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  Vitamin B12 Cobalamin | Vitamin Deficiencies and Essential Nutrients  

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Vitamin B12 Deficiency Effects

Vitamin B12 deficiency results in a macrocytic anemia, elevated homocysteine, peripheral neuropathy, memory loss and other cognitive deficits. Vitamin B12 deficiencies are most likely to occur among elderly people, as absorption through the gut declines with age; the autoimmune disease pernicious anemia is another common cause. Vitamin B12 deficiency can also cause symptoms of mania and psychosis. In rare extreme cases, paralysis can result from Vitamin B12 deficiencies.

Vitamin B12 CyanocobalaminVitamin B12 deficiency is a reduction in vitamin B12 from inadequate dietary intake or impaired absorption. The condition is commonly asymptomatic, but can also present as anemia characterized by enlarged blood corpuscles with characteristic changes in neutrophils, known as megaloblastic anemia.

In serious cases deficiency can potentially cause severe and irreversible damage to the nervous system, including subacute combined degeneration of spinal cord.

The anemia is thought to be due to problems in DNA synthesis, specifically in the synthesis of thymine, which is dependent on products of the MTR reaction. Other blood cell types such as white blood cells and platelets are often also low. Bone marrow examination may show megaloblastic hemopoiesis. The anemia responds completely to vitamin B12; the neurological symptoms (if any) respond partly or completely, depending on prior severity and duration.

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What is Vitamin B12? Cobalamin! Cobalt!

Cobalamin (Vitamin B12) |kōˈbaləmin| noun Biochemistry
Any of a group of cobalt-containing substances including Cyanocobalamin.
ORIGIN 1950s: blend of cobalt + vitamin.

Cyanocobalamin |ˌsīənōˌkōˈbaləmin; sīˌanō-| noun
A vitamin found in foods of animal origin such as liver, fish, and eggs, a deficiency of which can cause pernicious anemia. It contains a cyanide group bonded to the central cobalt atom of a cobalamin molecule. Also called Vitamin B12.
ORIGIN 1950s: from Cyanogen + Cobalamin (blend of cobalt + vitamin).

Hydroxocobalamin is used to treat of [Cyanocobalamin] cyanide poisoning!

Hydoxyocobalamin is marketed under the trade name Cyanokit for cyanide toxicity. The standard dose is 5 gm IV infused over 15 minutes. A second 5 gm dose can be given in patients with severe toxicity. Hydroxocobalamin will bind circulating and cellular cyanide molecules to form cyanocobalamin which is excreted in the urine.

B12 Corrinoids

Corrinoids are a group of compounds based on the skeleton of corrin, a cyclic system containing four pyrrole rings similar to porphyrins. These include compounds based on octadehydrocorrin, which has the trivial name corrole.

The cobalamins (vitamin B12) are the best known members of the group. Other prominent examples include cobyrinic acid and its hexaamide cobyric acid; cobinic acid and its hexaamide cobinamide; cobamic acid and cobamide.

Compounds containing the "Cob-" suffix (not corrin) are cobalt derivatives, and may include an oxidation state, as in "Cob(II)alamin". When cobalt is replaced by another metal or hydrogen, the name changes accordingly, as in ferrobamic acid or hydrogenobamic acid.

Corrin ring, numbered according to the 1975 IUPAC standard. Note that for consistency with the porphyrin numbering system, there is no 20 position. Positions 21-24 were numbered 20-23 in earlier literature.

Vitamin B12 Sources Vitamin B12 Benefits

Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins. 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. Neither fungi, plants, nor animals are capable of producing vitamin B12. Only bacteria and archaea have the enzymes required for its synthesis, although many foods are a natural source of B12 because of bacterial symbiosis. The vitamin is the largest and most structurally complicated vitamin and can be produced industrially only through bacterial fermentation-synthesis.

Vitamin B12 consists of a class of chemically related compounds (vitamers), all of which have vitamin activity. It contains the biochemically rare element cobalt. Biosynthesis of the basic structure of the vitamin is accomplished only by bacteria (which usually produce hydroxocobalamin), but conversion between different forms of the vitamin can be accomplished in the human body. A common semi-synthetic form of the vitamin, cyanocobalamin, does not occur in nature, but is produced from bacterial hydroxocobalamin and then used in many pharmaceuticals and supplements, and as a food additive, because of its stability and lower production cost. In the body it is converted to the human physiological forms methylcobalamin and adenosylcobalamin, leaving behind the cyanide, albeit in minimal concentration. More recently, hydroxocobalamin, methylcobalamin, and adenosylcobalamin can be found in more expensive pharmacological products and food supplements. The extra utility of these is currently debated.

Vitamin B12 was discovered from its relationship to the disease pernicious anemia, which is an autoimmune disease in which parietal cells of the stomach responsible for secreting intrinsic factor are destroyed. Intrinsic factor is crucial for the normal absorption of B12, so a lack of intrinsic factor, as seen in pernicious anemia, causes a vitamin B12 deficiency. Many other subtler kinds of vitamin B12 deficiency and their biochemical effects have since been elucidated.

Vitamin B12 Group

The term "vitamin B12" refers to a group of compounds called cobalamins that are available in the human body in a variety of mostly interconvertible forms. Together with folic acid, cobalamins are essential cofactors required for DNA synthesis in cells where chromosomal replication and division are occurring—most notably the bone marrow and myeloid cells. As a cofactor, cobalamins are essential for two cellular reactions:

  1. the mitochondrial methylmalonyl coenzyme A mutase conversion of methylmalonic acid (MMA) to succinate, which links lipid and carbohydrate metabolism, and
  2. activation of methionine synthase, which is the rate limiting step in the synthesis of methionine from homocysteine and tetrahydrofolate (Katzung, 1989).

Cobalamins are characterized by a porphyrin-like corrin nucleus that contains a single cobalt atom bound to a benzimidazolyl nucleotide and a variable residue (R) group. The variable R group gives rise to the four most commonly known cobalamins: CNCbl, methylcobalamin, 5-deoxyadenosylcobalamin, and OHCbl. In the serum, OHCbl and CNCbl are believed to function as storage or transport forms of the molecule, whereas methylcobalamin and 5-deoxyadenosylcobalamin are the active forms of the coenzyme required for cell growth and replication. CNCbl is usually converted to OHCbl in the serum, whereas OHCbl is converted to either methylcobalamin or 5-deoxyadenosyl cobalamin. Cobalamins circulate bound to serum proteins called transcobalamins (TC) and haptocorrins. OHCbl has a higher affinity to the TC II transport protein than CNCbl, or 5-deoxyadenosylcobalamin.

From a biochemical point of view, two essential enzymatic reactions require vitamin B12 (cobalamin). Intracellular vitamin B12 is maintained in two active coenzymes, methylcobalamin and 5-deoxyadenosylcobalamin, which are both involved in specific enzymatic reactions. In the face of vitamin B12 deficiency, conversion of methylmalonyl-CoA to succinyl-CoA cannot take place, which results in accumulation of methylmalonyl-CoA and aberrant fatty acid synthesis. In the other enzymatic reaction, methylcobalamin supports the methionine synthase reaction, which is essential for normal metabolism of folate. The folate-cobalamin interaction is pivotal for normal synthesis of purines and pyrimidines and the transfer of the methyl group to cobalamin is essential for the adequate supply of tetrahydrofolate, the substrate for metabolic steps that require folate. In a state of vitamin B12 deficiency, the cell responds by redirecting folate metabolic pathways to supply increasing amounts of methyltetrahydrofolate. The resulting elevated concentrations of homocysteine and MMA are often found in patients with low serum vitamin B12 and can usually be lowered with successful vitamin B12 replacement therapy.

However, elevated MMA and homocysteine concentrations may persist in patients with cobalamin concentrations between 200 to 350 pg/mL (Lindenbaum et al. 1994). Supplementation with vitamin B12 during conditions of deficiency restores the intracellular level of cobalamin and maintains a sufficient level of the two active coenzymes: methylcobalamin and deoxyadenosylcobalamin.

What is "Cobalamin" ?

Cobalamin may refer to several substances depending on the upper axial ligand of the cobalt ion. These are:

 

B12a Methylcobalamin

Methylcobalamin (mecobalamin, MeCbl, or MeB12) is a cobalamin used in the treatment of peripheral neuropathy, diabetic neuropathy, and as a preliminary treatment for amyotrophic lateral sclerosis. It is a form of vitamin B12 and differs from cyanocobalamin in that the cyanide is replaced by a methyl group. Methylcobalamin features an octahedral cobalt(III) centre. Methylcobalamin can be obtained as bright red crystals.

Methylcobalamin
From the perspective of coordination chemistry, methylcobalamin is notable as a rare example of an enzyme that contains metal-alkyl bonds. Nickel-methyl intermediates have been proposed for the final step of methanogenesis.

Methylcobalamin can be produced in the laboratory by reducing cyanocobalamin with sodium borohydride in alkaline solution, followed by the addition of methyl iodide.

Methylcobalamin physically resembles the other forms of vitamin B12, occurring as dark red crystals that freely form cherry-colored transparent solutions in water.

Functions

This vitamer is one of two active coenzymes used by vitamin B12-dependent enzymes and is the specific vitamin B12 form used by 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), also known as methionine synthase. In physiological terms, it is equivalent to vitamin B12, e.g. for addressing pathologies arising from a lack of vitamin B12, such as pernicious anemia.

Methylcobalamin participates in the Wood-Ljungdahl pathway, which is a pathway by which some organisms utilize carbon dioxide as their source of organic compounds. In this pathway, methylcobalamin provides the methyl group that couples to carbon monoxide (derived from CO2) to afford acetyl-CoA. Acetyl-CoA is a derivative of acetic acid that is converted to more complex molecules as required by the organism.

Methylcobalamin is produced by some bacteria. It plays an important role in the environment. In the environment, it is responsible for the biomethylation of certain heavy metals. For example, the highly toxic methylmercury is produced by the action of methylcobalamin. In this role, methylcobalamin serves as a source "CH3+".

Treatment for Cyanide [CYANOcobalamin] Poisoning

Hydroxocobalamin, a form (or vitamer) of vitamin B12 made by bacteria, and sometimes denoted vitamin B12a, is used to bind cyanide to form the harmless cyanocobalamin form of vitamin B12. Hydroxocobalamin is newly approved in the US and is available in Cyanokit antidote kits. Cyanocobalamin is then eliminated through the urine.

Hydroxocobalamin works both within the intravascular space and within the cells to combat cyanide intoxication. This versatility contrasts with methemoglobin, which acts only within the vascular space as an antidote. Hydroxocobalamin is superior as a single agent to thiosulfate however, administration of sodium thiosulfate improves the ability of hydroxocobalamin to detoxify cyanide poisoning.

This treatment is considered so effective and innocuous that it is administered routinely in Paris to victims of smoke inhalation to detoxify any associated cyanide intoxication. However it is relatively expensive and not universally available.

 

B12 Cobamamide (Adenosylcobalamin)

Cobamamide (AdoCbl), which is also known as adenosylcobalamin and dibencozide, is, along with methylcobalamin (MeCbl), one of the active forms of vitamin B12. As a nutritional supplement, it is available in tabletted form, but, (unlike cyanocobalamin, methylcobalamin, and hydroxocobalamin), it is not available in injectable form.

An enzyme that uses adenosylcobalamin as a cofactor is methylmalonyl-CoA mutase (MCM).

 

B12 Hydroxocobalamin

Hydroxocobalamin (OHCbl, or B12a) is a natural form, or vitamer, of vitamin B12, a basic member of the cobalamin family of compounds. Hydroxocobalamin is the form of vitamin B12 produced by many bacteria which are used to produce the vitamin commercially. Like other forms of vitamin B12, hydroxocobalamin has an intense red color. It is not a form normally found in the human body, but is easily converted in the body to usable coenzyme forms of vitamin B12. Pharmaceutically, hydroxycobalamin is usually produced as a sterile injectable solution and is used for treatment of the vitamin deficiency, and also (because of its affinity for cyanide ion) as a treatment for cyanide poisoning. Experimentally, it has been tested as a scavenger of nitric oxide.

Vitamin B12 is a term that refers to a group of compounds called cobalamins that are available in the human body in a variety of mostly interconvertible forms. Together with folic acid, cobalamins are essential cofactors required for DNA synthesis in cells where chromosomal replication and division are occurring—most notably the bone marrow and myeloid cells. As a cofactor, cobalamins are essential for two cellular reactions: (1) the mitochondrial methylmalonylcoenzyme A mutase conversion of methylmalonic acid (MMA) to succinate, which links lipid and carbohydrate metabolism, and (2) activation of methionine synthase, which is the rate-limiting step in the synthesis of methionine from homocysteine and 5-methyltetrahydrofolate.

 

B12 Cyanocobalamin

Vitamin B12 Injection Cyanocobalamin
Cyanocobalamin is the most common and widely produced of the chemical compounds that have vitamin activity as vitamin B12. Vitamin B12 is the "generic descriptor" name for any of such vitamers of vitamin B12. Because the body can convert cyanocobalamin to any one of the active vitamin B12 compounds, by definition this makes cyanocobalamin itself a form (or vitamer) of B12, albeit a largely artificial one.

Cyanocobalamin usually does not occur in living organisms, but animals can convert commercially produced cyanocobalamin into active (cofactor) forms of the vitamin, such as methylcobalamin. The amount of cyanide liberated in this process is so small that its toxicity is negligible.

Cyanocobalamin is the most famous and widely produced vitamer in the vitamin B12 family (the family of chemicals that function as B12 when put into the body), because cyanocobalamin is the most air-stable of the B12 forms. It is the easiest to crystallize and, therefore, easiest to purify after it is produced by bacterial fermentation, or synthesized in vitro. It can be obtained as dark red crystals or as an amorphous red powder. Cyanocobalamin is very hygroscopic in the anhydrous form, and sparingly soluble in water (1:80). It is stable to autoclaving for short periods at 121 °C. The vitamin B12 coenzymes are very unstable in light.

In animals the cyanide ligand is replaced by other groups (adenosyl, methyl), which are the biologically active. The remaining portion of the cyanocobalamin remains unchanged.

Production

Reduced Cyanocobalamin
Cyanocobalamin is commercially prepared by bacterial fermentation. Fermentation by a variety of microorganisms yields a mixture of methyl-, hydroxo-, and adenosylcobalamin. These compounds are converted to cyanocobalamin by addition of potassium cyanide in the presence of sodium nitrite and heat. Since a number of species of Propionibacterium produce no exotoxins or endotoxins and have been granted GRAS status (generally regarded as safe) by the Food and Drug Administration of the United States, they are currently the preferred bacterial fermentation organisms for vitamin B12 production.

Historically, a form of vitamin B12 called hydroxocobalamin is often produced by bacteria, and was then changed to cyanocobalamin in the process of being purified in activated charcoal columns after being separated from the bacterial cultures. This change was not immediately realized when vitamin B12 was first being extracted for characterization. Cyanide is naturally present in activated charcoal, and hydroxocobalamin, which has great affinity for cyanide, picks it up, and is changed to cyanocobalamin. Cyanocobalamin is the form in most pharmaceutical preparations because adding cyanide stabilizes the molecule.

France accounts for 80% of world production, and more than 10 tons/year of this compound is sold; 55% of sales is destined for animal feed, while the remaining 45% is for human consumption.

Pharmaceutical Use

Cyanocobalamin is usually prescribed for the following reasons: after surgical removal of part or all of the stomach or intestine to ensure there are adequate levels of vitamin B12 in the bloodstream; to treat pernicious anemia; vitamin B12 deficiency due to low intake from food; thyrotoxicosis; hemorrhage; malignancy; liver or kidney disease. Cyanocobalamin injections are often prescribed to gastric bypass patients having had part of their small intestine bypassed, making it difficult for B12 to be absorbed via food or vitamins. Cyanocobamide is also used to perform the Schilling test to check a person's ability to absorb vitamin B12.

End-Product of Cyanide Poisoning Treatment

In cases of cyanide poisoning the patient is given hydroxocobalamin, which is a precursor to cyanocobalamin. The hydroxocobalamin binds with the cyanide ion and forms cyanocobalamin which can then be secreted by the kidneys. This has been used for many years in France and was approved by the FDA in Dec 2006, marked under the name Cyanokit.

Possible Side Effects

The oral use of cyanocobalamin may lead to several allergic reactions such as hives; difficult breathing; swelling of the face, lips, tongue, or throat. Less-serious side effects may include headache, nausea, stomach upset, diarrhea, joint pain, itching, or rash.

In the treatment of some forms of anemia (e.g., megaloblastic anemia), the use of cyanocobalamin can lead to severe hypokalemia, sometimes fatal, due to intracellular potassium shift upon anemia resolution (but this same effect should be observed with any B12 vitamer, not just cyanocobalamin). When treated with vitamin B12, patients with Leber's disease may suffer rapid optic atrophy.

Forms of vitamin B12 for injection (such as hydroxocobalamin itself) are commonly available as pharmaceuticals, and are actually the most commonly used injectable forms of vitamin B12 in many countries. Injectable cyanocobalamin remains the most commonly injectable vitamin B12 in the United States.

 

 

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