Vitamin B
12, 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 Nutrient#Essential nutrients, essential micronutrient that an organism needs in small quantities for the proper functioning of its ...
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 cell ...
.
It is one of eight
B vitamins. It is required by animals, which use it as a
cofactor in
DNA synthesis
DNA synthesis is the natural or artificial creation of deoxyribonucleic acid (DNA) molecules. DNA is a macromolecule made up of nucleotide units, which are linked by covalent bonds and hydrogen bonds, in a repeating structure. DNA synthesis occur ...
, 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, fr ...
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 th ...
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 "holl ...
s in the
bone marrow
Bone marrow is a semi-solid tissue found within the 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 is composed of hematopoietic ce ...
.
[ 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 Archaebac ...
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 among ...
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 (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
, 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, quails, a ...
, eggs
Humans and human ancestors have scavenged and eaten animal eggs for millions of years. Humans in Southeast Asia had domesticated chickens and harvested their eggs for food by 1,500 BCE. The most widely consumed eggs are those of fowl, especial ...
, 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 in th ...
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
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 nutrien ...
. 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 have ...
.
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
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 ...
production ( achlorhydria), because acid exposure frees protein-bound vitamin. For the same reason, people on long-term antacid therapy, using proton-pump inhibitors
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 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 sto ...
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 fa ...
, a type of megaloblastic anemia
Megaloblastic anemia is a type of macrocytic anemia. An anemia is a red blood cell defect that can lead to an undersupply of oxygen. Megaloblastic anemia results from inhibition of DNA replication, DNA synthesis during red blood cell production. ...
, causing a feeling of tiredness and weakness, lightheadedness, headache, breathlessness, loss of appetite, abnormal sensations, changes in mobility, severe joint pain
Arthralgia (from Greek ''arthro-'', joint + ''-algos'', pain) literally means ''joint pain''. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication.
According to MeSH, ...
, 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 and ...
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 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. Many ...
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, pr ...
, 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 vitamer
Vitamins occur in a variety of related forms known as vitamers. A vitamer () of a particular vitamin is one of several related compounds that performs the functions of said vitamin and prevents the symptoms of deficiency of said vitamin.
Early r ...
s. 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 ass ...
, 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 fo ...
, 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. I ...
.
* methylcobalamin
Methylcobalamin (mecobalamin, MeCbl, or MeB) is a cobalamin, a form of vitamin B. It differs from cyanocobalamin in that the cyano group at the cobalt is replaced with a methyl group. Methylcobalamin features an octahedral cobalt(III) centre and c ...
, 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 many ...
.
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
Methylcobalamin (mecobalamin, MeCbl, or MeB) is a cobalamin, a form of vitamin B. It differs from cyanocobalamin in that the cyano group at the cobalt is replaced with a methyl group. Methylcobalamin features an octahedral cobalt(III) centre and c ...
in cytosol and adenosylcobalamin in mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
.
Cyanocobalamin is the most common form used in dietary supplements and food fortification
Food fortification or enrichment is the process of adding micronutrients (essential trace elements and vitamins) to food. It can be carried out by food manufacturers, or by governments as a public health policy which aims to reduce the number of p ...
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 fo ...
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
A mouth ulcer (aphtha) is an Ulcer (dermatology), ulcer that occurs on the mucous membrane of the oral cavity. Mouth ulcers are very common, occurring in association with many diseases and by many different mechanisms, but usually there is no ser ...
, 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 remembered, ...
, 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 wit ...
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 behavior ...
. 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 fa ...
. 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, th ...
with bone marrow promegaloblastosis (megaloblastic anemia
Megaloblastic anemia is a type of macrocytic anemia. An anemia is a red blood cell defect that can lead to an undersupply of oxygen. Megaloblastic anemia results from inhibition of DNA replication, DNA synthesis during red blood cell production. ...
). This is due to the inhibition of DNA synthesis
DNA synthesis is the natural or artificial creation of deoxyribonucleic acid (DNA) molecules. DNA is a macromolecule made up of nucleotide units, which are linked by covalent bonds and hydrogen bonds, in a repeating structure. DNA synthesis occur ...
(specifically purines
Purine is a heterocyclic aromatic organic compound that consists of two rings ( pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purines ...
and thymidine
Thymidine (symbol dT or dThd), also known as deoxythymidine, deoxyribosylthymine, or thymine deoxyriboside, is a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine (A) in double-stranded DNA. I ...
).
# 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 wi ...
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 movement ...
, 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 attack on the parietal cell
Parietal cells (also known as oxyntic cells) are epithelial cells in the stomach that secrete hydrochloric acid (HCl) and intrinsic factor. These cells are located in the gastric glands found in the lining of the fundus and body regions of the ...
s 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. T ...
(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, c ...
, regression
Regression or regressions may refer to:
Science
* Marine regression, coastal advance due to falling sea level, the opposite of marine transgression
* Regression (medicine), a characteristic of diseases to express lighter symptoms or less extent ( ...
, 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 a ...
.
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. Di ...
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
Vegetarianism is the practice of abstaining from the consumption of meat (red meat, poultry, seafood, insects, and the flesh of any other animal). It may also include abstaining from eating all by-products of animal slaughter.
Vegetarianism may ...
—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
Nutritional yeast (also known as nooch) is a deactivated yeast, often a strain of ''Saccharomyces cerevisiae'', that is sold commercially as a food product. It is sold in the form of yellow flakes, granules, or powder and can be found in the bul ...
as a regular part of their diet. The elderly are at increased risk because they tend to produce less stomach 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 ...
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
The European Food Safety Authority (EFSA) is the agency of the European Union (EU) that provides independent scientific advice and communicates on existing and emerging risks associated with the food chain. EFSA was established in February 2002, ...
(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 mater ...
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 hema ...
(MCV). In addition, on the peripheral blood smear
A blood smear, peripheral blood smear or blood film is a thin layer of blood smeared on a glass microscope slide and then stained in such a way as to allow the various blood cells to be examined microscopically. Blood smears are examined in the ...
, 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 leukocyte
Granulocytes are
cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear. They hav ...
s 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
Homocysteine is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In the b ...
over 15 micromol/L and methylmalonic acid
Methylmalonic acid (MMA) (conjugate base methylmalonate) is a dicarboxylic acid that is a ''C''-methylated derivative of malonate.
The coenzyme A linked form of methylmalonic acid, methylmalonyl-CoA, is converted into succinyl-CoA by methylmalonyl ...
(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
Methylmalonic acidemia, also called methylmalonic aciduria, is an autosomal recessive metabolic disorder that disrupts normal amino acid metabolism. It is a classical type of organic acidemia. The result of this condition is the inability to proper ...
. 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 to ...
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 bra ...
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
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
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 i ...
. 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 electr ...
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 excretion, excreted from the body through the urethra.
Cel ...
.
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 state (polity), 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 re ...
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 have ...
.[ 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. Di ...
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
The National Academy of Medicine (NAM), formerly called the Institute of Medicine (IoM) until 2015, is an American nonprofit, non-governmental organization. The National Academy of Medicine is a part of the National Academies of Sciences, En ...
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 level
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 Reco ...
s (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 Reco ...
s (DRIs).
The European Food Safety Authority
The European Food Safety Authority (EFSA) is the agency of the European Union (EU) that provides independent scientific advice and communicates on existing and emerging risks associated with the food chain. EFSA was established in February 2002, ...
(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 of h ...
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$
The United States dollar (symbol: $; code: USD; also abbreviated US$ or U.S. Dollar, to distinguish it from other dollar-denominated currencies; referred to as the dollar, U.S. dollar, American dollar, or colloquially buck) is the official ...
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 health ...
.
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 among ...
, 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 Archaebac ...
. 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 m ...
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 in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through the p ...
, where the absorption of most nutrients occurs. Ruminant
Ruminants (suborder Ruminantia) are ungulate, hoofed herbivorous grazing or browsing mammals that are able to acquire nutrients from plant-based food by Enteric fermentation, fermenting it in a specialized stomach prior to digestion, principally ...
s, 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 allow ...
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 speci ...
s, pika
A pika ( or ; archaically spelled pica) is a small, mountain-dwelling mammal found in Asia and North America. With short limbs, very round body, an even coat of fur, and no external tail, they resemble their close relative, the rabbit, but wi ...
s, 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 ar ...
, guinea pigs
The guinea pig or domestic guinea pig (''Cavia porcellus''), also known as the cavy or domestic cavy (), is a species of rodent belonging to the genus ''Cavia'' in the family Caviidae. Breeders tend to use the word ''cavy'' to describe the ani ...
) consume high-fibre plants which pass through the intestinal system and undergo bacterial fermentation in the cecum 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 being r ...
. 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), of ...
. 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, pr ...
. 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 (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
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 muscl ...
s and some pass the vitamin into their eggs
Humans and human ancestors have scavenged and eaten animal eggs for millions of years. Humans in Southeast Asia had domesticated chickens and harvested their eggs for food by 1,500 BCE. The most widely consumed eggs are those of fowl, especial ...
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 digestion, digest solid food. Immune factors and immune ...
. 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 (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
and other organ meat
Offal (), also called variety meats, pluck or organ meats, is the organs of a butchered animal. The word does not refer to a particular list of edible organs, which varies by culture and region, but usually excludes muscle. Offal may also refer ...
s from lamb
Lamb or The Lamb may refer to:
* A young sheep
* Lamb and mutton, the meat of sheep
Arts and media Film, television, and theatre
* ''The Lamb'' (1915 film), a silent film starring Douglas Fairbanks Sr. in his screen debut
* ''The Lamb'' (1918 ...
, 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 quantity ...
, and turkey
Turkey ( tr, Türkiye ), officially the Republic of Türkiye ( tr, Türkiye Cumhuriyeti, links=no ), is a list of transcontinental countries, transcontinental country located mainly on the Anatolia, Anatolian Peninsula in Western Asia, with ...
; 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 envir ...
and crab meat
Crab meat or crab marrow is the meat found within a crab. It is used in many cuisines around the world, prized for its soft, delicate and sweet taste. Crab meat is low in fat and provides around of food energy per serving. Brown crab (''Canc ...
.
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 mic ...
sources of vitamin B12 include fermented
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 ...
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, ''Rhizopus ...
and seaweed-derived foods such as nori
Nori is a dried edible seaweed used in Japanese cuisine, made from species of the red algae genus ''Pyropia'', including ''P. yezonesis'' and '' P. tenera''. It has a strong and distinctive flavor, and is often used to wrap rolls of sushi or '' ...
and laver. Other types of algae are rich in B12, with some species, such as '' Porphyra yezoensis'',[ containing as much cobalamin as ]liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
. 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 (nutrition), diet—and an associated philosophy that rejects the commodity status of animals. An individual who follows the diet or philosophy is kn ...
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 substitute
A milk substitute is any substance that resembles milk and can be used in the same ways as milk. Such substances may be variously known as non-dairy beverage, nut milk, grain milk, legume milk, mock milk and alternative milk.
For adults, milk ...
s such as soy milk
Soy milk (simplified Chinese: 豆浆; traditional Chinese: 豆漿) also known as soya milk or soymilk, is a plant-based drink produced by soaking and grinding soybeans, boiling the mixture, and filtering out remaining particulates. It is a sta ...
and oat milk
Oat milk is a plant milk derived from whole oat (''Avena spp.'') grains by extracting the plant material with water. Oat milk has a creamy texture and mild oatmeal-like flavor, and is manufactured in various flavors, such as sweetened, unsweetened ...
, energy bar
Energy bars are supplemental bars containing cereals, micronutrients, and flavor ingredients intended to supply quick food energy. Because most energy bars contain added protein (nutrient), protein, carbohydrates, dietary fiber, and other nutri ...
s, and nutritional yeast
Nutritional yeast (also known as nooch) is a deactivated yeast, often a strain of ''Saccharomyces cerevisiae'', that is sold commercially as a food product. It is sold in the form of yellow flakes, granules, or powder and can be found in the bul ...
.[ 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 shot
Energy shots are a specialized kind of energy drink that contain a dose of the stimulant caffeine in a small amount of liquid. Whereas most energy drinks are sold in cans or bottles, energy shots are usually sold in 50ml bottles. Energy shots can ...
s, 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 prima ...
methylcobalamin
Methylcobalamin (mecobalamin, MeCbl, or MeB) is a cobalamin, a form of vitamin B. It differs from cyanocobalamin in that the cyano group at the cobalt is replaced with a methyl group. Methylcobalamin features an octahedral cobalt(III) centre and c ...
, 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
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 fo ...
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
Methylmalonic acidemia, also called methylmalonic aciduria, is an autosomal recessive metabolic disorder that disrupts normal amino acid metabolism. It is a classical type of organic acidemia. The result of this condition is the inability to proper ...
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 inh ...
) 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
Nori is a dried edible seaweed used in Japanese cuisine, made from species of the red algae genus ''Pyropia'', including ''P. yezonesis'' and '' P. tenera''. It has a strong and distinctive flavor, and is often used to wrap rolls of sushi or '' ...
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
Silica gel is an amorphous and porous form of silicon dioxide (silica), consisting of an irregular tridimensional framework of alternating silicon and oxygen atoms with nanometer-scale voids and pores. The voids may contain water or some other l ...
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
Pepsin is an endopeptidase that breaks down proteins into smaller peptides. It is produced in the gastric chief cells of the stomach lining and is one of the main digestive enzymes in the digestive systems of humans and many other animals, w ...
, 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 inhibitors ...
(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 rec ...
, famotidine
Famotidine, sold under the brand name Pepcid among others, is a histamine H2 receptor antagonist medication that decreases stomach acid production. It is used to treat peptic ulcer disease, gastroesophageal reflux disease, and Zollinger-Elli ...
, nizatidine
Nizatidine is a histamine H2 receptor antagonist that inhibits stomach acid production, and is commonly used in the treatment of peptic ulcer disease and gastroesophageal reflux disease.
It was patented in 1980 and approved for medical use in ...
, and ranitidine
Ranitidine, sold under the brand name Zantac among others, is a medication used to decrease stomach acid production. It is commonly used in treatment of peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellison syndrome. I ...
. PPIs examples include omeprazole
Omeprazole, sold under the brand names Prilosec and Losec, among others, is a medication used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease, and Zollinger–Ellison syndrome. It is also used to prevent upper g ...
, lansoprazole
Lansoprazole, sold under the brand name Prevacid among others, is a medication which reduces stomach acid. It is used to treat peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellison syndrome. Effectiveness is similar to ...
, 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 heali ...
, and esomeprazole
Esomeprazole, sold under the brand name Nexium among others, is a medication which reduces stomach acid. It is used to treat gastroesophageal reflux disease, peptic ulcer disease, and Zollinger–Ellison syndrome. Effectiveness is similar to o ...
. 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
Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. ...
. 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, 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 atmosphe ...
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 e ...
, neomycin
Neomycin is an aminoglycoside antibiotic that displays bactericidal activity against gram-negative aerobic bacilli and some anaerobic bacilli where resistance has not yet arisen. It is generally not effective against gram-positive bacilli and an ...
and tobramycin
Tobramycin is an aminoglycoside antibiotic derived from '' Streptomyces tenebrarius'' that is used to treat various types of bacterial infections, particularly Gram-negative infections. It is especially effective against species of ''Pseudomonas ...
. 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
Pregabalin, sold under the brand name Lyrica among others, is an anticonvulsant, analgesic and anxiolytic medication used to treat epilepsy, neuropathic pain, fibromyalgia, restless leg syndrome, opioid withdrawal and generalized anxiety disord ...
, primidone
Primidone, sold under various brand names, is a barbiturate medication that is used to treat partial and generalized seizures, as well as essential tremors. It is taken by mouth.
Common side effects include sleepiness, poor coordination, nause ...
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 gener ...
are associated with lower than normal serum vitamin concentration. However, serum levels were higher in people prescribed valproate
Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those ...
. In addition, certain drugs may interfere with laboratory tests for the vitamin, such as amoxicillin, 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 duri ...
, 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
Pyrimethamine, sold under the brand name Daraprim among others, is a medication used with leucovorin (leucovorin is used to decrease side effects of pyrimethamine; it does not have intrinsic anti-parasitic activity) to treat the parasitic disea ...
.
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
Porphyrins ( ) are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). The parent of porphyrin is porphine, a rare chemical com ...
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 "consisti ...
. 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, pr ...
. 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
A reactive center, also called a propagating center, in chemistry is a particular location, usually an atom, within a chemical compound that is the likely center of a reaction in which the chemical is involved. In chain-growth polymer chemistry thi ...
, 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 hydroxy ...
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 many ...
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 hydrogenase A hydrogenase is an enzyme that catalyses the reversible oxidation of molecular hydrogen (H2), as shown below:
Hydrogen uptake () is coupled to the reduction of electron acceptors such as oxygen, nitrate, sulfate, carbon dioxide (), and fumara ...
s 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 ass ...
, 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):
# Isomerase
Isomerases are a general class of enzymes that convert a molecule from one isomer to another. Isomerases facilitate intramolecular rearrangements in which bonds are broken and formed. The general form of such a reaction is as follows:
A–B ...
s
#: 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 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 contain a Rossm ...
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 (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 Cyc ...
to succinyl-CoA
Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a thioester of succinic acid and coenzyme A.
Sources
It is an important intermediate in the citric acid cycle, where it is synthesized from α-ketoglutarate by α-ketoglutarate de ...
, 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 am ...
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 proteins ...
. This functionality is lost in vitamin B12 deficiency
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 nutrien ...
, and can be measured clinically as an increased serum methylmalonic acid
Methylmalonic acid (MMA) (conjugate base methylmalonate) is a dicarboxylic acid that is a ''C''-methylated derivative of malonate.
The coenzyme A linked form of methylmalonic acid, methylmalonyl-CoA, is converted into succinyl-CoA by methylmalonyl ...
(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 be ...
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
Methionine synthase also known as MS, MeSe, MTR is responsible for the regeneration of methionine from homocysteine. In humans it is encoded by the ''MTR'' gene (5-methyltetrahydrofolate-homocysteine methyltransferase). Methionine synthase forms ...
, coded by ''MTR'' gene, is a methyltransferase enzyme which uses the MeB12 and reaction type 2 to transfer a methyl group from 5-methyltetrahydrofolate
Levomefolic acid (INN, also known as L-5-MTHF, L-methylfolate and L-5-methyltetrahydrofolate and (6''S'')-5-methyltetrahydrofolate, and (6''S'')-5-MTHF) is the primary biologically active form of folate used at the cellular level for DNA reprodu ...
to homocysteine
Homocysteine is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In the b ...
, thereby generating tetrahydrofolate
Tetrahydrofolic acid (THFA), or tetrahydrofolate, is a folic acid derivative.
Metabolism
Human synthesis
Tetrahydrofolic acid is produced from dihydrofolic acid by dihydrofolate reductase. This reaction is inhibited by methotrexate.
It is co ...
(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 ro ...
. This functionality is lost in vitamin B12 deficiency
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 nutrien ...
, resulting in an increased homocysteine
Homocysteine is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In the b ...
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 and ...
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
Megaloblastic anemia is a type of macrocytic anemia. An anemia is a red blood cell defect that can lead to an undersupply of oxygen. Megaloblastic anemia results from inhibition of DNA replication, DNA synthesis during red blood cell production. ...
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 fa ...
, 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 inhibitors ...
s) may inhibit absorption of B12. After B12 has been freed from proteins in food by pepsin
Pepsin is an endopeptidase that breaks down proteins into smaller peptides. It is produced in the gastric chief cells of the stomach lining and is one of the main digestive enzymes in the digestive systems of humans and many other animals, w ...
in the stomach, R-protein
Haptocorrin also known as transcobalamin-1 (TC-1) or cobalophilin is a transcobalamin protein that in humans is encoded by the gene. The essential function of haptocorrin is protection of the acid-sensitive vitamin B12 while it moves through the ...
(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 cell
Parietal cells (also known as oxyntic cells) are epithelial cells in the stomach that secrete hydrochloric acid (HCl) and intrinsic factor. These cells are located in the gastric glands found in the lining of the fundus and body regions of the ...
s 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 discovered in ...
, 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.
Gastrin ...
and pentagastrin
Pentagastrin (trade name Peptavlon) is a synthetic polypeptide that has effects like gastrin when given parenterally. It stimulates the secretion of gastric acid, pepsin, and intrinsic factor, and has been used as a diagnostic aid as the pentagast ...
, 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
The ileum () is the final 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 posterior intestine or distal intestine ma ...
of the small bowel
The small intestine or small bowel is an organ in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through the pa ...
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, lipids, ...
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 endocri ...
, 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 fa ...
, 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 co ...
. 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
Megaloblastic anemia is a type of macrocytic anemia. An anemia is a red blood cell defect that can lead to an undersupply of oxygen. Megaloblastic anemia results from inhibition of DNA replication, DNA synthesis during red blood cell production. ...
, 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 prot ...
, 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 bile ...
is the main form of B12 excretion; most of the B12 secreted in the bile is recycled via enterohepatic circulation
Enterohepatic circulation refers to the circulation of biliary acids, bilirubin, drugs or other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver. ...
. 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
Porphobilinogen (PBG) is an organic compound that occurs in living organisms as an intermediate in the biosynthesis of porphyrins, which include critical substances like hemoglobin and chlorophyll.
The structure of the molecule can be described a ...
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
Uroporphyrinogen III is a tetrapyrrole, the first macrocyclic intermediate in the biosynthesis of heme, chlorophyll, vitamin B12, and siroheme. It is a colorless compound, like other porphyrinogens.
Structure
The molecular structure of uroporphyri ...
. The latter is the first macrocyclic
Macrocycles are often described as molecules and ions containing a ring of twelve or more atoms. Classical examples include the crown ethers, calixarenes, porphyrins, and cyclodextrins. Macrocycles describe a large, mature area of chemistry.
...
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 "consisti ...
, 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 a ...
, 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
Genetic engineering, also called genetic modification or genetic manipulation, is the modification and manipulation of an organism's genes using technology. It is a set of technologies used to change the genetic makeup of cells, including t ...
strain of ''Pseudomonas denitrificans
''Pseudomonas denitrificans'' is a Gram-negative aerobic bacterium that performs denitrification. It was first isolated from garden soil in Vienna, Austria. It overproduces cobalamin ( vitamin B12), which it uses for methionine synthesis and it h ...
'' 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 t ...
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 par ...
shermanii'', ''Pseudomonas
''Pseudomonas'' is a genus of Gram-negative, Gammaproteobacteria, belonging to the family Pseudomonadaceae and containing 191 described species. The members of the genus demonstrate a great deal of metabolic diversity and consequently are able ...
'' ''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-positive, ...
'' ''griseus'', ''Acetobacterium
''Acetobacterium'' is a genus of anaerobic, Gram-positive bacteria that belong to the Eubacteriaceae family.
The type species of this genus is ''Acetobacterium woodii''. The name, ''Acetobacterium'', has originated because they are acetogens ...
'', ''Aerobacter
''Enterobacter'' is a genus of common Gram-negative, facultatively anaerobic, rod-shaped, non-spore-forming bacteria of the family Enterobacteriaceae. It is the type genus of the order Enterobacterales. Several strains of these bacteria are pat ...
'', ''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'' is ...
'', '' Alcaligenes'', '' Azotobacter'', '' 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 ag ...
'', ''Corynebacterium
''Corynebacterium'' () is a genus of Gram-positive bacteria and most are aerobe, aerobic. They are bacillus (shape), bacilli (rod-shaped), and in some phases of life they are, more specifically, club (weapon), club-shaped, which inspired the gen ...
'', ''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 cause ...
'', ''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 diver ...
'', ''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 sources o ...
'', ''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'') and ...
'', ''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 spec ...
'', ''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 fur ...
'', ''Serratia
''Serratia'' is a genus of Gram-negative, facultatively anaerobic, rod-shaped bacteria of the family Yersiniaceae. According to the List of Prokaryotic names with Standing Nomenclature (LPSN), there are currently 19 species of ''Serratia'' that ar ...
'', ''Streptococcus
''Streptococcus'' is a genus of gram-positive ' (plural ) or spherical bacteria that belongs to the family Streptococcaceae, within the order Lactobacillales (lactic acid bacteria), in the phylum Bacillota. Cell division in streptococci occurs ...
'' and ''Xanthomonas
''Xanthomonas'' (from greek: ''xanthos'' – “yellow”; ''monas'' – “entity”) is a genus of bacteria, many of which cause plant diseases. There are at least 27 plant associated ''Xanthomonas spp.'', that all together infect at least 400 ...
''.
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 ...
of selected microorganisms. ''Streptomyces griseus
''Streptomyces griseus'' is a species of bacteria in the genus ''Streptomyces'' commonly found in soil. A few strains have been also reported from deep-sea sediments. It is a Gram-positive bacterium with high GC content. Along with most other s ...
'', 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 from th ...
, was the commercial source of vitamin B12 for many years. The species ''Pseudomonas denitrificans
''Pseudomonas denitrificans'' is a Gram-negative aerobic bacterium that performs denitrification. It was first isolated from garden soil in Vienna, Austria. It overproduces cobalamin ( vitamin B12), which it uses for methionine synthesis and it h ...
'' and ''Propionibacterium freudenreichii
''Propionibacterium freudenreichii'' is a gram-positive, non-motile bacterium that plays an important role in the creation of Emmental cheese, and to some extent, Jarlsberg cheese, Leerdammer and Maasdam cheese. Its concentration in Swiss-type ch ...
'' 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 par ...
'', 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, simi ...
s or endotoxin
Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer ...
s 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 List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
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
Robert Burns Woodward (April 10, 1917 – July 8, 1979) was an American organic chemist. He is considered by many to be the most preeminent synthetic organic chemist of the twentieth century, having made many key contributions to the subject, e ...
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
, ac ...
) 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
Thomas J Addison (April 179329 June 1860) was an English physician, chef, and scientist. He is traditionally regarded as one of the "great men" of Guy's Hospital in London.
Among other pathologies, he discovered Addison's disease (a degenerati ...
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 fa ...
, 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 (medicine), residency program for spec ...
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
Ludwig Lichtheim (7 December 1845 in Breslau – 13 January 1928) was a German physician of Jewish descent.
Biography
He was educated at the Gymnasium (school), gymnasium in Breslau, and studied medicine at the universities of University of B ...
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 spina ...
.[ 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
George Hoyt Whipple (August 28, 1878 – February 1, 1976) was an American physician, pathologist, biomedical researcher, and medical school educator and administrator. Whipple shared the Nobel Prize in Physiology or Medicine in 1934 with George ...
discovered that ingesting large amounts of raw liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
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 r ...
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, accord ...
with William P. Murphy
William Parry Murphy (Stoughton, Wisconsin, February 6, 1892 – October 9, 1987) was an American physician who shared the Nobel Prize in Physiology or Medicine in 1934 with George Richards Minot and George Hoyt Whipple for their combined work ...
and George Minot
George Richards Minot (December 2, 1885 – February 25, 1950) was an American medical researcher who shared the 1934 Nobel Prize in Physiology or Medicine, Nobel Prize with George Hoyt Whipple and William P. Murphy for their pioneering work on p ...
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 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
Merck refers primarily to the German Merck family and three companies founded by the family, including:
* the Merck Group, a German chemical, pharmaceutical and life sciences company founded in 1668
** Merck Serono (known as EMD Serono in the Unite ...
, 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 a ...
from that company, developed the LLD assay. This identified "LLD factor" as essential for the bacteria's growth. Shorb, Folker and Alexander R. Todd
Alexander Robertus Todd, Baron Todd (2 October 1907 – 10 January 1997) was a British people, British biochemist whose research on the structure and biosynthesis, synthesis of nucleotides, nucleosides, and nucleotide coenzymes gained him the N ...
, 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 at ...
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 word ...
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 o ...
.[
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 ...
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 Vitamin B12, cobalamin, vitamin B12. Many steps are involved in converting aminolevulinic acid via uroporphyrinogen III and adenosylcobyric acid to the final forms in which it ...
* 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 fo ...
* Methylcobalamin
Methylcobalamin (mecobalamin, MeCbl, or MeB) is a cobalamin, a form of vitamin B. It differs from cyanocobalamin in that the cyano group at the cobalt is replaced with a methyl group. Methylcobalamin features an octahedral cobalt(III) centre and c ...
* Vitamin
A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an Nutrient#Essential nutrients, essential micronutrient that an organism needs in small quantities for the proper functioning of its ...
s
Further reading
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References
External links
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{{Authority control
B vitamins
Cofactors
Organocobalt compounds