vitamin b12.pdf

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Vitamin B12

Systematic (IUPAC) name

-(5,6-

dimethylbenzimidazolyl)cobamidcyanide

Clinical data

AHFS/Drugs.com monograph

Pregnancy cat. ?

Legal status POM (UK) OTC (US)

Routes oral, IV, IM

Pharmacokinetic data

Bioavailability Readily absorbed indistal half of the

ileum

Protein binding Very high to specific

transcobalamins

plasma proteins

Binding of

hydroxocobalamin is

slightly higher than

cyanocobalamin.

Metabolism hepatic

Half-life Approximately 6 days

(400 days in the

liver)

Excretion Renal

Identifiers

CAS number 68-19-9

ATC code B03BA01

Vitamin B12

From Wikipedia, the free encyclopedia

Vitamin B12, vitamin B12or vitamin B-12, also calledcobalamin, is a water-soluble vitamin with a key role in thenormal functioning of the brain and nervous system, and for theformation of blood. It is one of the eight B vitamins. It is

normally involved in the metabolism of every cell of the humanbody, especially affecting DNA synthesis and regulation, butalso fatty acid synthesis and energy production. Neither fungi,plants, nor animals are capable of producing vitamin B12. Onlybacteria and archaea have the enzymes required for itssynthesis, although many foods are a natural source of B12because of bacterial symbiosis. The vitamin is the largest andmost structurally complicated vitamin and can be producedindustrially only through bacterial fermentation-synthesis.

Vitamin B12consists of a class of chemically related compounds(vitamers), all of which have vitamin activity. It contains thebiochemically rare element cobalt. Biosynthesis of the basicstructure of the vitamin is accomplished only by bacteria (whichusually produce hydroxocobalamin), but conversion betweendifferent forms of the vitamin can be accomplished in thehuman body. A common semi-synthetic form of the vitamin,cyanocobalamin, does not occur in nature, but is produced frombacterial hydroxocobalamin and then used in manypharmaceuticals and supplements, and as a food additive,because of its stability and lower production cost. In the body itis converted to the human physiological forms methylcobalaminand adenosylcobalamin, leaving behind the cyanide, albeit inminimal concentration. More recently, hydroxocobalamin,methylcobalamin, and adenosylcobalamin can be found in moreexpensive pharmacological products and food supplements.

The extra utility of these is currently debated.

Vitamin B12was discovered from its relationship to the diseasepernicious anemia, which is an autoimmune disease in whichparietal cells of the stomach responsible for secreting intrinsicfactor are destroyed. Intrinsic factor is crucial for the normalabsorption of B12, so a lack of intrinsic factor, as seen inpernicious anemia, causes a vitamin B12deficiency. Many othersubtler kinds of vitamin B12deficiency and their biochemical

effects have since been elucidated.[1]

Contents

1 Terminology

2 Medical uses

2.1 Recommended intake

3 Controversial sources in algae

3.1 Deficiency

4 Adverse effects

4.1 Allergies

Vitamin B12 - Wikipedia, the free encyclopedia https://en.wikipedia.org/wiki/Vitamin_

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PubChem CID 5479203

DrugBank DB00115

ChemSpider 10469504

KEGG D00166

ChEMBL CHEMBL1697777

Chemical data

Formula C63H88CoN14O14P

Mol. mass 1355.37 g/mol

(what is this?) (verify)

Methylcobalamin (shown) is a form of vitamin

B12. Physically it resembles the other forms of

vitamin B12, occurring as dark red crystals that

freely form cherry-colored transparent solutions

in water.

4.2 Interactions

5 Structure

6 Synthesis and industrial production

7 Mechanism of action

7.1 Enzyme function

8 Absorption and distribution

9 History10 Sources

10.1 Foods

10.2 Supplements

10.2.1 Non-cyano forms as supplements

11 See also

12 References

13 External links

Terminology

The names vitamin B12, vitamin B12, or vitamin B-12,and the alternative name cobalamin, generally refer toall forms of the vitamin. Some medical practitionershave suggested that its use be split into twocategories.

In a broad sense, B12refers to a group of cobalt-

containing vitamer compounds known as

cobalamins: these include cyanocobalamin (an

artifact formed from using activated charcoal,

which always contains trace cyanide, to purify

hydroxycobalamin), hydroxocobalamin (anothermedicinal form, produced by bacteria), and

finally, the two naturally occurring cofactor forms

of B12in the human body:

5'-deoxyadenosylcobalamin (adenosylcobalamin

AdoB12), the cofactor of Methylmalonyl

Coenzyme A mutase (MUT), and

methylcobalamin (MeB12), the cofactor of

5-methyltetrahydrofolate-homocysteine

methyltransferase (MTR).

The term B12may be properly used to refer to

cyanocobalamin, the principal B12form used forfoods and in nutritional supplements. This ordinarily creates no problem, except perhaps in rare

cases of eye nerve damage, where the body is only marginally able to use this form due to high

cyanide levels in the blood due to cigarette smoking; it thus requires cessation of smoking or B12

given in another form, for the optic symptoms to abate[citation needed]

. However, tobacco

amblyopia is a rare condition, and it is yet unclear whether it represents a peculiar B12deficiency

that is resistant to treatment with cyanocobalamin.

SMILES

InChI


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Finally, so-called pseudovitamin-B12refers to B12-like analogues that are biologically inactive in humans

and yet found to be present alongside B12in humans,[2][3]

many food sources (including animals[4]

), and

possibly supplements and fortified foods.[5][6]

In most cyanobacteria, including Spirulina, and some

algae, such as dried Asakusa-nori (Porphyra tenera), pseudovitamin-B12is found to predominate.[7][8]

Medical uses

Vitamin B12is used to treat vitamin B12deficiency, cyanide poisoning, and hereditary deficiency oftranscobalamin II.

[9]It is given as part of the Schilling test for detecting pernicious anemia.

[9]

For cyanide poisoning, a large amount may be given intravenously and sometimes in combination with

sodium thiosulfate.[10]

The mechanism of action is straightforward: the hydroxycobalamin hydroxideligand is displaced by the toxic cyanide ion, and the resulting harmless B12complex is excreted in urine.In the United States, the Food and Drug Administration approved (in 2006) the use of hydroxocobalamin

for acute treatment of cyanide poisoning.[11]

High vitamin B12level in elderly individuals may protect against brain atrophy or shrinkage associated

with Alzheimer's disease and impaired cognitive function.[12]

High-dose administration of Vitamin B12has been additionally validated to stimulate the activity of the

body's TH1 suppressor T-Cells, which then down-regulates the over-production of the allergen antibodyIgE in allergic individuals.

[13]

Recommended intake

The dietary reference intake for an adult ranges from 2 to 3 g per day (USA),[14]

and 1.5 g per day

(UK).[15]

Vitamin B12is believed to be safe when used orally in amounts that do not exceed the recommendeddietary allowance (RDA). There have been studies that showed no adverse consequences of doses

above the RDA.[16]

The RDA for vitamin B12in pregnant women is 2.6 g per day and 2.8 g during

lactation periods.[17]

There is insufficient reliable information available about the safety of consuming

greater amounts of vitamin B12during pregnancy.[citation needed]

The Institute of Medicine states that because 10 to 30% of older people may be unable to absorbnaturally occurring vitamin B12in foods, it is advisable for those 51 years old and older to consume

B12-fortified foods or B12supplements to meet the recommended intake.[18]

Controversial sources in algae

The UK Vegan Society, the Vegetarian Resource Group, and the Physicians Committee for ResponsibleMedicine, among others, recommend that vegans either consistently eat B12-fortified foods or take a

daily or weekly B12supplement to meet the recommended intake.[19][20][21]

It is important for vegans, whose food provides few sources of B12, and anyone else wishing to obtain

B12from food sources other than animals, to consume foods that contain little or no pseudovitamin-B12and are high in biologically active B12. However, there have been no significant human trials ofsufficient size to demonstrate enzymatic activity of B12from nonbacterial sources, such as Chlorellaandedible sea algae (seaweeds, such as lavers), although chemically some of these sources have been

reported to contain B12that seems chemically identical to active vitamin.[22][23]

However, among these

sources, only fresh sea algae such as Susabi-nori (Porphyra yezoensis)[24][25]

have been reported todemonstrate vitamin B12activity in B12deficient rats. This has yet to be demonstrated for Chlorella, andno study in rats of any algal B12source has yet to be confirmed by a second independent study. The


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possibility of algae-derived active forms of B12presently remains an active topic of research, with noresults that have yet reached consensus in the nutritional community.

Deficiency

Main article: Vitamin B12 deficiency

Vitamin B12deficiency can potentially cause severe and irreversible damage, especially to the brain and

nervous system. At levels only slightly lower than normal, a range of symptoms such as fatigue,depression, and poor memory may be experienced.

[1]

Vitamin B12deficiency can also cause symptoms of mania and psychosis.[26][27]

Adverse effects

Vitamin B12has extremely low toxicity, and even taking enormous doses does not appear to be

harmful to healthy individuals.[28][29]

Hematologic: Peripheral vascular thrombosis has been reported. Treatment of vitamin B 12

deficiency can unmask polycythemia vera, which is characterized by an increase in blood volume

and the number of red blood cells. The correction of megaloblastic anemia with vitamin B12canresult in fatal hypokalemia and gout in susceptible individuals, and it can obscure folate

deficiency in megaloblastic anemia. Caution is warranted.

Leber's disease: Vitamin B12in the form of cyanocobalamin is contraindicated in early Leber's

disease, which is hereditary optic nerve atrophy. Cyanocobalamin can cause severe and swift

optic atrophy, but other forms of vitamin B12are available. However, the sources of this

statement are not clear, while an opposing view[30]

concludes: "The clinical picture of optic

neuropathy associated with vitamin B12deficiency shows similarity to that of Leber's disease

optic neuropathy. Both involve the nerve fibers of the papillomacular bundle. The present case

reports suggest that optic neuropathy in patients carrying a primary LHON mtDNA mutation may

be precipitated by vitamin B12deficiency. Therefore, known carriers should take care to have an

adequate dietary intake of vitamin B12and malabsorption syndromes like those occurring in

familial pernicious anaemia or after gastric surgery should be excluded."

Allergies

Vitamin B12supplements in theory should be avoided in people sensitive or allergic to cobalamin,cobalt, or any other product ingredients. However, direct allergy to a vitamin or nutrient is extremelyrare, and if reported, other causes should be sought.

Interactions

Alcohol (ethanol): Excessive alcohol intake lasting longer than two weeks can decrease vitamin

B12absorption from the gastrointestinal tract.[citation needed]

Aminosalicylic acid (para-aminosalicylic acid, PAS, Paser): Aminosalicylic acid can reduce oral

vitamin B12absorption, possibly by as much as 55%, as part of a general malabsorption

syndrome. Megaloblastic changes, and occasional cases of symptomatic anemia have occurred,

usually after doses of 8 to 12 g/day for several months. Vitamin B12levels should be monitored in

people taking aminosalicylic acid for more than one month.

Antibiotics: An increased bacterial load can bind significant amounts of vitamin B12in the gut,


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preventing its absorption. In people with bacterial overgrowth of the small bowel, antibiotics such

as metronidazole (Flagyl) can actually improve vitamin B12status. The effects of most antibiotics

on gastrointestinal bacteria are unlikely to have clinically significant effects on vitamin B12levels.

Hormonal contraception: The data regarding the effects of oral contraceptives on vitamin B12

serum levels are conflicting. Some studies have found reduced serum levels in oral contraceptive

users, but others have found no effect despite use of oral contraceptives for up to 6 months.

When oral contraceptive use is stopped, normalization of vitamin B12levels usually occurs. Lowervitamin B12serum levels seen with oral contraceptives probably are not clinically significant.

Chloramphenicol (Chloromycetin): Limited case reports suggest that chloramphenicol can delay

or interrupt the reticulocyte response to supplemental vitamin B12in some patients. Blood counts

should be monitored closely if this combination cannot be avoided.

Cobalt irradiation: Cobalt irradiation of the small bowel can decrease gastrointestinal (GI)

absorption of vitamin B12.

Colchicine: Colchicine in doses of 1.9 to 3.9 mg/day can disrupt normal intestinal mucosal

function, leading to malabsorption of several nutrients, including vitamin B12. Lower doses do not

seem to have a significant effect on vitamin B12absorption after 3 years of colchicine therapy.

The significance of this interaction is unclear. Vitamin B12levels should be monitored in people

taking large doses of colchicine for prolonged periods.Colestipol (Colestid), cholestyramine (Questran): These resins used for sequestering bile acids to

decrease cholesterol, can decrease gastrointestinal (GI) absorption of vitamin B12. It is unlikely

this interaction will deplete body stores of vitamin B12unless there are other factors contributing

to deficiency. In a group of children treated with cholestyramine for up to 2.5 years, there was not

any change in serum vitamin B12levels. Routine supplements are not necessary.

H2-receptor antagonists: include cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid), and

ranitidine (Zantac). Reduced secretion of gastric acid and pepsin produced by H2blockers can

reduce absorption of protein-bound (dietary) vitamin B12, but not of supplemental vitamin B12.

Gastric acid is needed to release vitamin B12from protein for absorption. Clinically significant

vitamin B12deficiency and megaloblastic anemia are unlikely, unless H2blocker therapy is

prolonged (2 years or more), or the person's diet is poor. It is also more likely if the person is

rendered achlorhydric(with complete absence of gastric acid secretion), which occurs more

frequently with proton pump inhibitors than H2blockers. Vitamin B12levels should be monitored

in people taking high doses of H2blockers for prolonged periods.

Metformin (Glucophage): Metformin may reduce serum folic acid and vitamin B12levels.

Long-term use of metformin substantially increases the risk of B12deficiency and (in those

patients who become deficient) hyperhomocysteinemia, which is "an independent risk factor for

cardiovascular disease, especially among individuals with type 2 diabetes."[31]

There are also rare

reports of megaloblastic anemia in people who have taken metformin for five years or more.

Reduced serum levels of vitamin B12occur in up to 30% of people taking metformin chronically.[32][33]

However, clinically significant deficiency is not likely to develop if dietary intake of vitaminB12is adequate. Deficiency can be corrected with vitamin B12supplements even if metformin is

continued. The metformin-induced malabsorption of vitamin B12is reversible by oral calcium

supplementation.[34]

The general clinical significance of metformin upon B12levels is as yet

unknown.[35]

Neomycin: Absorption of vitamin B12can be reduced by neomycin, but prolonged use of large

doses is needed to induce pernicious anemia. Supplements are not usually needed with normal


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doses.

Nicotine: Nicotine can reduce serum vitamin B12levels. The need for vitamin B12supplementation

in smokers has not been adequately studied.

Nitrous oxide: Nitrous oxide inactivates the cobalamin form of vitamin B12by oxidation.

Symptoms of vitamin B12deficiency, including sensory neuropathy, myelopathy, and

encephalopathy, can occur within days or weeks of exposure to nitrous oxide anesthesia in people

with subclinical vitamin B12deficiency. Symptoms are treated with high doses of vitamin B12, butrecovery can be slow and incomplete. People with normal vitamin B12levels have sufficient

vitamin B12stores to make the effects of nitrous oxide insignificant, unless exposure is repeated

and prolonged (such as recreational use). Vitamin B12levels should be checked in people with risk

factors for vitamin B12deficiency prior to using nitrous oxide anesthesia. Chronic nitrous oxide B12

poisoning (usually from use of nitrous oxide as a recreational drug), however, may result in B 12

functional deficiency even with normal measured blood levels of B12.[36]

Phenytoin (Dilantin), phenobarbital, primidone (Mysoline): These anticonvulsants have been

associated with reduced vitamin B12absorption, and reduced serum and cerebrospinal fluidlevels

in some patients. This may contribute to the megaloblastic anemia, primarily caused by folate

deficiency, associated with these drugs. It is also suggested that reduced vitamin B12levels may

contribute to the neuropsychiatric side effects of these drugs. Patients should be encouraged tomaintain adequate dietary vitamin B12intake. Folate and vitamin B12status should be checked if

symptoms of anemia develop.

Proton pump inhibitors (PPIs): The PPIs include omeprazole (Prilosec, Losec), lansoprazole

(Prevacid), rabeprazole (Aciphex), pantoprazole (Protonix, Pantoloc), and esomeprazole (Nexium).

The reduced secretion of gastric acid and pepsin produced by PPIs can reduce absorption of

protein-bound (dietary) vitamin B12, but not supplemental vitamin B12. Gastric acid is needed to

release vitamin B12from protein for absorption. Reduced vitamin B12levels may be more

common with PPIs than with H2-blockers, because they are more likely to produce achlorhydria

(complete absence of gastric acid secretion). However, clinically significant vitamin B12deficiency

is unlikely, unless PPI therapy is prolonged (2 years or more) or dietary vitamin intake is low.

Vitamin B12levels should be monitored in people taking high doses of PPIs for prolonged periods.

Zidovudine (AZT, Combivir, Retrovir): Reduced serum vitamin B12levels may occur when

zidovudine therapy is started. This adds to other factors that cause low vitamin B12levels in

people with HIV, and might contribute to the hematological toxicity associated with zidovudine.

However, the data suggest vitamin B12supplements are not helpful for people taking zidovudine.[citation needed]

Folic acid: Folic acid, particularly in large doses, can mask vitamin B12deficiency by completely

correcting hematological abnormalities. In vitamin B12deficiency, folic acid can produce complete

resolution of the characteristic megaloblastic anemia, while allowing potentially irreversible

neurological damage (from continued inactivity of methylmalonyl mutase) to progress. Thus,

vitamin B12status should be determined before folic acid is given as monotherapy.[37]

Potassium: Potassium supplements can reduce absorption of vitamin B12in some people. This

effect has been reported with potassium chloride and, to a lesser extent, with potassium citrate.

Potassium might contribute to vitamin B12deficiency in some people with other risk factors, but

routine supplements are not necessary.[38]

Structure


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B12is the most chemically complex of all the vitamins. The structure of B12is based on a corrin ring,which is similar to the porphyrin ring found in heme, chlorophyll, and cytochrome. The central metal ionis cobalt. Four of the six coordination sites are provided by the corrin ring, and a fifth by adimethylbenzimidazole group. The sixth coordination site, the center of reactivity, is variable, being acyano group (-CN), a hydroxyl group (-OH), a methyl group (-CH 3) or a 5'-deoxyadenosyl group (here theC5' atom of the deoxyribose forms the covalent bond with Co), respectively, to yield the four B12formsmentioned below. Historically, the covalent C-Co bond is one of first examples of carbon-metal bonds tobe discovered in biology. The hydrogenases and, by necessity, enzymes associated with cobalt

utilization, involve metal-carbon bonds.[39]

Vitamin B12is a generic descriptor name referring to a collection of cobalt and corrin ring moleculeswhich are defined by their particular vitamin function in the body. All of the substrate cobalt-corrinmolecules from which B12is made, must be synthesized by bacteria. However, after this synthesis iscomplete, except in rare cases, the human body has the ability to convert any form of B12to an activeform, by means of enzymatically removing certain prosthetic chemical groups from the cobalt atom,and replacing them with others.

The various forms (vitamers) of B12are all deeply red colored crystals and water solutions, due to thecolor of the cobalt-corrin complex.

Cyanocobalaminis one such "vitamer" in this B complex, because it can be metabolized in the body toan active co-enzyme form. However, the cyanocobalamin form of B12does not occur in nature normally,but is a byproduct of the fact that other forms of B12are avid binders of cyanide (-CN) which they pickup in the process of activated charcoal purification of the vitamin after it is made by bacteria in thecommercial process. Since the cyanocobalamin form of B12is easy to crystallize and is not sensitive toair-oxidation, it is typically used as a form of B12for food additives and in many common multivitamins.However, this form is not perfectly synonymous with B12, in as much as a number of substances(vitamers) have B12vitamin activity and can properly be labeled vitamin B12, and cyanocobalamin isbut one of them. (Thus, all cyanocobalamin is vitamin B12, but not all vitamin B12is

cyanocobalamin).[40]

Pure cyanocobalamin possesses the deep pink color associated with mostoctahedral cobalt(II) complexes and the crystals are well formed and easily grown up to millimeter size.

Hydroxocobalaminis another form of B12commonly encountered in pharmacology, but which is notnormally present in the human body. Hydroxocobalamin is sometimes denoted B12a. This form of B12isthe form produced by bacteria, and is what is converted to cyanocobalmin in the commercial charcoal

filtration step of production. Hydroxocobalamin has an avid affinity for cyanide ion and has been usedas an antidote to cyanide poisoning. It is supplied typically in water solution for injection.Hydroxocobalamin is thought to be converted to the active enzymic forms of B 12more easily thancyanocobalamin, and since it is little more expensive than cyanocobalamin, and has longer retentiontimes in the body, has been used for vitamin replacement in situations where added reassurance ofactivity is desired. Intramuscular administration of hydroxocobalamin is also the preferred treatment forpediatric patients with intrinsic cobalamin metabolic diseases, for vitamin B12deficient patients withtobacco amblyopia (which is thought to perhaps have a component of cyanide poisoning from cyanidein cigarette smoke); and for treatment of patients with pernicious anemia who have optic neuropathy.

Adenosylcobalamin(adoB12) and methylcobalamin(MeB12) are the two enzymatically activecofactor forms of B12that naturally occur in the body. Most of the body's reserves are stored as adoB12in the liver. These are converted to the other methylcobalamin form as needed.

Synthesis and industrial production

Neither plants nor animals are independently capable of constructing vitamin B12.[41]

Only bacteria and

archaea[42]

have the enzymes required for its biosynthesis. The total synthesis of B12was reported by

Robert Burns Woodward[43]

and Albert Eschenmoser in 1972,[44][45]

and remains one of the classic featsof organic synthesis. Species from the following genera are known to synthesize B12:Acetobacterium,

erobacter,Agrobacterium,Alcaligenes,Azotobacter, Bacillus, Clostridium, Corynebacterium,


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Metabolism of folic acid. The role of Vitamin B12is

seen at bottom-left.

Flavobacterium, Lactobacillus, Micromonospora, Mycobacterium, Nocardia, Propionibacterium,Protaminobacter, Proteus, Pseudomonas, Rhizobium, Salmonella, Serratia, Streptomyces, StreptococcusandXanthomonas.

Industrial production of B12is through fermentation of selected microorganisms.[46]

Streptomycesgriseus, a bacterium once thought to be a yeast, was the commercial source of vitamin B12for many

years.[47][48]

The species Pseudomonas denitrificansand Propionibacterium shermaniiare more

commonly used today.[49]

These are frequently grown under special conditions to enhance yield, and atleast one company, Rhne-Poulenc of France, which has merged into Sanofi-Aventis, used geneticallyengineered versions of one or both of these species. Since a number of species of Propionibacteriumproduce no exotoxins or endotoxins and are generally regarded as safe (have been granted GRASstatus) by the Food and Drug Administration of the United States, they are presently the FDA-preferred

bacterial fermentation organisms for vitamin B12production.[50]

The total world production of vitamin B12, by four companies (the French Sanofi-Aventis and three

Chinese companies) is said to have been 35 tonnes in 2008.[51]

Most of this production is used as an

additive to animal feed.[52]

See cyanocobalamin for discussion of the chemical preparation of reduced-cobalt vitamin analogs andpreparation of physiological forms of the vitamin such as adenosylcobalamin and methylcobalamin.

Mechanism of action

Vitamin B12normally plays a significant role in themetabolism of every cell of the body, especiallyaffecting the DNA synthesis and regulation but also

fatty acid synthesis and energy production.[53]

However, many (though not all) of the effects offunctions of B12can be replaced by sufficientquantities of folic acid (vitamin B9), since B12is usedto regenerate folate in the body. Most vitamin B12deficiency symptoms are actually folate deficiencysymptoms, since they include all the effects of

pernicious anemia and megaloblastosis, which aredue to poor synthesis of DNA when the body doesnot have a proper supply of folic acid for the

production of thymine.[37]

When sufficient folic acidis available, all known B12related deficiencysyndromes normalize, save those narrowlyconnected with the vitamin B12-dependent enzymesMethylmalonyl Coenzyme A mutase, and 5-methyltetrahydrofolate-homocysteine methyltransferase(MTR), also known as methionine synthase; and the buildup of their respective substrates(methylmalonic acid, MMA) and homocysteine.

Coenzyme B12's reactive C-Co bond participates in three main types of enzyme-catalyzed reactions.[54][55]

Isomerases

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 alcohol, or an amine. These use the adoB12

(adenosylcobalamin) form of the vitamin.

1.

Methyltransferases

Methyl (-CH3) group transfers between two molecules. These use MeB12(methylcobalamin)

2.


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form of the vitamin.

Dehalogenases

Reactions in which a halogen atom is removed from an organic molecule. Enzymes in this

class have not been identified in humans.

3.

In humans, two major coenzyme B12-dependent enzyme families corresponding to the first two reactiontypes, are known. These are typified by the following two enzymes:

MUT is an isomerase which uses the AdoB12form 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). This functionality is lost in vitamin B12deficiency, and can be measured clinically as

an increased methylmalonic acid (MMA) level. Unfortunately, an elevated MMA, though sensitive

to B12deficiency, is probably overly sensitive, and not all who have it actually have B12

deficiency. For example, MMA is elevated in 9098% of patients with B12deficiency; however

2025% of patients over the age of 70 have elevated levels of MMA, yet 2533% of them do not

have B12deficiency. For this reason, assessment of MMA levels is not routinely recommended in

the elderly. There is no "gold standard" test for B12deficiency because as a B12deficiency occurs,

serum values may be maintained while tissue B12stores become depleted. Therefore, serum B12values above the cut-off point of deficiency do not necessarily indicate adequate B12status

[18]

The MUT function cannot be affected by folate supplementation, which is necessary for myelin

synthesis (see mechanism below) and certain other functions of the central nervous system.

Other functions of B12related to DNA synthesis related to MTR dysfunction (see below) can often

be corrected with supplementation with the vitamin folic acid, but not the elevated levels of

homocysteine, which is normally converted to methionine by MTR.

1.

MTR, also known as methionine synthase, is a methyltransferase enzyme, which uses the MeB12

and reaction type 2 to catalyze the conversion of the amino acid homocysteine (Hcy) back into

methionine (Met) (for more see MTR's reaction mechanism).[56]

This functionality is lost in vitamin

B12deficiency, and can be measured clinically as an increased homocysteine level in vitro.

Increased homocysteine can also be caused by a folic acid deficiency, since B12helps to

regenerate the tetrahydrofolate (THF) active form of folic acid. Without B12, folate is trapped as

5-methyl-folate, from which THF cannot be recovered unless a MTR process reacts the 5-methyl-

folate with homocysteine to produce methionine and THF, thus decreasing the need for fresh

sources of THF from the diet. THF may be produced in the conversion of homocysteine to

methionine, or may be obtained in the diet. It is converted by a non-B12-dependent process to

5,10-methylene-THF, which is involved in the synthesis of thymine. Reduced availability of

5,10-methylene-THF results in problems with DNA synthesis, and ultimately in ineffective

production cells with rapid turnover, in particular blood cells, and also intestinal wall cells which

are responsible for absorption. The failure of blood cell production results in the once-dreaded and

fatal disease, pernicious anemia. All of the DNA synthetic effects, including the megaloblasticanemia of pernicious anemia, resolve if sufficient folate is present (since levels of

5,10-methylene-THF still remain adequate with enough dietary folate). Thus the best-known

"function" of B12(that which is involved with DNA synthesis, cell-division, and anemia) is actually

a facultative function which is mediated by B12-conservation of an active form of folate which is

needed for efficient DNA production.[57]

Other cobalamin-requiring methyltransferase enzymes

are also known in bacteria, such as Me-H4-MPT, coenzyme M methyl transferase.

2.


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Enzyme function

If folate is present in quantity, then of the two absolutely vitamin B12-dependent enzyme-familyreactions in humans, the MUT-family reactions show the most direct and characteristic secondaryeffects, focusing on the nervous system (see below). This is because the MTR (methyltransferase-type)reactions are involved in regenerating folate, and thus are less evident when folate is in good supply.

Since the late 1990s, folic acid has begun to be added to fortify flour in many countries, so folate

deficiency is now more rare. At the same time, since DNA synthetic-sensitive tests for anemia anderythrocyte size are routinely done in even simple medical test clinics (so that these folate-mediatedbiochemical effects are more often directly detected), the MTR-dependent effects of B12deficiency arebecoming apparent not as anemia due to DNA-synthetic problems (as they were classically), but nowmainly as a simple and less obvious elevation of homocysteine in the blood and urine(homocysteinuria). This condition may result in long term damage to arteries and in clotting (stroke andheart attack), but this effect is difficult to separate from other common processes associated withatherosclerosis and aging.

The specific myelin damage resulting from B12deficiency, even in the presence of adequate folate andmethionine, is more specifically and clearly a vitamin deficiency problem. It has been connected to B12most directly by reactions related to MUT, which is absolutely required to convert methylmalonylcoenzyme A into succinyl coenzyme A. Failure of this second reaction to occur results in elevated levels

of MMA, a myelin destabilizer. Excessive MMA will prevent normal fatty acid synthesis, or it will beincorporated into fatty acid itself rather than normal malonic acid. If this abnormal fatty acidsubsequently is incorporated into myelin, the resulting myelin will be too fragile, and demyelination willoccur. Although the precise mechanism(s) are not known with certainty, the result is subacute combined

degeneration of central nervous system and spinal cord.[58]

Whatever the cause, it is known that B12deficiency causes neuropathies, even if folic acid is present in good supply, and therefore anemia is notpresent.

Vitamin B12-dependent MTR reactions may also have neurological effects, through an indirectmechanism. Adequate methionine (which, like folate, must otherwise be obtained in the diet, if it is notregenerated from homocysteine by a B12dependent reaction) is needed to make S-adenosyl-methionine (SAMe), which is in turn necessary for methylation of myelin sheath phospholipids. Althoughproduction of SAMe is not B12dependent, help in recycling for provision of one adequate substrate for it(the essential amino acid methionine) is assisted by B12. In addition, SAMe is involved in themanufacture of certain neurotransmitters, catecholamines and in brain metabolism. Theseneurotransmitters are important for maintaining mood, possibly explaining why depression is associatedwith B12deficiency. Methylation of the myelin sheath phospholipids may also depend on adequatefolate, which in turn is dependent on MTR recycling, unless ingested in relatively high amounts.

Absorption and distribution

The human physiology of vitamin B12is complex, and therefore is prone to mishaps leading to vitaminB12deficiency. Protein-bound vitamin B12must be released from the proteins by the action of digestive

proteases in both the stomach and small intestine.[59]

Gastric acid releases the vitamin from foodparticles; therefore antacid and acid-blocking medications (especially proton-pump inhibitors) mayinhibit absorption of B12. In addition some elderly people produce less stomach acid as they age thereby

increasing their probability of B12deficiencies.[60]

B12taken in a low-solubility, non-chewable supplement pill form may bypass the mouth and stomachand not mix with gastric acids, but these are not necessary for the absorption of free B12not bound toprotein.

R-proteins (such as haptocorrins and cobalaphilin) are B12binding proteins that are produced in thesalivary glands. They must wait until B12has been freed from proteins in food by pepsin in the stomach.

B12then binds to the R-Proteins to avoid degradation of it in the acidic environment of the stomach.[61]


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This pattern of secretion of a binding protein secreted in a previous digestive step, is repeated oncemore before absorption. The next binding protein is intrinsic factor (IF), a protein synthesized by gastricparietal cells that is secreted in response to histamine, gastrin and pentagastrin, as well as thepresence of food. In the duodenum, proteases digest R-proteins and release B12, which then binds to IF,to form a complex (IF/B12). B12must be attached to IF for it to be absorbed, as receptors on theenterocytes in the terminal ileum of the small bowel only recognize the B12-IF complex; in addition,intrinsic factor protects the vitamin from catabolism by intestinal bacteria.

Absorption of food vitamin B12thus requires an intact and functioning stomach, exocrine pancreas,intrinsic factor, and small bowel. Problems with any one of these organs makes a vitamin B 12deficiencypossible. Individuals who lack intrinsic factor have a decreased ability to absorb B12. In perniciousanemia, there is a lack of IF due to autoimmune atrophic gastritis, in which antibodies form againstparietal cells. Antibodies may alternately form against and bind to IF, inhibiting it from carrying out itsB12protective function. Due to the complexity of B12absorption, geriatric patients, many of whom are

hypoacidic due to reduced parietal cell function, have an increased risk of B12deficiency.[62]

This resultsin 80100% excretion of oral doses in the feces versus 3060% excretion in feces as seen in individuals

with adequate IF.[62]

Once the IF/B12complex is recognized by specialized ileal receptors, it is transported into the portalcirculation. The vitamin is then transferred to transcobalamin II (TC-II/B12), which serves as the plasmatransporter. Hereditary defects in production of the transcobalamins and their receptors may produce

functional deficiencies in B12and infantile megaloblastic anemia, and abnormal B12relatedbiochemistry, even in some cases with normal blood B12levels.

[63]For the vitamin to serve inside cells,

the TC-II/B12complex must bind to a cell receptor, and be endocytosed. The transcobalamin-II isdegraded within a lysosome, and free B12is finally released into the cytoplasm, where it may betransformed into the proper coenzyme, by certain cellular enzymes (see above).

It's important to note that investigations into the intestinal absorption of B12point out that the upperlimit per single dose, under normal conditions, is about 1.5 g: "Studies in normal persons indicatedthat about 1.5 g is assimilated when a single dose varying from 5 to 50 g is administered by mouth.

In a similar study Swendseid et al.stated that the average maximum absorption was 1.6 g [...]"[64]

The total amount of vitamin B12stored in body is about 25 mg in adults. Around 50% of this is stored in

the liver.[18]

Approximately 0.1% of this is lost per day by secretions into the gut, as not all these

secretions are reabsorbed. Bile is the main form of B12excretion; however, most of the B12secreted inthe bile is recycled via enterohepatic circulation. Excess B12 beyond the blood's binding capacity is

typically excreted in urine.[18]

Owing to the extremely efficient enterohepatic circulation of B12, the livercan store several years worth of vitamin B12; therefore, nutritional deficiency of this vitamin is rare.How fast B12levels change depends on the balance between how much B12is obtained from the diet,how much is secreted and how much is absorbed. B12deficiency may arise in a year if initial stores arelow and genetic factors unfavourable, or may not appear for decades. In infants, B12deficiency can

appear much more quickly.[65]

History

B12deficiency is the cause of pernicious anemia, an anemic disease that was usually fatal and hadunknown etiology when it was first described in medicine. The cure, and B12, were discovered by

accident. George Whipple had been doing experiments in which he induced anemia in dogs by bleedingthem, and then fed them various foods to observe which diets allowed them fastest recovery from theanemia produced. In the process, he discovered that ingesting large amounts of liver seemed tomost-rapidly cure the anemia of blood loss. Thus, he hypothesized that liver ingestion might treatpernicious anemia. He tried this and reported some signs of success in 1920.

After a series of careful clinical studies, George Richards Minot and William Murphy set out to partlyisolate the substance in liver which cured anemia in dogs, and found that it was iron. They also foundthat an entirely different liver substance cured pernicious anemia in humans, that had no effect on dogs


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Food[68] g vitamin B12/100g

Beef, variety meats and by-products, liver, cooked, pan-fried 83.1

Turkey, all classes, giblets, cooked, simmered, some giblet fat 33.2

Braunschweiger pork liver sausage 20.1

Raw Pacific oysters 16.0

Cooked Alaska king crab 11.5

Raw clams 11.3

Simmered chicken giblets 9.4

Beef (uncooked sirloin) 1.15

Egg (raw, whole chicken's egg) 0.89

Yogurt 0.75[69]

Whole cow's milk 0.45

Raw chicken breast 0.20

Animal Sources of Vitamin B12

under the conditions used. The specific factor treatment for pernicious anemia, found in liver juice, hadbeen found by this coincidence. Minot and Murphy reported these experiments in 1926. This was thefirst real progress with this disease. Despite this discovery, for several years patients were still requiredto eat large amounts of raw liver or to drink considerable amounts of liver juice.

In 1928, the chemist Edwin Cohn prepared a liver extract that was 50 to 100 times more potent thanthe natural liver products. The extract was the first workable treatment for the disease. For their initialwork in pointing the way to a working treatment, Whipple, Minot, and Murphy shared the 1934 Nobel

Prize in Physiology or Medicine.

These events in turn eventually led to discovery of the soluble vitamin, called vitamin B12, in the liveruice. In 1947, while working for the Poultry Science Department at the University of Maryland, MaryShaw Shorb (in a collaborative project with Folkers and Merck) was provided with a $400 grant todevelop the so-called "LLD assay" for B12. LLD stood for Lactobacilis lactisDorner, a strain of bacteriumwhich required "LLD factor" for growth, which was eventually identified as B12. Shorb and colleaguesused the LLD assay to rapidly extract the anti-pernicious anemia factor from liver extracts, and pure B12

was isolated in this way by 1948, with the contributions of chemists Shorb,[66]

Karl A. Folkers of theUnited States and Alexander R. Todd of Great Britain. For this discovery, in 1949 Mary Shorb and Karl

Folkers received the Mead Johnson Award from the American Society of Nutritional Sciences.[66]

The chemical structure of the molecule was determined by Dorothy Crowfoot Hodgkin and her team in

1956, based on crystallographic data.[67]

Eventually, methods of producing the vitamin in largequantities from bacteria cultures were developed in the 1950s, and these led to the modern form oftreatment for the disease.

Sources

Foods

Ultimately,animalsmust obtainvitamin B12directly or

indirectlyfrombacteria,and thesebacteriamay inhabita section ofthe gutwhich isdistal to thesectionwhere B12isabsorbed.

Thus,herbivorousanimalsmust eitherobtain B12frombacteria intheir rumens, or (if fermenting plant material in the hindgut) by reingestion of cecotrope feces.


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Vitamin B12is found in most animal derived foods, including fish and shellfish, meat (especially liver),

poultry, eggs, milk, and milk products.[1]

However, the binding capacity of egg yolks and egg whites is

markedly diminished after heat treatment.[70]

An NIH Fact Sheet lists a variety of animal food sources of

B12.[1]

Besides certain fermented foods,[71][72]

there are currently only a few non-animal food sources of

biologically active B12suggested,[citation needed]

and none of these have been subjected to human trials.

Certain makers of kombucha cultured tea, such as GT's Kombucha, list vitamin B12as naturally present

in their product. One brand purports to contain 20% of the daily value of B12in a single bottle,[73]

making kombucha a potential "high" food source of B12. Because kombucha is produced by a symbiosisbetween yeast and bacteria, the possibility that kombucha contains B12does not contradict currentknowledge. But no scientific studies have yet been published confirming the fact, nor whether the B12inkombucha is the biologically active B12.

A Japanese fermented black tea known as Batabata-cha has been found to contain biologically active

B12.[74]

Unlike kombucha which is made by fermenting already prepared tea, Batabata-cha is fermentedwhile still in the tea leaf state.

Chlorella,[22][23][75]

a fresh-water single cell green algae has been suggested as a vitamin B12source

but not proven by any live animal assay. Algae are thought to acquire B 12through a symbioticrelationship with heterotrophic bacteria, in which the bacteria supply B12in exchange for fixed carbon.[76][77]

Spirulinaand dried Asakusa-nori (Porphyra tenera) have been found to contain mostly

pseudovitamin-B12(see Terminology) instead of biologically active B12.[8][7]

While Asakusa-nori(Porphyra tenera) contains mostly pseudovitamin-B12in the dry state, it has been reported to contain

mostly biologically active B12in the fresh state,[8]

but even its fresh state vitamin activity has not beenverified by animal enzyme assay.

One group of researchers has reported that the purple laver seaweed known as Susabi-nori (Porphyra

ezoensis).[24][25]

in its fresh state contains B12activity in the rat model, which implies that sourcewould be active in humans. These results have not been confirmed.

Foods fortified with B12are also sources of the vitamin although they cannot be regarded as true food

sources of B12since the vitamin is added in supplement form, from commercial bacterial productionsources, such as cyanocobalamin. Examples of B12-fortified foods include fortified breakfast cereals,fortified soy products, fortified energy bars, and fortified nutritional yeast. The UK Vegan Society, theVegetarian Resource Group, and the Physicians Committee for Responsible Medicine, among others,deny that non-animal food sources of vitamin B12are reliable and recommend that every vegan who is

not supplementing consume B12-fortified foods.[78][20][21]

Not all of these may contain labeled amountsof vitamin activity. Supplemental B12added to beverages in one study was found to degrade to containvarying levels of pseudovitamin-B12. One report has found B12analogues present in varying amounts in

some multivitamins.[5][6]

Unconventional natural sources of B12also exist, but their utility as food sources of B12are doubtful. Forexample, plants pulled from the ground and not washed scrupulously may contain remnants of B12from

the bacteria present in the surrounding soil.[79]

B12is also found in lakes if the water has not been

sanitized.[80]Certain insects such as termites contain B12produced by their gut bacteria, in a way

analogous to ruminant animals.[81]

The human intestinal tract itself may contain B12producing bacteria

in the small intestine,[82]

but it is unclear whether sufficient amounts of the vitamin could be producedto meet nutritional needs.

Supplements

Vitamin B12is provided as a supplement in many processed foods, and is also available in vitamin pill


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Hydroxocobalamin injection USP (1000 g/mL) is a

clear red liquid solution of hydoxocobalamin which

is available in a 30 mL brown glass multidose vial

packaged in a paper box. Shown is 500 g B-12 (as

1/2 cc) drawn up in a 1/2 cc U-100 27 gauge x 1/2"

insulin syringe, as prepared for subcutaneous

injection.

form, including multi-vitamins. Vitamin B12can besupplemented in healthy subjects also by liquid,transdermal patch, nasal spray, or injection and isavailable singly or in combination with othersupplements. It is a common ingredient in energydrinks and energy shots, usually at several times theminimum recommended daily allowance of B12.Vitamin B12supplements are effective for preventing

deficiencies, especially in vegetarians, and are oftenmarketed as weight loss supplements.

[83]However,

no scientific studies have shown that B12is effective

for weight loss.[84]

Cyanocobalamin is converted to its active forms, firsthydroxocobalamin and then methylcobalamin andadenosylcobalamin in the liver.

The sublingual route, in which B12is presumably orsupposedly absorbed more directly under thetongue, has not proven to be necessary or helpful,even though a number of lozenges, pills, and even a

lollipop designed for sublingual absorption, are beingmarketed. A 2003 study found no significantdifference in absorption for serum levels from oral

vs. sublingual delivery of 0.5 mg of cobalamin.[85]

Sublingual methods of replacement are effective onlybecause of the typically high doses (0.5 mg), which are swallowed, not because of placement of thetablet. As noted below, such very high doses of oral B12may be effective as treatments, even if gastro-intestinal tract absorption is impaired by gastric atrophy (pernicious anemia).

Injection and patches are sometimes used if digestive absorption is impaired, but there is evidence thatthis course of action may not be necessary with modern high potency oral supplements (such as 0.5 to

1 mg or more). Even pernicious anemia can be treated entirely by the oral route.[86][87][88]

Thesesupplements carry such large doses of the vitamin that 1% to 5% of high oral doses of free crystallineB12is absorbed along the entire intestine by passive diffusion.

However, if the patient has inborn errors in the methyltransfer pathway (cobalamin C disease, combinedmethylmalonic aciduria and homocystinuria), treatment with intravenous, intramuscular

hydroxocobalamin or transdermal B12is needed.[89][90][91][92][93]

Non-cyano forms as supplements

Recently sublingual methylcobalamin has become available in 1 mg tablets. Such tablets have higherbioavailability than the older cyanocobalamin. No cyanide is released with methylcobolamin, althoughthe amount of cyanide (2% of the weight, or 20 microgramscyanide in a 1 mg cyanocobalamin tab) isfar less than ingested in many natural foods. Although the safety of cyanocobalamin has not been

seriously questioned, the safety of the other types is also well established.[94]

See also

Cobamamide

Cyanocobalamin includes discussion of chemistry of preparation of reduced-cobalt B12analogs

Hydroxocobalamin

Methylcobalamin


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External links

Vitamin B12 Fact Sheet (http://ods.od.nih.gov/factsheets/vitaminb12.asp) from the U.S. National

Institutes of Health

Jane Higdon, "Vitamin B12 (http://lpi.oregonstate.edu/infocenter/vitamins/vitaminB12/)",Micronutrient Information Center, Linus Pauling Institute, Oregon State University

Vitamin B12 deficiency (http://www.aafp.org/afp/20030301/979.html) article inAmerican Family

Physicianjournal

Vitamin B12 and Folate at Lab Tests Online (http://labtestsonline.org/understanding/analytes

/vitamin-b12/tab/test)

Cyanocobalamin (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Cyanocobalamin)


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