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Vitamin B12, also known as cobalamin or extrinsic factor, is a water-soluble vitamin involved in metabolism.
One of eight B vitamins, Vitamin B12 serves as a vital cofactor in DNA synthesis and both fatty acid and amino acid metabolism.
Vitamin B12 plays an essential role in the nervous system by supporting myelin synthesis and is critical for the maturation of red blood cells in the bone marrow.
CAS: 13408-78-1
MF: C63H88CoN14O14P
MW: 1355.37
EINECS: 236-500-2
Synonyms:VIT B12;A-(5,6-DIMETHYLBENZIMIDAZOLYL)COBAMIDE CYANIDE;ANTIANEMIC VITAMIN B;ALPHA-(5,6-DIMETHYLBENZIMIDAZOLYL)CYANOCOBAMIDE;METHYLCOBALAMIN;CYTACON;CYTAMEN;CYANOCOBALAMINE;
Cobinamide,dihydrogen phosphate (ester),inner salt,3′-ester with (5,6-dimethyl-1-α-D-ribofuranosyl-1H-benzimidazole-κN3),ion(1+);Cobinamide,hydroxide,ion(1+),dihydrogen phosphate (ester),inner salt,3′-ester with 5,6-dimethyl-1-α-D-ribofuranosylbenzimidazole;Cobinamide,hydroxide,ion(1+),dihydrogen phosphate (ester),inner salt,3′-ester with 5,6-dimethyl-1-α-D-ribofuranosyl-1H-benzimidazole;Cobinamide,ion(1+),dihydrogen phosphate (ester),inner salt,3′-ester with 5,6-dimethyl-1-α-D-ribofuranosyl-1H-benzimidazole;Cobalamine;Cobalamin;58846-82-5
A cobalamin in which the central cobalt atom has an oxidation state of +3.
While animals require B12, plants do not, relying instead on alternative enzymatic pathways.
Vitamin B12 is the most chemically complex of all vitamins, and is synthesized exclusively by certain archaea and bacteria.
Natural food sources include meat, shellfish, liver, fish, poultry, eggs, and dairy products.
Vitamin B12 is also added to many breakfast cereals through food fortification and is available in dietary supplement and pharmaceutical forms.
Supplements are commonly taken orally but may be administered via intramuscular injection to treat deficiencies.
Vitamin B12 deficiency is prevalent worldwide, particularly among persons with low or no intake of animal products, such as those following vegan or vegetarian diets, or those with low socioeconomic status.
The most common cause in developed countries is impaired absorption due to loss of gastric intrinsic factor (IF), required for absorption.
A related cause is reduced stomach acid production with age or from long-term use of proton-pump inhibitors, H2 blockers, or other antacids.
Deficiency is especially harmful in pregnancy, childhood, and older adults.
Vitamin B12 can lead to neuropathy, megaloblastic anemia, and pernicious anemia, causing symptoms such as fatigue, paresthesia, cognitive decline, ataxia, and even irreversible nerve damage.
In infants, untreated deficiency may result in neurological impairment and anemia. Maternal deficiency increases the risk of miscarriage, neural tube defects, and developmental delays in offspring.
Folate levels may modify the presentation of symptoms and disease course.
Vitamin B12 is a coordination complex of cobalt, which occupies the center of a corrin ligand and is further bound to a benzimidazole ligand and adenosyl group.
Several related species behave similarly to function as vitamins.
This collection of compounds is sometimes referred to as "cobalamins".
These chemical compounds have a similar molecular structure, each of which shows vitamin activity in a vitamin-deficient biological system.
They are referred to as vitamers having vitamin activity as a coenzyme, meaning that its presence is required for some enzyme-catalyzed reactions.
Adenosylcobalamin
Cyanocobalamin, the adenosyl ligand in vitamin B12 is replaced by cyanide.
Hydroxocobalamin, the adenosyl ligand in vitamin B12 is replaced by hydroxide.
Methylcobalamin, the adenosyl ligand in vitamin B12 is replaced by methyl.
Cyanocobalamin is a manufactured form of B12.
Bacterial fermentation creates AdoB12 and MeB12, which are converted to cyanocobalamin by the addition of potassium cyanide in the presence of sodium nitrite and heat.
Once consumed, cyanocobalamin is converted to the biologically active AdoB12 and MeB12.
The two bioactive forms of vitamin B12 are methylcobalamin in cytosol and adenosylcobalamin in mitochondria.
Cyanocobalamin is the most common form used in dietary supplements and food fortification because cyanide stabilizes the molecule against degradation.
Methylcobalamin is also offered as a dietary supplement.
There is no advantage to the use of adenosylcobalamin or methylcobalamin forms for the treatment of vitamin B12 deficiency.
Hydroxocobalamin can be injected intramuscularly to treat vitamin B12 deficiency.
Vitamin B12 can also be injected intravenously for the purpose of treating cyanide poisoning, as the hydroxyl group is displaced by cyanide, creating a non-toxic cyanocobalamin that is excreted in urine.
Medical uses
Treatment of deficiency
Severe vitamin B12 deficiency is initially corrected with daily intramuscular injections of 1000 μg of the vitamin, followed by maintenance via monthly injections of the same amount or daily oral dosing of 1000 μg.
The oral daily dose far exceeds the vitamin requirement because the normal transporter protein-mediated absorption is absent, leaving only very inefficient intestinal passive absorption.
Injection side effects include skin rash, itching, chills, fever, hot flushes, nausea and dizziness.
There are not enough studies on whether pills are as effective in improving or eliminating symptoms as parenteral treatment.
Cyanide poisoning
For cyanide poisoning, a large amount of hydroxocobalamin may be given intravenously and sometimes in combination with sodium thiosulfate.
The mechanism of action is straightforward: the hydroxycobalamin hydroxide ligand is displaced by the toxic cyanide ion, and the resulting non-toxic cyanocobalamin is excreted in urine.
Chemistry
Vitamin B12 is the most chemically complex of all the vitamins.
The structure of Vitamin B12 is based on a corrin ring, which is similar to the porphyrin ring found in heme.
The central metal ion is cobalt.
As isolated as an air-stable solid and available commercially, cobalt in vitamin B12 (cyanocobalamin and other vitamers) is present in its +3 oxidation state.
Biochemically, the cobalt center can take part in both two-electron and one-electron reductive processes to access the "reduced" (B12r, +2 oxidation state) and "super-reduced" (B12s, +1 oxidation state) forms.
The ability to shuttle between the +1, +2, and +3 oxidation states is responsible for the versatile chemistry of vitamin B12, allowing it to serve as a donor of deoxyadenosyl radical (radical alkyl source) and as a methyl cation equivalent (electrophilic alkyl source).
Four of the six coordination sites are provided by the corrin ring and a fifth by a dimethylbenzimidazole group.
The sixth coordination site, the reactive center, is variable, being a cyano group (–CN), a hydroxyl group (–OH), a methyl group (–CH3) or a 5′-deoxyadenosyl group.
Historically, the covalent carbon–cobalt bond is one of the first examples of carbon-metal bonds to be discovered in biology.
The hydrogenases and, by necessity, enzymes associated with cobalt utilization, involve metal-carbon bonds.
Animals can convert cyanocobalamin and hydroxocobalamin to the bioactive forms adenosylcobalamin and methylcobalamin by enzymatically replacing the cyano or hydroxyl groups.
Synthesis
In 1960, the research group of the biochemist Konrad Bernhauer in Stuttgart had reconstituted vitamin B12 from one of its naturally occurring derivatives, cobyric acid, by stepwise construction of the vitamin's nucleotide loop.
Therefore, cobyric acid was chosen as the target molecule for a total synthesis of vitamin B12 (cobalamin).
Biosynthesis
Vitamin B12 is derived from a tetrapyrrolic structural framework created by the enzymes deaminase and cosynthetase which transform aminolevulinic acid via porphobilinogen and hydroxymethylbilane to uroporphyrinogen III.
The latter is the first macrocyclic intermediate common to heme, chlorophyll, siroheme and Vitamin B12 itself.
Later steps, especially the incorporation of the additional methyl groups of its structure, were investigated using 13C methyl-labelled S-adenosyl methionine.
Vitamin B12 was not until a genetically engineered strain of Pseudomonas denitrificans was used, in which eight of the genes involved in the biosynthesis of the vitamin had been overexpressed, that the complete sequence of methylation and other steps could be determined, thus fully establishing all the intermediates in the pathway.
