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Vitamin B12, also known as cobalamin, is a water-soluble
vitamin A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an essential micronutrient that an organism needs in small quantities for the proper functioning of its metabolism. Essential nutrie ...
involved in
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run ...
. It is one of eight B vitamins. It is required by animals, which use it as a cofactor in DNA synthesis, in both
fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...
and amino acid metabolism. It is important in the normal functioning of the
nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes ...
via its role in the synthesis of myelin, and in the
circulatory system The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
in the maturation of
red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "hol ...
s in the
bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
. Plants do not need cobalamin and carry out the reactions with enzymes that are not dependent on it. Vitamin B12 is the most chemically complex of all vitamins, and for humans, the only vitamin that must be sourced from animal-derived foods or from supplements. Only some
archaea Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaeba ...
and
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...
can synthesize vitamin B12. Most people in
developed countries A developed country (or industrialized country, high-income country, more economically developed country (MEDC), advanced country) is a sovereign state that has a high quality of life, developed economy and advanced technological infrastruct ...
get enough B12 from the consumption of
meat Meat is animal flesh that is eaten as food. Humans have hunted, farmed, and scavenged animals for meat since prehistoric times. The establishment of settlements in the Neolithic Revolution allowed the domestication of animals such as chic ...
or foods with animal sources. Foods containing vitamin B12 include meat, clams,
liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
, fish,
poultry Poultry () are domesticated birds kept by humans for their eggs, their meat or their feathers. These birds are most typically members of the superorder Galloanserae (fowl), especially the order Galliformes (which includes chickens, qu ...
, eggs, and
dairy product Dairy products or milk products, also known as lacticinia, are food products made from (or containing) milk. The most common dairy animals are cow, water buffalo, nanny goat, and ewe. Dairy products include common grocery store food items i ...
s. Many breakfast cereals are
fortified A fortification is a military construction or building designed for the defense of territories in warfare, and is also used to establish rule in a region during peacetime. The term is derived from Latin ''fortis'' ("strong") and ''facere' ...
with the vitamin. Supplements and medications are available to treat and prevent vitamin B12 deficiency. They are taken by mouth, but for the treatment of deficiency may also be given as an
intramuscular injection Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles hav ...
. The most common cause of vitamin B12 deficiency in developed countries is impaired absorption due to a loss of
gastric intrinsic factor Intrinsic factor (IF), cobalamin binding intrinsic factor, also known as gastric intrinsic factor (GIF), is a glycoprotein produced by the parietal cells (in humans) or chief cells (in rodents) of the stomach. It is necessary for the absorption o ...
(IF) which must be bound to a food-source of B12 in order for absorption to occur. A second major cause is age-related decline in stomach acid production ( achlorhydria), because acid exposure frees protein-bound vitamin. For the same reason, people on long-term antacid therapy, using proton-pump inhibitors,
H2 blocker H2 antagonists, sometimes referred to as H2RAs and also called H2 blockers, are a class of medications that block the action of histamine at the histamine H2 receptors of the parietal cells in the stomach. This decreases the production of s ...
s or other antacids are at increased risk. The diets of vegetarians and vegans may not provide sufficient B12 unless a dietary supplement is consumed. A deficiency in vitamin B12 may be characterized by limb
neuropathy Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or o ...
or a blood disorder called
pernicious anemia Pernicious anemia is a type of vitamin B12 deficiency anemia, a disease in which not enough red blood cells are produced due to the malabsorption of vitamin B12. Malabsorption in pernicious anemia results from the lack or loss of intrinsic ...
, a type of megaloblastic anemia, causing a feeling of tiredness and weakness, lightheadedness, headache, breathlessness, loss of appetite, abnormal sensations, changes in mobility, severe joint pain, muscle weakness, memory problems,
decreased level of consciousness An altered level of consciousness is any measure of arousal other than normal. Level of consciousness (LOC) is a measurement of a person's arousability and responsiveness to stimuli from the environment. A mildly depressed level of consciousne ...
, brain fog, and many others. If left untreated in infants, deficiency may lead to neurological damage and anemia.
Folate Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing an ...
levels in the individual may affect the course of pathological changes and symptomatology of vitamin B12 deficiency. Vitamin B12 was discovered as a result of pernicious anemia, an
autoimmune disorder An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly ...
in which the blood has a lower than normal number of red blood cells, due to a deficiency in vitamin B12. The ability to absorb the vitamin declines with age, especially in people over 60 years old.


Definition

Vitamin B12 is a
coordination complex A coordination complex consists of a central atom or ion, which is usually metallic and is called the ''coordination centre'', and a surrounding array of bound molecules or ions, that are in turn known as '' ligands'' or complexing agents. M ...
of
cobalt Cobalt is a chemical element with the symbol Co and atomic number 27. As with nickel, cobalt is found in the Earth's crust only in a chemically combined form, save for small deposits found in alloys of natural meteoric iron. The free element, p ...
, which occupies the center of a corrin ligand and is further bound to a benzimidazole ligand and adenosyl group. It is a deep red solid that dissolves in water to give red solutions. A number of related species are known and these behave similarly, in particular all function as vitamins. This collection of compounds, of which vitamin B12 is one member, are often 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. The vitamin activity is as a
coenzyme A cofactor is a non- protein chemical compound or metallic ion that is required for an enzyme's role as a catalyst (a catalyst is a substance that increases the rate of a chemical reaction). Cofactors can be considered "helper molecules" that as ...
, meaning that its presence is required for some enzyme-catalyzed reactions. * adenosylcobalamin * cyanocobalamin, the adenosyl ligand in vitamin B12 is replaced by
cyanide Cyanide is a naturally occurring, rapidly acting, toxic chemical that can exist in many different forms. In chemistry, a cyanide () is a chemical compound that contains a functional group. This group, known as the cyano group, consists of ...
. *
hydroxocobalamin Hydroxocobalamin, also known as vitamin B12a and hydroxycobalamin, is a vitamin found in food and used as a dietary supplement. As a supplement it is used to treat vitamin B12 deficiency including pernicious anemia. Other uses include treatment ...
, the adenosyl ligand in vitamin B12 is replaced by
hydroxide Hydroxide is a diatomic anion with chemical formula OH−. It consists of an oxygen and hydrogen atom held together by a single covalent bond, and carries a negative electric charge. It is an important but usually minor constituent of water. ...
. * methylcobalamin, the adenosyl ligand in vitamin B12 is replaced by
methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in ...
. Cyanocobalamin is a manufactured form of B12. Bacterial fermentation creates AdoB12 and MeB12, which are converted to cyanocobalamin by 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 are methylcobalamin in cytosol and adenosylcobalamin in
mitochondria A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...
. 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 for treatment of vitamin B12 deficiency.
Hydroxocobalamin Hydroxocobalamin, also known as vitamin B12a and hydroxycobalamin, is a vitamin found in food and used as a dietary supplement. As a supplement it is used to treat vitamin B12 deficiency including pernicious anemia. Other uses include treatment ...
can be injected intramuscularly to treat vitamin B12 deficiency. It 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. "Pseudovitamin B12" refers to compounds that are
corrinoid 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 ( vi ...
s with a structure similar to the vitamin but without vitamin activity. Pseudovitamin B12 is the majority corrinoid in spirulina, an algal health food sometimes erroneously claimed as having this vitamin activity.


Deficiency

Vitamin B12 deficiency 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 feeling tired, weak, feeling like one may faint,
dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a common medical c ...
, breathlessness, headaches, mouth ulcers, upset stomach, decreased appetite, difficulty walking (staggering balance problems), muscle weakness, depression, poor
memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remember ...
, poor reflexes, confusion, and pale skin, feeling abnormal sensations, among others, may be experienced, especially in people over age 60. Vitamin B12 deficiency can also cause symptoms of
mania Mania, also known as manic syndrome, is a mental and behavioral disorder defined as a state of abnormally elevated arousal, affect, and energy level, or "a state of heightened overall activation with enhanced affective expression together wi ...
and
psychosis Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavi ...
. Among other problems, weakened immunity, reduced fertility and interruption of blood circulation in women may occur. The main type of
vitamin B12 deficiency Vitamin B12 deficiency, also known as cobalamin deficiency, is the medical condition in which the blood and tissue have a lower than normal level of vitamin B12. Symptoms can vary from none to severe. Mild deficiency may have few or absent symp ...
anemia is
pernicious anemia Pernicious anemia is a type of vitamin B12 deficiency anemia, a disease in which not enough red blood cells are produced due to the malabsorption of vitamin B12. Malabsorption in pernicious anemia results from the lack or loss of intrinsic ...
. It is characterized by a triad of symptoms: #
Anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...
with bone marrow promegaloblastosis ( megaloblastic anemia). This is due to the inhibition of DNA synthesis (specifically purines and thymidine). # Gastrointestinal symptoms: alteration in bowel motility, such as mild
diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...
or
constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel moveme ...
, and loss of bladder or bowel control. These are thought to be due to defective DNA synthesis inhibiting replication in tissue sites with a high turnover of cells. This may also be due to the
autoimmune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...
attack on the parietal cells of the stomach in pernicious anemia. There is an association with
gastric antral vascular ectasia Gastric antral vascular ectasia (GAVE) is an uncommon cause of chronic gastrointestinal bleeding or iron deficiency anemia. The condition is associated with dilated small blood vessels in the pyloric antrum, which is a distal part of the stomach. ...
(which can be referred to as watermelon stomach), and pernicious anemia. # Neurological symptoms: sensory or motor deficiencies (absent reflexes, diminished vibration or soft touch sensation) and subacute combined degeneration of the spinal cord. Deficiency symptoms in children include
developmental delay Global developmental delay is an umbrella term used when children are significantly delayed in their cognitive and physical development. It can be diagnosed when a child is delayed in one or more milestones, categorised into motor skills, speech ...
, regression,
irritability Irritability (also called as crankiness) is the excitatory ability that living organisms have to respond to changes in their environment. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessi ...
, involuntary movements and
hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases ...
. Vitamin B12 deficiency is most commonly caused by malabsorption, but can also result from low intake, immune gastritis, low presence of binding proteins, or use of certain medications.
Vegan Veganism is the practice of abstaining from the use of animal product—particularly in diet—and an associated philosophy that rejects the commodity status of animals. An individual who follows the diet or philosophy is known as a vegan. ...
s—people who choose to not consume any animal-sourced foods—are at risk because plant-sourced foods do not contain the vitamin in sufficient amounts to prevent vitamin deficiency. Vegetarians—people who consume animal byproducts such as dairy products and eggs, but not the flesh of any animal—are also at risk. Vitamin B12 deficiency has been observed in between 40% and 80% of the vegetarian population who do not also take a vitamin B12 supplement or consume vitamin-fortified food. In Hong Kong and India, vitamin B12 deficiency has been found in roughly 80% of the vegan population. As with vegetarians, vegans can avoid this by consuming a dietary supplement or eating B12 fortified food such as cereal, plant-based milks, and nutritional yeast as a regular part of their diet. The elderly are at increased risk because they tend to produce less stomach acid as they age, a condition known as achlorhydria, thereby increasing their probability of B12 deficiency due to reduced absorption.


Pregnancy, lactation and early childhood

The U.S. Recommended Dietary Allowance (RDA) for pregnancy is 2.6 µg/day, for lactation 2.8 µg/day. Determination of these values was based on the RDA of 2.4 µg/day for non-pregnant women plus what will be transferred to the fetus during pregnancy and what will be delivered in breast milk. However, looking at the same scientific evidence, the European Food Safety Authority (EFSA) sets adequate intake (AI) at 4.5μg/day for pregnancy and 5.0 μg/day for lactation. Low maternal vitamin B12, defined as serum concentration less than 148 pmol/L, increases the risk of miscarriage, preterm birth and newborn low birth weight. During pregnancy the
placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...
concentrates B12, so that newborn infants have a higher serum concentration than their mothers. As it is recently absorbed vitamin content that more effectively reaches the placenta, the vitamin consumed by the mother-to-be is more important than that contained in her liver tissue. Women who consume little animal-sourced food, or who are vegetarian or vegan, are at higher risk of becoming vitamin depleted during pregnancy than those who consume more animal products. This depletion can lead to anemia, and also an increased risk that their breastfed infants become vitamin deficient. Low vitamin concentrations in human milk occur in families with low socioeconomic status or low consumption of animal products. Only a few countries, primarily in Africa, have mandatory food fortification programs for either wheat flour or maize flour; India has a voluntary fortification program. What the nursing mother consumes is more important than her liver tissue content, as it is recently absorbed vitamin that more effectively reaches breast milk. Breast milk B12 decreases over months of nursing in both well-nourished and vitamin-deficient mothers. Exclusive or near-exclusive breastfeeding beyond six months is a strong indicator of low serum vitamin status in nursing infants. This is especially true when the vitamin status was poor during the pregnancy and if the early-introduced foods fed to the still breastfeeding infant are vegan. Risk of deficiency persists if the post-weaning diet is low in animal products. Signs of low vitamin levels in infants and young children can include anemia, poor physical growth and neurodevelopmental delays. Children diagnosed with low serum B12 can be treated with intramuscular injections, then transitioned to an oral dietary supplement.


Gastric bypass surgery

Various methods of gastric bypass or gastric restriction surgery are used to treat morbid obesity. Roux-en-Y gastric bypass surgery (RYGB) but not sleeve gastric bypass surgery or gastric banding, increases the risk of vitamin B12 deficiency and requires preventive post-operative treatment with either injected or high-dose oral supplementation. For post-operative oral supplementation, 1000 μg/day may be needed to prevent vitamin deficiency.


Diagnosis

According to one review: "At present, no 'gold standard' test exists for the diagnosis of vitamin B12 deficiency and as a consequence the diagnosis requires consideration of both the clinical state of the patient and the results of investigations." The vitamin deficiency is typically suspected when a routine complete blood count shows anemia with an elevated
mean corpuscular volume The mean corpuscular volume, or mean cell volume (MCV), is a measure of the average volume of a red blood corpuscle (or red blood cell). The measure is obtained by multiplying a volume of blood by the proportion of blood that is cellular (the hem ...
(MCV). In addition, on the peripheral blood smear,
macrocyte Macrocytosis is the enlargement of red blood cells with near-constant hemoglobin concentration, and is defined by a mean corpuscular volume (MCV) of greater than 100 femtolitres (the precise criterion varies between laboratories). The enlarged er ...
s and hypersegmented polymorphonuclear leukocytes may be seen. Diagnosis is supported based on vitamin B12 blood levels below 150–180 pmol/L (200–250 pg/mL) in adults. However, serum values can be maintained while tissue B12 stores are becoming depleted. Therefore, serum B12 values above the cut-off point of deficiency do not necessarily confirm adequate B12 status. For this reason, elevated serum homocysteine over 15 micromol/L and methylmalonic acid (MMA) over 0.271 micromol/L are considered better indicators of B12 deficiency, rather than relying only on the concentration of B12 in blood. However, elevated MMA is not conclusive, as it is seen in people with B12 deficiency, but also in elderly people who have renal insufficiency, and elevated homocysteine is not conclusive, as it is also seen in people with folate deficiency. In addition, elevated methylmalonic acid levels may also be related to metabolic disorders such as methylmalonic acidemia. If nervous system damage is present and blood testing is inconclusive, a
lumbar puncture Lumbar puncture (LP), also known as a spinal tap, is a medical procedure in which a needle is inserted into the spinal canal, most commonly to collect cerebrospinal fluid (CSF) for diagnostic testing. The main reason for a lumbar puncture is ...
may be carried out to measure
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...
B12 levels.


Medical uses


Repletion of deficiency

Severe vitamin B12 deficiency is corrected with frequent intramuscular injections of large doses of the vitamin, followed by maintenance doses of injections or oral dosing at longer intervals. In the UK, standard initial therapy consists of intramuscular injections of 1000 μg of hydroxocobalamin three times a week for two weeks or until neurological symptoms improve, followed by 1000 μg every two or three months. Injection side effects include skin rash, itching, chills, fever, hot flushes, nausea and dizziness.


Cyanide poisoning

For
cyanide Cyanide is a naturally occurring, rapidly acting, toxic chemical that can exist in many different forms. In chemistry, a cyanide () is a chemical compound that contains a functional group. This group, known as the cyano group, consists of ...
poisoning, a large amount of hydroxocobalamin may be given intravenously and sometimes in combination with
sodium thiosulfate Sodium thiosulfate (sodium thiosulphate) is an inorganic compound with the formula . Typically it is available as the white or colorless pentahydrate, . The solid is an efflorescent (loses water readily) crystalline substance that dissolves well ...
. The mechanism of action is straightforward: the hydroxycobalamin hydroxide
ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elect ...
is displaced by the toxic cyanide ion, and the resulting non-toxic cyanocobalamin is excreted in
urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellul ...
.


Dietary recommendations

Most people in the United States and the United Kingdom consume sufficient vitamin B12. However, proportions of people with low or marginal levels of vitamin B12 reach up to 40% in the
Western world The Western world, also known as the West, primarily refers to the various nations and states in the regions of Europe, North America, and Oceania.
.
Grain A grain is a small, hard, dry fruit ( caryopsis) – with or without an attached hull layer – harvested for human or animal consumption. A grain crop is a grain-producing plant. The two main types of commercial grain crops are cereals and legum ...
-based foods can be
fortified A fortification is a military construction or building designed for the defense of territories in warfare, and is also used to establish rule in a region during peacetime. The term is derived from Latin ''fortis'' ("strong") and ''facere' ...
by having the vitamin added to them. Vitamin B12 supplements are available as single or multivitamin tablets.
Pharmaceutical A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...
preparations of vitamin B12 may be given by
intramuscular injection Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles hav ...
. Since there are few non-animal sources of the vitamin,
vegan Veganism is the practice of abstaining from the use of animal product—particularly in diet—and an associated philosophy that rejects the commodity status of animals. An individual who follows the diet or philosophy is known as a vegan. ...
s are advised to consume a
dietary supplement A dietary supplement is a manufactured product intended to supplement one's diet by taking a pill, capsule, tablet, powder, or liquid. A supplement can provide nutrients either extracted from food sources or that are synthetic in order ...
or fortified foods for B12 intake, or risk serious health consequences. Children in some regions of
developing countries A developing country is a sovereign state with a lesser developed industrial base and a lower Human Development Index (HDI) relative to other countries. However, this definition is not universally agreed upon. There is also no clear agreem ...
are at particular risk due to increased requirements during growth coupled with diets low in animal-sourced foods. The US National Academy of Medicine updated estimated average requirements (EARs) and recommended dietary allowances (RDAs) for vitamin B in 1998. The EAR for vitamin B for women and men ages 14 and up is 2.0μg/day; the RDA is 2.4μg/day. RDA is higher than EAR so as to identify amounts that will cover people with higher than average requirements. RDA for pregnancy equals 2.6μg/day. RDA for lactation equals 2.8 μg/day. For infants up to 12 months the adequate intake (AI) is 0.4–0.5μg/day. (AIs are established when there is insufficient information to determine EARs and RDAs.) For children ages 1–13 years the RDA increases with age from 0.9 to 1.8μg/day. Because 10 to 30 percent of older people may be unable to effectively absorb vitamin B naturally occurring in foods, it is advisable for those older than 50 years to meet their RDA mainly by consuming foods fortified with vitamin B or a supplement containing vitamin B. As for safety, tolerable upper intake levels (known as ULs) are set for vitamins and minerals when evidence is sufficient. In the case of vitamin B there is no UL, as there is no human data for adverse effects from high doses. Collectively the EARs, RDAs, AIs and ULs are referred to as
dietary reference intake The Dietary Reference Intake (DRI) is a system of nutrition recommendations from the National Academy of Medicine (NAM) of the National Academies (United States). It was introduced in 1997 in order to broaden the existing guidelines known as Re ...
s (DRIs). The European Food Safety Authority (EFSA) refers to the collective set of information as "dietary reference values", with population reference intake (PRI) instead of RDA, and average requirement instead of EAR. AI and UL are defined by EFSA the same as in the United States. For women and men over age 18 the adequate intake (AI) is set at 4.0μg/day. AI for pregnancy is 4.5 μg/day, for lactation 5.0μg/day. For children aged 1–17 years the AIs increase with age from 1.5 to 3.5μg/day. These AIs are higher than the U.S. RDAs. The EFSA also reviewed the safety question and reached the same conclusion as in the United States—that there was not sufficient evidence to set a UL for vitamin B. The Japan National Institute of Health and Nutrition set the RDA for people ages 12 and older at 2.4μg/day. The
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level o ...
also uses 2.4μg/day as the adult recommended nutrient intake for this vitamin. For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a "percent of daily value" (%DV). For vitamin B labeling purposes 100% of the daily value was 6.0μg, but on May 27, 2016, it was revised downward to 2.4μg. Compliance with the updated labeling regulations was required by 1 January 2020 for manufacturers with US$10 million or more in annual food sales, and by 1 January 2021 for manufacturers with lower volume food sales. A table of the old and new adult daily values is provided at
Reference Daily Intake The Reference Daily Intake (RDI) used in nutrition labeling on food and dietary supplement products in the U.S. and Canada is the daily intake level of a nutrient that is considered to be sufficient to meet the requirements of 97–98% of healt ...
.


Sources


Bacteria and archaea

Vitamin B12 is produced in nature by certain
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...
, and
archaea Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaeba ...
. It is synthesized by some bacteria in the
gut microbiota Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut mi ...
in humans and other animals, but it has long been thought that humans cannot absorb this as it is made in the colon, downstream from the
small intestine The small intestine or small bowel is an organ (anatomy), organ in the human gastrointestinal tract, gastrointestinal tract where most of the #Absorption, absorption of nutrients from food takes place. It lies between the stomach and large intes ...
, where the absorption of most nutrients occurs. Ruminants, such as cows and sheep, are foregut fermenters, meaning that plant food undergoes microbial fermentation in the
rumen The rumen, also known as a paunch, is the largest stomach compartment in ruminants and the larger part of the reticulorumen, which is the first chamber in the alimentary canal of ruminant animals. The rumen's microbial favoring environment al ...
before entering the true stomach ( abomasum), and thus they are absorbing vitamin B12 produced by bacteria. Other mammalian species (examples:
rabbit Rabbits, also known as bunnies or bunny rabbits, are small mammals in the family Leporidae (which also contains the hares) of the order Lagomorpha (which also contains the pikas). ''Oryctolagus cuniculus'' includes the European rabbit sp ...
s, pikas,
beaver Beavers are large, semiaquatic rodents in the genus ''Castor'' native to the temperate Northern Hemisphere. There are two extant species: the North American beaver (''Castor canadensis'') and the Eurasian beaver (''C. fiber''). Beavers a ...
, guinea pigs) consume high-fibre plants which pass through the intestinal system and undergo bacterial fermentation in the
cecum The cecum or caecum is a pouch within the peritoneum that is considered to be the beginning of the large intestine. It is typically located on the right side of the body (the same side of the body as the appendix, to which it is joined). The wo ...
and
large intestine The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces before bein ...
. The first-passage of feces produced by this
hindgut fermentation Hindgut fermentation is a digestive process seen in monogastric herbivores, animals with a simple, single-chambered stomach. Cellulose is digested with the aid of symbiotic bacteria.cecotrope Cecotropes, also called caecotrophs, caecal pellets, or night fecs, are the product of the cecum, a part of the digestive system in mammals of the order Lagomorpha, which includes two families: Leporidae (hares and rabbits), and Ochotonidae (pika ...
s", are re-ingested, a practice referred to as cecotrophy or
coprophagy Coprophagia () or coprophagy () is the consumption of feces. The word is derived from the grc, κόπρος , "feces" and , "to eat". Coprophagy refers to many kinds of feces-eating, including eating feces of other species (heterospecifics), o ...
. Re-ingestion allows for absorption of nutrients made available by bacterial digestion, and also of vitamins and other nutrients synthesized by the gut bacteria, including vitamin B12. Non-ruminant, non-hindgut herbivores may have an enlarged forestomach and/or small intestine to provide a place for bacterial fermentation and B-vitamin production, including B12. For gut bacteria to produce vitamin B12 the animal must consume sufficient amounts of
cobalt Cobalt is a chemical element with the symbol Co and atomic number 27. As with nickel, cobalt is found in the Earth's crust only in a chemically combined form, save for small deposits found in alloys of natural meteoric iron. The free element, p ...
. Soil that is deficient in cobalt may result in B12 deficiency, and B12 injections or cobalt supplementation may be required for livestock.


Animal-derived foods

Animals store vitamin B12 from their diets in their
liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
s and
muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of mus ...
s and some pass the vitamin into their eggs and
milk Milk is a white liquid food produced by the mammary glands of mammals. It is the primary source of nutrition for young mammals (including breastfed human infants) before they are able to digest solid food. Immune factors and immune-modulat ...
. Meat, liver, eggs and milk are therefore sources of the vitamin for other animals, including humans. For humans, the bioavailability from eggs is less than 9%, compared to 40% to 60% from fish, fowl and meat. Insects are a source of B12 for animals (including other insects and humans). Animal-derived food sources with a high concentration of vitamin B12 include
liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
and other organ meats from lamb,
veal Veal is the meat of calves, in contrast to the beef from older cattle. Veal can be produced from a calf of either sex and any breed, however most veal comes from young male calves of dairy breeds which are not used for breeding. Generally, v ...
,
beef Beef is the culinary name for meat from cattle (''Bos taurus''). In prehistoric times, humankind hunted aurochs and later domesticated them. Since that time, numerous breeds of cattle have been bred specifically for the quality or quantit ...
, and
turkey Turkey ( tr, Türkiye ), officially the Republic of Türkiye ( tr, Türkiye Cumhuriyeti, links=no ), is a transcontinental country located mainly on the Anatolian Peninsula in Western Asia, with a small portion on the Balkan Peninsula ...
; also
shellfish Shellfish is a colloquial and fisheries term for exoskeleton-bearing aquatic invertebrates used as food, including various species of molluscs, crustaceans, and echinoderms. Although most kinds of shellfish are harvested from saltwater environ ...
and crab meat.


Plants and algae

Natural plant and
algae Algae (; singular alga ) is an informal term for a large and diverse group of photosynthetic eukaryotic organisms. It is a polyphyletic grouping that includes species from multiple distinct clades. Included organisms range from unicellular micr ...
sources of vitamin B12 include fermented plant foods such as
tempeh Tempeh or tempe (; jv, ꦠꦺꦩ꧀ꦥꦺ, témpé, ) is a traditional Indonesian food made from fermented soybeans. It is made by a natural culturing and controlled fermentation process that binds soybeans into a cake form. A fungus, '' Rhizo ...
and seaweed-derived foods such as nori and laver. Other types of algae are rich in B12, with some species, such as '' Porphyra yezoensis'', containing as much
cobalamin Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is required by animals, which use it as a cofactor in DNA synthesis, in both fatty acid and amino acid metabolism. ...
as
liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
. Methylcobalamin has been identified in '' Chlorella vulgaris''. Since only bacteria and some archea possess the genes and enzymes necessary to synthesize vitamin B12, plant and algae sources all obtain the vitamin secondarily from symbiosis with various species of bacteria, or in the case of fermented plant foods, from bacterial fermentation. The Academy of Nutrition and Dietetics considers plant and algae sources "unreliable", stating that
vegans Veganism is the practice of abstaining from the use of animal product—particularly in diet—and an associated philosophy that rejects the commodity status of animals. An individual who follows the diet or philosophy is known as a vegan. Di ...
should turn to fortified foods and supplements instead.


Fortified foods

Foods for which vitamin B12-fortified versions are available include breakfast cereals, plant-derived milk substitutes such as soy milk and oat milk, energy bars, and nutritional yeast. The fortification ingredient is cyanocobalamin. Microbial fermentation yields adenosylcobalamin, which is then converted to cyanocobalamin by addition of potassium cyanide or thiocyanate in the presence of sodium nitrite and heat. As of 2019, nineteen countries require food fortification of wheat flour, maize flour or rice with vitamin B12. Most of these are in southeast Africa or Central America. Vegan advocacy organizations, among others, recommend that every vegan consume B12 from either fortified foods or supplements.


Supplements

Vitamin B12 is included in multivitamin pills; in some countries grain-based foods such as bread and pasta are fortified with B12. In the US, non-prescription products can be purchased providing up to 5,000µg each, and it is a common ingredient in energy drinks and energy shots, usually at many times the recommended dietary allowance of B12. The vitamin can also be a prescription product via injection or other means.
Sublingual Sublingual (abbreviated SL), from the Latin for "under the tongue", refers to the pharmacological route of administration by which substances diffuse into the blood through tissues under the tongue. The sublingual glands receive their primary ...
methylcobalamin, which contains no
cyanide Cyanide is a naturally occurring, rapidly acting, toxic chemical that can exist in many different forms. In chemistry, a cyanide () is a chemical compound that contains a functional group. This group, known as the cyano group, consists of ...
, is available in 5mg tablets. The metabolic fate and biological distribution of methylcobalamin are expected to be similar to that of other sources of vitamin B12 in the diet. "the metabolic fate and biological distribution of methylcobalamin and 5′-deoxyadenosylcobalamin are expected to be similar to that of other sources of vitamin B12 in the diet". The amount of cyanide in cyanocobalamin is generally not a concern, even in the 1,000µg dose, since the amount of cyanide there (20µg in a 1,000µg cyanocobalamin tablet) is less than the daily consumption of cyanide from food, and therefore cyanocobalamin is not considered a health risk. People who have kidney problems should not take large doses of cyanocobalamin due to their inability to efficiently metabolize cyanide.


Intramuscular or intravenous injection

Injection of hydroxycobalamin is often used if digestive absorption is impaired, but this course of action may not be necessary with high-dose oral supplements (such as 0.5–1.0mg or more), because with large quantities of the vitamin taken orally, even the 1% to 5% of free crystalline B12 that is absorbed along the entire intestine by passive diffusion may be sufficient to provide a necessary amount. A person with cobalamin C disease (which results in combined methylmalonic aciduria and
homocystinuria Homocystinuria or HCU is an inherited disorder of the metabolism of the amino acid methionine due to a deficiency of cystathionine beta synthase or methionine synthase. It is an inherited autosomal recessive trait, which means a child needs to i ...
) may require treatment with intravenous or intramuscular hydroxocobalamin or transdermal B12, because oral cyanocobalamin is inadequate in the treatment of cobalamin C disease.


Nanotechnologies used in vitamin B12 supplementation

Conventional administration does not ensure specific distribution and controlled release of vitamin B12. Moreover, therapeutic protocols involving injection require health care people and commuting of patients to the hospital thus increasing the cost of the treatment and impairing the lifestyle of patients. Targeted delivery of vitamin B12 is a major focus of modern prescriptions. For example, conveying the vitamin to the bone marrow and nerve cells would help myelin recovery. Currently, several nanocarriers strategies are being developed for improving vitamin B12 delivery with the aim to simplify administration, reduce costs, improve pharmacokinetics, and ameliorate the quality of patients' lives.


Pseudovitamin-B12

Pseudovitamin-B12 refers to B12-like analogues that are biologically inactive in humans. Most cyanobacteria, including '' Spirulina'', and some algae, such as ''
Porphyra ''Porphyra'' is a genus of coldwater seaweeds that grow in cold, shallow seawater. More specifically, it belongs to red algae phylum of laver species (from which comes laverbread), comprising approximately 70 species.Brodie, J.A. and Irvine, ...
tenera'' (used to make a dried seaweed food called nori in Japan), have been found to contain mostly pseudovitamin-B12 instead of biologically active B12. These pseudo-vitamin compounds can be found in some types of shellfish, in edible insects, and at times as metabolic breakdown products of cyanocobalamin added to dietary supplements and fortified foods. Pseudovitamin-B12 can show up as biologically active vitamin B12 when a microbiological assay with ''Lactobacillus delbrueckii'' subsp. lactis is used, as the bacteria can utilize the pseudovitamin despite it being unavailable to humans. To get a reliable reading of B12 content, more advanced techniques are available. One such technique involves pre-separation by silica gel and then assessment with B12-dependent ''E. coli'' bacteria. A related concept is antivitamin B12, compounds (often synthetic B12 analogues) that not only have no vitamin action, but also actively interfere with the activity of true vitamin B12. The design of these compounds mainly involved replacement of the metal ion. These compounds have the potential to be used for analyzing B12 utilization pathways or even attacking B12-dependent pathogens.


Drug interactions


H2-receptor antagonists and proton-pump inhibitors

Gastric acid is needed to release vitamin B12 from protein for absorption. Reduced secretion of
gastric acid Gastric acid, gastric juice, or stomach acid is a digestive fluid formed within the stomach lining. With a pH between 1 and 3, gastric acid plays a key role in digestion of proteins by activating digestive enzymes, which together break down the ...
and pepsin, from the use of H2 blocker or
proton-pump inhibitor Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump. They are the most potent inhibitor ...
(PPI) drugs, can reduce absorption of protein-bound (dietary) vitamin B12, although not of supplemental vitamin B12. H2-receptor antagonist examples include
cimetidine Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers. The development of longer-acting H2 r ...
, famotidine, nizatidine, and ranitidine. PPIs examples include omeprazole, lansoprazole,
rabeprazole Rabeprazole, sold under the brand name Aciphex, among others, is a medication that decreases stomach acid. It is used to treat peptic ulcer disease, gastroesophageal reflux disease, and excess stomach acid production such as in Zollinger–Elli ...
,
pantoprazole Pantoprazole, sold under the brand name Protonix, among others, is a proton pump inhibitor used for the treatment of stomach ulcers, short-term treatment of erosive esophagitis due to gastroesophageal reflux disease (GERD), maintenance of heal ...
, and esomeprazole. Clinically significant vitamin B12 deficiency and megaloblastic anemia are unlikely, unless these drug therapies are prolonged for two or more years, or if in addition the person's dietary intake is below recommended levels. Symptomatic vitamin deficiency is more likely if the person is rendered achlorhydric (a complete absence of gastric acid secretion), which occurs more frequently with proton pump inhibitors than H2 blockers.


Metformin

Reduced serum levels of vitamin B12 occur in up to 30% of people taking long-term
anti-diabetic Drugs used in diabetes treat diabetes mellitus by altering the glucose level in the blood. With the exceptions of insulin, most GLP receptor agonists (liraglutide, exenatide, and others), and pramlintide, all are administered orally and are thu ...
metformin. Deficiency does not develop if dietary intake of vitamin B12 is adequate or prophylactic B12 supplementation is given. If the deficiency is detected, metformin can be continued while the deficiency is corrected with B12 supplements.


Other drugs

Certain medications can decrease the absorption of orally consumed vitamin B12, including:
colchicine Colchicine is a medication used to treat gout and Behçet's disease. In gout, it is less preferred to NSAIDs or steroids. Other uses for colchicine include the management of pericarditis and familial Mediterranean fever. Colchicine is taken b ...
, extended-release
potassium Potassium is the chemical element with the symbol K (from Neo-Latin '' kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmos ...
products, and antibiotics such as
gentamicin Gentamicin is an antibiotic used to treat several types of bacterial infections. This may include bone infections, endocarditis, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, and sepsis among others. It is not ...
, neomycin and tobramycin. Anti-seizure medications
phenobarbital Phenobarbital, also known as phenobarbitone or phenobarb, sold under the brand name Luminal among others, is a medication of the barbiturate type. It is recommended by the World Health Organization (WHO) for the treatment of certain types of ep ...
, pregabalin, primidone and
topiramate Topiramate, sold under the brand name Topamax among others, is a carbonic anhydrase inhibitor medication used to treat epilepsy and prevent migraines. It has also been used in alcohol dependence. For epilepsy this includes treatment for genera ...
are associated with lower than normal serum vitamin concentration. However, serum levels were higher in people prescribed valproate. In addition, certain drugs may interfere with laboratory tests for the vitamin, such as
amoxicillin Amoxicillin is an antibiotic medication used to treat a number of bacterial infections. These include middle ear infection, strep throat, pneumonia, skin infections, and urinary tract infections among others. It is taken by mouth, or less c ...
,
erythromycin Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used durin ...
,
methotrexate Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...
and pyrimethamine.


Chemistry

Vitamin B12 is the most chemically complex of all the vitamins. The structure of B12 is based on a corrin ring, which is similar to the porphyrin ring found in
heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consis ...
. The central metal ion is
cobalt Cobalt is a chemical element with the symbol Co and atomic number 27. As with nickel, cobalt is found in the Earth's crust only in a chemically combined form, save for small deposits found in alloys of natural meteoric iron. The free element, p ...
. 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 Cyanide is a naturally occurring, rapidly acting, toxic chemical that can exist in many different forms. In chemistry, a cyanide () is a chemical compound that contains a functional group. This group, known as the cyano group, consists of a ...
(–CN), a
hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydrox ...
group (–OH), a
methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in ...
group (–CH3) or a 5′-deoxy adenosyl 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 have the ability to convert cyanocobalamin and hydroxocobalamin to the bioactive forms adenosylcobalamin and methylcobalamin by means of enzymatically replacing the cyano or hydroxyl groups.


Methods for the analysis of vitamin B12 in food

Several methods have been used to determine the vitamin B12 content in foods including microbiological assays, chemiluminescence assays, polarographic, spectrophotometric and high-performance liquid chromatography processes. The microbiological assay has been the most commonly used assay technique for foods, utilizing certain vitamin B12-requiring microorganisms, such as ''Lactobacillus delbrueckii'' subsp. ''lactis'' ATCC7830. However, it is no longer the reference method due to the high measurement uncertainty of vitamin B12. Furthermore, this assay requires overnight incubation and may give false results if any inactive vitamin B12 analogues are present in the foods. Currently, radioisotope dilution assay (RIDA) with labelled vitamin B12 and hog IF (pigs) have been used to determine vitamin B12 content in food. Previous reports have suggested that the RIDA method is able to detect higher concentrations of vitamin B12 in foods compared to the microbiological assay method.


Biochemistry


Coenzyme function

Vitamin B12 functions as a
coenzyme A cofactor is a non- protein chemical compound or metallic ion that is required for an enzyme's role as a catalyst (a catalyst is a substance that increases the rate of a chemical reaction). Cofactors can be considered "helper molecules" that as ...
, meaning that its presence is required in some enzyme-catalyzed reactions. Listed here are the three classes of enzymes that sometimes require B12 to function (in animals): # 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. #
Methyltransferase Methyltransferases are a large group of enzymes that all Methylation, methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which co ...
s #: Methyl (–CH3) group transfers between two molecules. These use the MeB12 (methylcobalamin) form of the vitamin. #
Dehalogenase A dehalogenase is a type of enzyme that catalyzes the removal of a halogen atom from a substrate. Examples include: *Reductive dehalogenases *4-chlorobenzoate dehalogenase * 4-chlorobenzoyl-CoA dehalogenase * Dichloromethane dehalogenase * Fluoroa ...
s #: Some species of anaerobic bacteria synthesize B12-dependent dehalogenases, which have potential commercial applications for degrading chlorinated pollutants. The microorganisms may either be capable of ''de novo'' corrinoid biosynthesis or are dependent on exogenous vitamin B12. In humans, two major coenzyme B12-dependent enzyme families corresponding to the first two reaction types, are known. These are typified by the following two enzymes:
Methylmalonyl coenzyme A mutase Methylmalonyl-CoA mutase (, MCM), mitochondrial, also known as methylmalonyl-CoA isomerase, is a protein that in humans is encoded by the ''MUT'' gene. This vitamin B12-dependent enzyme catalyzes the isomerization of methylmalonyl-CoA to succiny ...
(MUT) is an isomerase enzyme which uses the AdoB12 form and reaction type 1 to convert
L-methylmalonyl-CoA Methylmalonyl-CoA is the thioester consisting of coenzyme A linked to methylmalonic acid. It is an important intermediate in the biosynthesis of succinyl-CoA, which plays an essential role in the tricarboxylic acid cycle (aka the Citric Acid Cycle ...
to succinyl-CoA, an important step in the catabolic breakdown of some
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
s into succinyl-CoA, which then enters energy production via the
citric acid cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and prot ...
. This functionality is lost in vitamin B12 deficiency, and can be measured clinically as an increased serum methylmalonic acid (MMA) concentration. The MUT function is necessary for proper
myelin Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can ...
synthesis. Based on animal research, it is thought that the increased methylmalonyl-CoA hydrolyzes to form methylmalonate (methylmalonic acid), a neurotoxic dicarboxylic acid, causing neurological deterioration. Methionine synthase, coded by ''MTR'' gene, is a methyltransferase enzyme which uses the MeB12 and reaction type 2 to transfer a methyl group from 5-methyltetrahydrofolate to homocysteine, thereby generating tetrahydrofolate (THF) and
methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ...
. This functionality is lost in vitamin B12 deficiency, resulting in an increased homocysteine level and the trapping of
folate Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing an ...
as 5-methyl-tetrahydrofolate, from which THF (the active form of folate) cannot be recovered. THF plays an important role in DNA synthesis so reduced availability of THF results in ineffective production of cells with rapid turnover, in particular red blood cells, and also intestinal wall cells which are responsible for absorption. THF may be regenerated via MTR or may be obtained from fresh folate in the diet. Thus all of the DNA synthetic effects of B12 deficiency, including the megaloblastic anemia of
pernicious anemia Pernicious anemia is a type of vitamin B12 deficiency anemia, a disease in which not enough red blood cells are produced due to the malabsorption of vitamin B12. Malabsorption in pernicious anemia results from the lack or loss of intrinsic ...
, resolve if sufficient dietary folate is present. Thus the best-known "function" of B12 (that which is involved with DNA synthesis, cell-division, and anemia) is actually a
facultative {{wiktionary, facultative Facultative means "optional" or "discretionary" (antonym '' obligate''), used mainly in biology in phrases such as: * Facultative (FAC), facultative wetland (FACW), or facultative upland (FACU): wetland indicator statuses ...
function which is mediated by B12-conservation of an active form of folate which is needed for efficient DNA production. Other cobalamin-requiring methyltransferase enzymes are also known in bacteria, such as Me-H4-MPT, coenzyme M methyltransferase.


Physiology


Absorption

Food B12 is absorbed by two processes. The first is a vitamin B12-specific intestinal mechanism using intrinsic factor through which 1–2 micrograms can be absorbed every few hours, by which most food consumption of the vitamin is absorbed. The second is a passive diffusion process. The human physiology of active vitamin B12 absorption from food is complex. Protein-bound vitamin B12 must be released from the proteins by the action of digestive proteases in both the stomach and small intestine.
Gastric acid Gastric acid, gastric juice, or stomach acid is a digestive fluid formed within the stomach lining. With a pH between 1 and 3, gastric acid plays a key role in digestion of proteins by activating digestive enzymes, which together break down the ...
releases the vitamin from food particles; therefore antacid and acid-blocking medications (especially
proton-pump inhibitor Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump. They are the most potent inhibitor ...
s) may inhibit absorption of B12. After B12 has been freed from proteins in food by pepsin in the stomach, R-protein (also known as haptocorrin and transcobalamin-1), a B12 binding protein that is produced in the salivary glands, binds to B12. This protects the vitamin from degradation in the acidic environment of the stomach. This pattern of B12 transfer to a special binding protein secreted in a previous digestive step, is repeated once more before absorption. The next binding protein for B12 is intrinsic factor (IF), a protein synthesized by gastric parietal cells that is secreted in response to
histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discover ...
,
gastrin Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas. Gast ...
and pentagastrin, as well as the presence of food. In the
duodenum The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear, and the terms anterior intestine or proximal intestine m ...
,
protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
s digest R-proteins and release their bound B12, which then binds to IF, to form a complex (IF/B12). B12 must be attached to IF for it to be efficiently absorbed, as receptors on the enterocytes in the terminal ileum of the small bowel only recognize the B12-IF complex; in addition, intrinsic factor protects the vitamin from
catabolism Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, li ...
by intestinal bacteria. Absorption of food vitamin B12 thus requires an intact and functioning
stomach The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...
,
exocrine pancreas The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an endocr ...
, intrinsic factor, and small bowel. Problems with any one of these organs makes a vitamin B12 deficiency possible. Individuals who lack intrinsic factor have a decreased ability to absorb B12. In
pernicious anemia Pernicious anemia is a type of vitamin B12 deficiency anemia, a disease in which not enough red blood cells are produced due to the malabsorption of vitamin B12. Malabsorption in pernicious anemia results from the lack or loss of intrinsic ...
, there is a lack of IF due to autoimmune atrophic gastritis, in which antibodies form against parietal cells. Antibodies may alternately form against and bind to IF, inhibiting it from carrying out its B12 protective function. Due to the complexity of B12 absorption, geriatric patients, many of whom are hypoacidic due to reduced parietal cell function, have an increased risk of B12 deficiency. This results in 80–100% excretion of oral doses in the feces versus 30–60% excretion in feces as seen in individuals with adequate IF. Once the IF/B12 complex is recognized by specialized ileal receptors, it is transported into the
portal circulation In the circulatory system of animals, a portal venous system occurs when a capillary bed pools into another capillary bed through veins, without first going through the heart. Both capillary beds and the blood vessels that connect them are con ...
. The vitamin is then transferred to
transcobalamin II Transcobalamins are carrier proteins which bind cobalamin (B12). Types * Transcobalamin I (TCN1), also known as haptocorrin, R-factor, and R-protein, is a glycoprotein produced by the salivary glands of the mouth. It primarily serves to protect ...
(TC-II/B12), which serves as the plasma transporter. Hereditary defects in production of the transcobalamins and their receptors may produce functional deficiencies in B12 and infantile megaloblastic anemia, and abnormal B12 related biochemistry, even in some cases with normal blood B12 levels. For the vitamin to serve inside cells, the TC-II/B12 complex must bind to a cell receptor, and be endocytosed. The transcobalamin II is degraded within a
lysosome A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane p ...
, and free B12 is finally released into the cytoplasm, where it may be transformed into the proper coenzyme, by certain cellular enzymes (see above). Investigations into the intestinal absorption of B12 point out that the upper limit of absorption per single oral dose, under normal conditions, is about 1.5µg. The passive diffusion process of B12 absorption—normally a very small portion of total absorption of the vitamin from food consumption—may exceed the R-protein and IF mediated absorption when oral doses of B12 are very large (a thousand or more µg per dose) as commonly happens in dedicated-pill oral B12 supplementation. This allows pernicious anemia and certain other defects in B12 absorption to be treated with oral megadoses of B12, even without any correction of the underlying absorption defects. See the section on supplements above.


Storage and excretion

How fast B12 levels change depends on the balance between how much B12 is obtained from the diet, how much is secreted and how much is absorbed. The total amount of vitamin B12 stored in the body is about 2–5mg in adults. Around 50% of this is stored in the liver. Approximately 0.1% of this is lost per day by secretions into the gut, as not all these secretions are reabsorbed.
Bile Bile (from Latin ''bilis''), or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver bi ...
is the main form of B12 excretion; most of the B12 secreted in the bile is recycled via enterohepatic circulation. Excess B12 beyond the blood's binding capacity is typically excreted in urine. Owing to the extremely efficient enterohepatic circulation of B12, the liver can store 3 to 5 years' worth of vitamin B12; therefore, nutritional deficiency of this vitamin is rare in adults in the absence of malabsorption disorders. In the absence of enterohepatic reabsorption, only months to a year of vitamin B12 are stored.


Synthesis


Biosynthesis

Vitamin B12 is derived from a tetrapyrrolic structural framework created by the enzymes
deaminase Deamination is the removal of an amino group from a molecule. Enzymes that catalyse this reaction are called deaminases. In the human body, deamination takes place primarily in the liver, however it can also occur in the kidney. In situations of ...
and cosynthetase which transform
aminolevulinic acid δ-Aminolevulinic acid (also dALA, δ-ALA, 5ALA or 5-aminolevulinic acid), an endogenous non-proteinogenic amino acid, is the first compound in the porphyrin synthesis pathway, the pathway that leads to heme in mammals, as well as chlorophyll in p ...
via porphobilinogen and
hydroxymethylbilane Hydroxymethylbilane, also known as preuroporphyrinogen, is an organic compound that occurs in living organisms during the synthesis of porphyrins, a group of critical substances that include haemoglobin, myoglobin, and chlorophyll. The name is ofte ...
to uroporphyrinogen III. The latter is the first macrocyclic intermediate common to
heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consis ...
,
chlorophyll Chlorophyll (also chlorophyl) is any of several related green pigments found in cyanobacteria and in the chloroplasts of algae and plants. Its name is derived from the Greek words , ("pale green") and , ("leaf"). Chlorophyll allow plants to ...
,
siroheme Siroheme (or sirohaem) is a heme-like prosthetic group at the active sites of some enzymes to accomplish the six-electron reduction of sulfur and nitrogen. It is a cofactor at the active site of sulfite reductase, which plays a major role in su ...
and B12 itself. Later steps, especially the incorporation of the additional methyl groups of its structure, were investigated using 13C methyl-labelled
S-adenosyl methionine ''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throug ...
. It 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 In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These ...
and other steps could be determined, thus fully establishing all the intermediates in the pathway. Species from the following
genera Genus ( plural genera ) is a taxonomic rank used in the biological classification of living and fossil organisms as well as viruses. In the hierarchy of biological classification, genus comes above species and below family. In binomial nomenclat ...
and the following individual species are known to synthesize B12: ''
Propionibacterium ''Propionibacterium'' is a gram-positive, anaerobic, rod-shaped genus of bacteria named for their unique metabolism: They are able to synthesize propionic acid by using unusual transcarboxylase enzymes. Its members are primarily facultative ...
shermanii'', '' Pseudomonas'' ''denitrificans'', ''
Streptomyces ''Streptomyces'' is the largest genus of Actinomycetota and the type genus of the family Streptomycetaceae. Over 500 species of ''Streptomyces'' bacteria have been described. As with the other Actinomycetota, streptomycetes are gram-positiv ...
'' ''griseus'', '' Acetobacterium'', '' Aerobacter'', ''
Agrobacterium ''Agrobacterium'' is a genus of Gram-negative bacteria established by H. J. Conn that uses horizontal gene transfer to cause tumors in plants. ''Agrobacterium tumefaciens'' is the most commonly studied species in this genus. ''Agrobacterium ...
'', '' Alcaligenes'', ''
Azotobacter ''Azotobacter'' is a genus of usually motile, oval or spherical bacteria that form thick-walled cysts (and also has hard crust) and may produce large quantities of capsular slime. They are aerobic, free-living soil microbes that play an impo ...
'', '' Bacillus'', ''
Clostridium ''Clostridium'' is a genus of anaerobic, Gram-positive bacteria. Species of ''Clostridium'' inhabit soils and the intestinal tract of animals, including humans. This genus includes several significant human pathogens, including the causative a ...
'', ''
Corynebacterium ''Corynebacterium'' () is a genus of Gram-positive bacteria and most are aerobic. They are bacilli (rod-shaped), and in some phases of life they are, more specifically, club-shaped, which inspired the genus name ('' coryneform'' means "club- ...
'', ''
Flavobacterium ''Flavobacterium'' is a genus of Gram-negative, nonmotile and motile, rod-shaped bacteria that consists of 130 recognized species. Flavobacteria are found in soil and fresh water in a variety of environments. Several species are known to caus ...
'', ''
Lactobacillus ''Lactobacillus'' is a genus of Gram-positive, aerotolerant anaerobes or microaerophilic, rod-shaped, non-spore-forming bacteria. Until 2020, the genus ''Lactobacillus'' comprised over 260 phylogenetically, ecologically, and metabolically div ...
'', ''
Micromonospora ''Micromonospora'' is a genus of bacteria of the family Micromonosporaceae. They are gram-positive, spore-forming, generally aerobic, and form a branched mycelium; they occur as saprotrophic forms in soil and water. Various species are source ...
'', ''
Mycobacterium ''Mycobacterium'' is a genus of over 190 species in the phylum Actinomycetota, assigned its own family, Mycobacteriaceae. This genus includes pathogens known to cause serious diseases in mammals, including tuberculosis ('' M. tuberculosis'') ...
'', ''
Nocardia ''Nocardia'' is a genus of weakly staining Gram-positive, catalase-positive, rod-shaped bacteria. It forms partially acid-fast beaded branching filaments (acting as fungi, but being truly bacteria). It contains a total of 85 species. Some sp ...
'', ''
Proteus In Greek mythology, Proteus (; Ancient Greek: Πρωτεύς, ''Prōteus'') is an early prophetic sea-god or god of rivers and oceanic bodies of water, one of several deities whom Homer calls the "Old Man of the Sea" ''(hálios gérôn)''. ...
'', ''
Rhizobium ''Rhizobium'' is a genus of Gram-negative soil bacteria that fix nitrogen. ''Rhizobium'' species form an endosymbiotic nitrogen-fixing association with roots of (primarily) legumes and other flowering plants. The bacteria colonize plant cells ...
'', ''
Salmonella ''Salmonella'' is a genus of rod-shaped (bacillus) Gram-negative bacteria of the family Enterobacteriaceae. The two species of ''Salmonella'' are '' Salmonella enterica'' and '' Salmonella bongori''. ''S. enterica'' is the type species and is ...
'', '' Serratia'', '' Streptococcus'' and '' Xanthomonas''.


Industrial

Industrial production of B12 is achieved through
fermentation Fermentation is a metabolic process that produces chemical changes in organic substrates through the action of enzymes. In biochemistry, it is narrowly defined as the extraction of energy from carbohydrates in the absence of oxygen. In food p ...
of selected microorganisms. '' Streptomyces griseus'', a bacterium once thought to be a
fungus A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately fr ...
, was the commercial source of vitamin B12 for many years. The species '' Pseudomonas denitrificans'' and '' Propionibacterium freudenreichii'' subsp. ''shermanii'' are more commonly used today. These are grown under special conditions to enhance yield. Rhone-Poulenc improved yield via genetic engineering ''P. denitrificans''. ''
Propionibacterium ''Propionibacterium'' is a gram-positive, anaerobic, rod-shaped genus of bacteria named for their unique metabolism: They are able to synthesize propionic acid by using unusual transcarboxylase enzymes. Its members are primarily facultative ...
'', the other commonly used bacteria, produce no
exotoxin An exotoxin is a toxin secreted by bacteria. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, sim ...
s or endotoxins and are generally recognized as safe (have been granted GRAS status) by the
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
of the United States. The total world production of vitamin B12 in 2008 was 35,000 kg (77,175 lb).


Laboratory

The complete laboratory synthesis of B12 was achieved by Robert Burns Woodward and Albert Eschenmoser in 1972. The work required the effort of 91 postdoctoral fellows (mostly at Harvard) and 12 PhD students (at
ETH Zurich (colloquially) , former_name = eidgenössische polytechnische Schule , image = ETHZ.JPG , image_size = , established = , type = Public , budget = CHF 1.896 billion (2021) , rector = Günther Dissertori , president = Joël Mesot , a ...
) from 19 nations. The synthesis constitutes a formal total synthesis, since the research groups only prepared the known intermediate cobyric acid, whose chemical conversion to vitamin B12 was previously reported. This synthesis of vitamin B12 is of no practical consequence due to its length, taking 72 chemical steps and giving an overall chemical yield well under 0.01%. Although there have been sporadic synthetic efforts since 1972, the Eschenmoser–Woodward synthesis remains the only completed (formal) total synthesis.


History


Descriptions of deficiency effects

Between 1849 and 1887, Thomas Addison described a case of
pernicious anemia Pernicious anemia is a type of vitamin B12 deficiency anemia, a disease in which not enough red blood cells are produced due to the malabsorption of vitamin B12. Malabsorption in pernicious anemia results from the lack or loss of intrinsic ...
,
William Osler Sir William Osler, 1st Baronet, (; July 12, 1849 – December 29, 1919) was a Canadian physician and one of the "Big Four" founding professors of Johns Hopkins Hospital. Osler created the first residency program for specialty training of phys ...
and William Gardner first described a case of neuropathy, Hayem described large red cells in the peripheral blood in this condition, which he called "giant blood corpuscles" (now called
macrocyte Macrocytosis is the enlargement of red blood cells with near-constant hemoglobin concentration, and is defined by a mean corpuscular volume (MCV) of greater than 100 femtolitres (the precise criterion varies between laboratories). The enlarged er ...
s),
Paul Ehrlich Paul Ehrlich (; 14 March 1854 – 20 August 1915) was a Nobel Prize-winning German physician and scientist who worked in the fields of hematology, immunology, and antimicrobial chemotherapy. Among his foremost achievements were finding a cure ...
identified
megaloblasts A nucleated red blood cell (NRBC), also known by several other names, is a red blood cell that contains a cell nucleus. Almost all vertebrate organisms have hemoglobin-containing cells in their blood, and with the exception of mammals, all of the ...
in the bone marrow, and Ludwig Lichtheim described a case of
myelopathy Myelopathy describes any neurologic deficit related to the spinal cord. The most common form of myelopathy in humans, '' cervical spondylotic myelopathy (CSM)'', also called ''degenerative cervical myelopathy'', results from narrowing of the spin ...
. Chapter 36: Megaloblastic anemias: disorders of impaired DNA synthesis by Ralph Carmel


Identification of liver as an anti-anemia food

During the 1920s, George Whipple discovered that ingesting large amounts of raw
liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
seemed to most rapidly cure the anemia of blood loss in dogs, and hypothesized that eating liver might treat pernicious anemia.
Edwin Cohn Edwin Joseph Cohn (December 17, 1892 – October 1, 1953) was a protein scientist. A graduate of Phillips Academy, Andover 911 and the University of Chicago 914, PhD 1917 he made important advances in the physical chemistry of proteins, and was ...
prepared a liver extract that was 50 to 100 times more potent in treating pernicious anemia than the natural liver products.
William Castle William Castle (born William Schloss Jr.; April 24, 1914 – May 31, 1977) was an American film director, producer, screenwriter, and actor. Orphaned at 11, Castle dropped out of high school at 15 to work in the theater. He came to the attenti ...
demonstrated that gastric juice contained an "intrinsic factor" which when combined with meat ingestion resulted in absorption of the vitamin in this condition. In 1934, George Whipple shared the 1934
Nobel Prize in Physiology or Medicine The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accordi ...
with William P. Murphy and George Minot for discovery of an effective treatment for pernicious anemia using liver concentrate, later found to contain a large amount of vitamin B12.


Identification of the active compound

While working at the Bureau of Dairy Industry, U.S. Department of Agriculture,
Mary Shaw Shorb Mary Shaw Shorb (January 11, 1907 – August 18, 1990), a research scientist, was best known for the development of a bacteriological assay procedure for the chemical compound now known as Vitamin B12. Early years Mary Shaw was born on January 7, ...
was assigned work on the bacterial strain ''Lactobacillus lactis'' Dorner (LLD), which was used to make yogurt and other cultured dairy products. The culture medium for LLD required liver extract. Shorb knew that the same liver extract was used to treat pernicious anemia (her father-in-law had died from the disease), and concluded that LLD could be developed as an assay method to identify the active compound. While at the University of Maryland she received a small grant from Merck, and in collaboration with
Karl Folkers Karl August Folkers (September 1, 1906 – December 7, 1997) was an American biochemist who made major contributions to the isolation and identification of bioactive natural products. Career Folkers graduated from the College of Liberal Arts and ...
from that company, developed the LLD assay. This identified "LLD factor" as essential for the bacteria's growth. Shorb, Folker and Alexander R. Todd, at the
University of Cambridge , mottoeng = Literal: From here, light and sacred draughts. Non literal: From this place, we gain enlightenment and precious knowledge. , established = , other_name = The Chancellor, Masters and Schola ...
, used the LLD assay to extract the anti-pernicious anemia factor from liver extracts, purify it, and name it vitamin B12. In 1955, Todd helped elucidate the structure of the vitamin, for which he was awarded the Nobel Prize in Chemistry in 1957. The complete
chemical structure A chemical structure determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target molecule or other solid. Molecular geometry refers to the spatial arrangement of ...
of the molecule was determined by
Dorothy Hodgkin Dorothy Mary Crowfoot Hodgkin (née Crowfoot; 12 May 1910 – 29 July 1994) was a Nobel Prize-winning British chemist who advanced the technique of X-ray crystallography to determine the structure of biomolecules, which became essential fo ...
, based on
crystallographic Crystallography is the experimental science of determining the arrangement of atoms in crystalline solids. Crystallography is a fundamental subject in the fields of materials science and solid-state physics (condensed matter physics). The wor ...
data in 1956, for which for that and other crystallographic analyses she was awarded the Nobel Prize in Chemistry in 1964. Hodgkin went on to decipher the structure of
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism ...
. Five people have been awarded
Nobel Prize The Nobel Prizes ( ; sv, Nobelpriset ; no, Nobelprisen ) are five separate prizes that, according to Alfred Nobel's will of 1895, are awarded to "those who, during the preceding year, have conferred the greatest benefit to humankind." Alfr ...
s for direct and indirect studies of vitamin B12: George Whipple, George Minot and William Murphy (1934), Alexander R. Todd (1957), and Dorothy Hodgkin (1964).


Commercial production

Industrial production of vitamin B12 is achieved through
fermentation Fermentation is a metabolic process that produces chemical changes in organic substrates through the action of enzymes. In biochemistry, it is narrowly defined as the extraction of energy from carbohydrates in the absence of oxygen. In food p ...
of selected microorganisms. As noted above, the completely synthetic laboratory synthesis of B12 was achieved by Robert Burns Woodward and Albert Eschenmoser in 1972, though this process has no commercial potential, requiring almost 70 steps and having a yield well below 0.01%.


Society and culture

In the 1970s, John A. Myers, a physician residing in Baltimore, developed a program of injecting vitamins and minerals intravenously for various medical conditions. The formula included 1000 µg of cyanocobalamin. This came to be known as the
Myers' cocktail Myers' cocktail is an intravenous (IV) vitamin therapy that lacks scientific evidence to support its use as a medical treatment. The term, Myers' cocktail, is included in Quackwatch's index of questionable treatments. The name is attributed to ...
. After his death in 1984, other physicians and naturopaths took up prescribing "intravenous micro-nutrient therapy" with unsubstantiated health claims for treating fatigue, low energy, stress, anxiety, migraine, depression, immunocompromised, promoting weight loss and more. However, other than a report on case studies there are no benefits confirmed in the scientific literature. Healthcare practitioners at clinics and spas prescribe versions of these intravenous combination products, but also intramuscular injections of just vitamin B12. A Mayo Clinic review concluded that there is no solid evidence that vitamin B12 injections provide an energy boost or aid weight loss. There is evidence that for elderly people, physicians often repeatedly prescribe and administer cyanocobalamin injections inappropriately, evidenced by the majority of subjects in one large study either having had normal serum concentrations or had not been tested prior to the injections.


See also

* Adenosylcobalamin *
Cobalamin biosynthesis Cobalamin biosynthesis is the process by which bacteria and archea make cobalamin, vitamin B12. Many steps are involved in converting aminolevulinic acid via uroporphyrinogen III and adenosylcobyric acid to the final forms in which it is used by ...
* Cyanocobalamin *
Hydroxocobalamin Hydroxocobalamin, also known as vitamin B12a and hydroxycobalamin, is a vitamin found in food and used as a dietary supplement. As a supplement it is used to treat vitamin B12 deficiency including pernicious anemia. Other uses include treatment ...
* Methylcobalamin *
Vitamin A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an essential micronutrient that an organism needs in small quantities for the proper functioning of its metabolism. Essential nutrie ...
s


Further reading

*


References


External links

* * * * * {{Authority control B vitamins Cofactors Organocobalt compounds