Vitamin B12/ja: Difference between revisions

<div lang="en" dir="ltr" class="mw-content-ltr">

==Biochemistry==

<div lang="en" dir="ltr" class="mw-content-ltr">

===Coenzyme function===

Vitamin B₁₂ functions as a [[coenzyme]], 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]]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]]s

#: Methyl (–CH₃) group transfers between two molecules. These use the MeB₁₂ (methylcobalamin) form of the vitamin.

# [[Dehalogenase]]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:

[[File:Folate methionine cycle.svg|thumb|Simplified schematic diagram of the folate methionine cycle. Methionine synthase transfers the methyl group to the vitamin and then transfers the methyl group to homocysteine, converting that to methionine.|400px]]

[[Methylmalonyl-CoA mutase|Methylmalonyl coenzyme A mutase]] (MUT) is an isomerase enzyme which uses the AdoB₁₂ form and reaction type 1 to convert [[L-methylmalonyl-CoA]] to [[succinyl-CoA]], an important step in the catabolic breakdown of some [[amino acid]]s into succinyl-CoA, which then enters energy production via the [[citric acid cycle]]. This functionality is lost in [[vitamin B12 deficiency|vitamin B₁₂ deficiency]], and can be measured clinically as an increased serum [[methylmalonic acid]] (MMA) concentration. The MUT function is necessary for proper [[myelin]] synthesis. Based on animal research, it is thought that the increased methylmalonyl-CoA hydrolyzes to form methylmalonate (methylmalonic acid), a neurotoxic dicarboxylic acid, causing neurological deterioration.

[[Methionine synthase]], coded by ''MTR'' gene, is a methyltransferase enzyme which uses the MeB₁₂ and reaction type 2 to transfer a methyl group from [[5-methyltetrahydrofolate]] to [[homocysteine]], thereby generating [[tetrahydrofolate]] (THF) and [[methionine]]. 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.

<div lang="en" dir="ltr" class="mw-content-ltr">

==Physiology==

===Absorption===

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.

Investigations into the intestinal absorption of B₁₂ confirm that the upper limit of absorption per single oral dose is about 1.5{{nbsp}}µg, with 50% efficiency. In contrast, the passive diffusion process of B₁₂ absorption — normally a very small portion of total absorption of the vitamin from food consumption — may exceed the haptocorrin- and IF-mediated absorption when oral doses of B₁₂ are very large, with roughly 1% efficiency. Thus, dietary supplement B₁₂ supplementation at 500 to 1000{{nbsp}}µg per day allows [[pernicious anemia]] and certain other defects in B₁₂ absorption to be treated with daily oral megadoses of B₁₂ without any correction of the underlying absorption defects.

After the IF/B₁₂ complex binds to cubam the complex is disassociated and the free vitamin is transported into the [[portal circulation]]. The vitamin is then transferred to TC2, which serves as the circulating plasma transporter,  Hereditary defects in production of TC2 and its receptor may produce functional deficiencies in B₁₂ and infantile [[megaloblastic anemia]], and abnormal B₁₂ related biochemistry, even in some cases with normal blood B₁₂ levels. For the vitamin to serve inside cells, the TC2-B₁₂ complex must bind to a cell receptor protein and be [[endocytosis|endocytosed]]. TC2 is degraded within a [[lysosome]], and free B₁₂ is released into the cytoplasm, where it is transformed into the bioactive coenzyme by cellular enzymes.

[[Antacid]] drugs that neutralize stomach acid and drugs that block acid production (such as [[proton-pump inhibitor]]s) will inhibit absorption of B₁₂ by preventing release from food in the stomach. Other causes of B12 malabsorption include [[intrinsic factor]] deficiency, [[pernicious anemia]], [[bariatric surgery]] pancreatic insufficiency, obstructive jaundice, tropical sprue and celiac disease, and radiation enteritis of the distal ileum. Age can be a factor. Elderly people are often [[achlorhydria|achlorhydric]] due to reduced stomach parietal cell function, and thus have an increased risk of B₁₂ deficiency.

<div lang="en" dir="ltr" class="mw-content-ltr">

===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 2–5{{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.

=== Cellular reprogramming ===

Vitamin B₁₂ through its involvement in one-carbon metabolism plays a key role in [[Induced pluripotent stem cell|cellular reprogramming]] and tissue regeneration and epigenetic regulation. Cellular reprogramming is the process by which somatic cells can be converted to a pluripotent state. Vitamin B₁₂ levels affect the histone modification [[H3K36me3]], which suppresses illegitimate transcription outside of [[Promoter (genetics)|gene promoters]]. Mice undergoing in vivo reprogramming were found to become depleted in B₁₂ and show signs of [[methionine]] starvation while supplementing reprogramming mice and cells with B₁₂ increased reprogramming efficiency, indicating a cell-intrinsic effect.