Vitamin B12: Difference between revisions

The diets of vegetarians and vegans may not provide sufficient B₁₂ unless a dietary supplement is taken. A deficiency may be characterized by limb [[neuropathy]] or a blood disorder called [[pernicious anemia]], [[Megaloblastic anemia|a type of anemia]] in which red blood cells become abnormally large. This can result in [[fatigue]], decreased ability to think, lightheadedness, shortness of breath, frequent [[infection]]s, [[Anorexia (symptom)|poor appetite]], [[Paresthesia|numbness]] in the hands and feet, depression, memory loss, confusion, [[Ataxia|difficulty walking]], [[Optic neuropathy|blurred vision]], irreversible nerve damage, and many others. If left untreated in infants, deficiency may lead to neurological damage and anemia. [[Folate]] levels in the individual may affect the course of pathological changes and symptomatology of vitamin B₁₂ deficiency. Vitamin B₁₂ deficiency in pregnant women is strongly associated with an increased risk of spontaneous abortion, congenital malformations such as neural tube defects, problems with brain development growth in the unborn child.

Cyanocobalamin is the most common form used in dietary supplements and [[food fortification]] because cyanide stabilizes the molecule against degradation. Methylcobalamin is also offered as a dietary supplement. There is no advantage to the use of adenosylcobalamin or methylcobalamin forms for the treatment of vitamin B₁₂ deficiency.

Some research shows that most people in the United States and the United Kingdom consume sufficient vitamin B₁₂. However, other research suggests that the proportion of people with low or marginal levels of vitamin B₁₂ is up to 40% in the [[Western world]]. [[Grain]]-based foods can be [[food fortification|fortified]] by having the vitamin added to them. Vitamin B₁₂ supplements are available as single or multivitamin tablets. [[Pharmaceutical]] preparations of vitamin B₁₂ may be given by [[intramuscular injection]]. Since there are few non-animal sources of the vitamin, [[vegan]]s are advised to consume a [[dietary supplement]] or fortified foods for B₁₂ intake, or risk serious health consequences. Children in some regions of [[developing countries]] are at particular risk due to increased requirements during growth coupled with diets low in animal-sourced foods.

Pseudovitamin-B₁₂ refers to B₁₂-like analogues that are biologically inactive in humans. Most cyanobacteria, including ''[[Spirulina (dietary supplement)|Spirulina]]'', and some algae, such as ''[[Porphyra]] tenera'' (used to make a dried seaweed food called [[nori]] in Japan), have been found to contain mostly pseudovitamin-B₁₂ instead of biologically active B₁₂. These pseudo-vitamin compounds can be found in some types of shellfish, in edible insects, and at times as metabolic breakdown products of cyanocobalamin added to dietary supplements and fortified foods.

Vitamin B₁₂ is the most chemically complex of all the vitamins. The structure of B₁₂ is based on a [[corrin]] ring, which is similar to the [[porphyrin]] ring found in [[heme]]. The central metal ion is [[cobalt]].  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" (B_12r, +2 oxidation state) and "super-reduced" (B_12s, +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).

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|''Lactobacillus delbrueckii'' subsp. ''lactis'']] ATCC7830. However, it is no longer the reference method due to the high measurement uncertainty of vitamin B₁₂.

[[Methionine synthase]], coded by ''MTR'' gene, is a methyltransferase enzyme which uses the MeB₁₂ and reaction type 2 to transfer a methyl group from [[5-methyltetrahydrofolate]] to [[homocysteine]], thereby generating [[tetrahydrofolate]] (THF) and [[methionine]]. This functionality is lost in [[vitamin B12 deficiency|vitamin B₁₂ deficiency]], resulting in an increased [[homocysteine]] level and the trapping of [[folate]] as 5-methyl-tetrahydrofolate, from which THF (the active form of folate) cannot be recovered. THF plays an important role in DNA synthesis, so reduced availability of THF results in ineffective production of cells with rapid turnover, in particular red blood cells, and also intestinal wall cells which are responsible for absorption. THF may be regenerated via MTR or may be obtained from fresh folate in the diet. Thus all of the DNA synthetic effects of B₁₂ deficiency, including the [[megaloblastic anemia]] of [[pernicious anemia]], 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 [[:wikt:facultative|facultative]] 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.

Vitamin B₁₂ is absorbed by a B₁₂-specific transport proteins or via passive diffusion. Transport-mediated absorption and tissue delivery is a complex process involving three transport proteins: [[haptocorrin]] (HC), [[intrinsic factor]] (IF) and [[transcobalamin II]] (TC2), and respective membrane receptor proteins. HC is present in saliva. As vitamin-containing food is digested by [[hydrochloric acid]] and [[pepsin]] secreted into the stomach, HC binds the vitamin and protected it from acidic degradation. Upon leaving the stomach the hydrochloric acid of the [[chyme]] is neutralized in the [[duodenum]] by [[sodium bicarbonate|bicarbonate]], and pancreatic proteases release the vitamin from HC, making it available to be bound by IF, which is a protein secreted by gastric [[parietal cell]]s in response to the presence of food in the stomach. IF delivers the vitamin to receptor proteins [[cubilin]] and [[amnionless]], which together form the [[cubam]] receptor in the distal [[ileum]]. The receptor is specific to the IF-B₁₂ complex, and so will not bind to any vitamin content that is not bound to IF.

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 2–5{{nbsp}}mg 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]] is the main form of B₁₂ excretion; most of the B₁₂ secreted in the bile is recycled via [[enterohepatic circulation]]. Excess B₁₂ beyond the blood's binding capacity is typically excreted in urine. Owing to the extremely efficient enterohepatic circulation of B₁₂, the liver can store 3 to 5 years' worth of vitamin B₁₂; therefore, nutritional deficiency of this vitamin is rare in adults in the absence of malabsorption disorders. In the absence of enterohepatic reabsorption, only months to a year of vitamin B₁₂ are stored.

Industrial production of B₁₂ is achieved through [[Fermentation (biochemistry)|fermentation]] of selected microorganisms. ''[[Streptomyces griseus]]'', a bacterium once thought to be a [[fungus]], was the commercial source of vitamin B₁₂ for many years. The species ''[[Pseudomonas denitrificans]]'' and ''[[Propionibacterium freudenreichii]]'' subsp. ''shermanii'' are more commonly used today. These are grown under special conditions to enhance yield. [[Rhone-Poulenc]] improved yield via genetic engineering ''P. denitrificans''. ''[[Propionibacterium]]'', the other commonly used bacteria, produce no [[exotoxin]]s or [[endotoxin]]s and are generally recognized as safe (have been granted [[GRAS]] status) by the [[Food and Drug Administration]] of the United States.

The complete laboratory [[vitamin B12 total synthesis|synthesis of B₁₂]] was achieved by [[Robert Burns Woodward]] and [[Albert Eschenmoser]] in 1972. The work required the effort of 91 postdoctoral fellows (mostly at Harvard) and 12 PhD students (at [[ETH Zurich]]) 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.

Industrial production of vitamin B₁₂ is achieved through [[Fermentation (biochemistry)|fermentation]] 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 more than 70 steps and having a yield well below 0.01%.