Article: Cyanocobalamin

Cyanocobalamin
General
Molecular formula	C63H88CoN14O14P
Molar mass	1355.37 g/mol
Infobox disclaimer and references source [1] (all but the picture)

The name vitamin B₁₂ (or B₁₂ for short) is used in two different ways. In a broader sense it refers to a group of cobalt-containing compounds known as cobalamins - cyanocobalamin (an artefact formed as a result of the use of cyanide in the purification procedures), hydroxocobalamin and the two coenzyme forms of B₁₂, methylcobalamin (MeB₁₂) and 5-deoxyadenosylcobalamin (adenosylcobalamin - AdoB₁₂). In a more specific way, the term B₁₂ is used to refer to only one of these forms, cyanocobalamin, which is the principal B₁₂ form used for foods and in nutritional supplements.

Pseudo-B₁₂ refers to B₁₂-like substances which are found in certain organisms, such as Spirulina spp. (blue-green algae, cyanobacteria). However, these substances do not have B₁₂ biological activity for humans.

Structure

B₁₂ is the most chemically complex of all the vitamins. B₁₂'s structure is based on a corrin ring, which, although similar to the porphyrin ring found in heme, chlorophyll, and cytochrome, has two of the pyrrole rings directly bonded. The central metal ion is Co (cobalt). Four of the six coordinations are provided by the corrin ring nitrogens, and a fifth by a dimethylbenzimidazole group. The sixth coordination partner varies, being a cyano group (-CN), a hydroxyl group (-OH), a methyl group (-CH₃) or a 5'-deoxyadenosyl group (here the C5' atom of the deoxyribose forms the covalent bond with Co), respectively, to yield the four B₁₂ forms mentioned above. The covalent C-Co bond is the only carbon-metal bond known in biology. ^[2]

Synthesis

B₁₂ cannot be made by plants or by animals^[3], as the only type of organisms that have the enzymes required for the synthesis of B₁₂ are bacteria and archaea. The total synthesis of B₁₂ was reported in 1973 by Robert Burns Woodward, and remains one of the classic feats of total synthesis.

Functions

Coenzyme B₁₂'s reactive C-Co bond participates in two types of enzyme-catalyzed reactions. ^[4]

1. Rearrangements in which a hydrogen atom is directly transferred between two adjacent atoms with concomitant exchange of the second substituent, X, which may be a carbon atom with substituents, an oxygen atom of an alcochol, or an amine.
2. Methyl (-CH₃) group transfers between two molecules.

In humans there are only two coenzyme B₁₂-dependent enzymes:

1. MUT which uses the AdoB₁₂ form and reaction type 1 to catalyze a carbon skeleton rearrangement (the X group is -COSCoA). MUT's reaction converts MMl-CoA to Su-CoA, an important step in the extraction of energy from proteins and fats (for more see MUT's reaction mechanism)
2. MTR, a methyl transfer enzyme, which uses the MeB₁₂ and reaction type 2 to catalyzes the conversion of the amino acid Hcy into Met (for more see MTR's reaction mechanism).

History as a treatment for anemia

B₁₂ deficiency is the cause of several forms of anemia. The treatment for this disease was first devised by William Murphy who bled dogs to make them anemic and then fed them various substances to see what (if anything) would make them healthy again. He discovered that ingesting large amounts of liver seemed to cure the disease. George Minot and George Whipple then set about to chemically isolate the curative substance and ultimately were able to isolate vitamin B₁₂ from the liver. For this, all three shared the 1934 Nobel Prize in Medicine.

The chemical structure of the molecule was determined by Dorothy Crowfoot Hodgkin and her team in 1956, based on crystallographic data.

Other medical uses

Hydroxycobalamin is used in Europe as a treatment for cyanide poisoning, with a large amount (5-10 g) given intravenously. The treatment is marketed under the tradename Cyanokit ^[5]. The mechanism of action is straightforward, the hydroxycobalamin hydroxide ligand is displaced by the toxic cyanide ion, and the resulting harmless B₁₂ is excreted in urine.

Deficiency

The usual daily intake in the Western diet is 5–7 µg (Food and Drug Administration (FDA) Daily Value ^[6]); the daily requirement is 1–2 µg. B₁₂ is mostly absorbed in the terminal ileum. The production of intrinsic factor in the stomach is vital to absorption of this vitamin. Megaloblastic anemia can result from inadequate intake of B₁₂, inadequate production of intrinsic factor (pernicious anemia), disorders of the terminal ileum resulting in malabsorption, or by competition for available B₁₂ (such as fish tapeworms or bacteria present in blind loop syndrome). Neurological signs of B₁₂ deficiency, which can occur without accompanying hematologic abnormalities, include demyelination and irreversible nerve cell death. Symptoms include numbness or tingling of the extremities and an ataxic gait.

The American Psychiatric Association's American Journal of Psychiatry has published studies showing a relationship between depression levels and deficient B₁₂ blood levels in elderly people in 2000 ^[7] and 2002 ^[8].

Traditionally, treatment for B₁₂ deficiency was through intramuscular injections of cyanocobalamin. However, it has recently been appreciated that deficiency can be treated with oral B₁₂ supplements when given in sufficient doses. When given in oral doses ranging from 0.1–100 mg daily, B₁₂ can be absorbed in a pathway that does not require an intact ileum or intrinsic factor.^[9] The Schilling test can determine whether symptoms of B₁₂ deficiency are caused by lack of intrinsic factor, though this is being performed less often due to the lack of availability of reagent for the test.