin deficiency states. This is because, in high doses, vitamin C can behave as an oxidant and form free radicals which damage the cobalamin and intrinsic factor in the presence of iron,.
The treatment of pernicious anemia provides for the administration of cobalamin intravenously or orally; in this case must it be taken in large quantities to remedy the shortcomings of absorption (for this you prefer the intravenous route).
Have been recently used new laboratory markers, like holotranscobalamin and methylmalonic acid, to diagnose pernicious anemia. The introduction of these markers has led to reduce instances of false negatives, that is important to avoid the damage especially at the nervous system, typical of this type of anemia if not treated in a timely manner. This diagnostic strategy may significantly improve assessing vitamin B12 deficiency.
Utility and limitations of biochemical markers of vitamin B12 deficiency. 2012
