Cyanocobalamin/ja: Difference between revisions

{{chem|B|12s}} is one of the most nucleophilic species known in aqueous solution. This property allows the convenient preparation of cobalamin analogs with different [[substituents]], via [[nucleophilic]] attack on [[alkyl halide]]s and vinyl halides.

For example, cyanocobalamin can be converted to its analog cobalamins via reduction to {{chem|B|12s}}, followed by the addition of the corresponding [[alkyl halides]], [[acyl halides]], [[alkene]] or [[alkyne]]. [[Steric hindrance]] is the major limiting factor in the synthesis of the {{chem|B|12}} coenzyme analogs. For example, no reaction occurs between [[neopentyl]] chloride and {{chem|B|12s}}, whereas the secondary alkyl halide analogs are too unstable to be isolated. This effect may be due to the strong coordination between [[benzimidazole]] and the central cobalt atom, pulling it down into the plane of the [[corrin]] ring. The [[trans effect]] determines the polarizability of the Co–C bond so formed. However, once the [[benzimidazole]] is detached from cobalt by quaternization with [[methyl iodide]], it is replaced by {{chem|H|2|O}} or [[hydroxyl]] ions. Various secondary alkyl halides are then readily attacked by the modified {{chem|B|12s}} to give the corresponding stable cobalamin analogs. The products are usually extracted and purified by phenol-methylene chloride extraction or by column chromatography.

Cobalamin analogs prepared by this method include the naturally occurring coenzymes [[methylcobalamin]] and [[cobamamide]], and other cobalamins that do not occur naturally, such as vinylcobalamin, carboxymethylcobalamin and cyclohexylcobalamin. This reaction is under review for use as a catalyst for [[chemical dehalogenation]], organic reagent and photosensitized catalyst systems.

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

==Production==

Cyanocobalamin is commercially prepared by [[bacterial fermentation]]. Fermentation by a variety of [[microorganism]]s yields a mixture of [[methylcobalamin]], [[hydroxocobalamin]] and [[adenosylcobalamin]]. These compounds are converted to cyanocobalamin by addition of [[potassium cyanide]] in the presence of [[sodium nitrite]] and heat. Since multiple species of ''[[Propionibacterium]]'' produce no [[exotoxin]]s or [[endotoxin]]s and have been granted [[GRAS]] status (generally regarded as safe) by the [[United States Food and Drug Administration]], they are the preferred bacterial fermentation organisms for vitamin {{chem|B|12}} production.

Historically, the physiological form was initially thought to be cyanocobalamin. This was because [[hydroxocobalamin]] produced by bacteria was changed to cyanocobalamin during purification in [[activated charcoal]] columns after separation from the bacterial cultures (because [[cyanide]] is naturally present in activated charcoal). Cyanocobalamin is the form in most pharmaceutical preparations because adding cyanide stabilizes the molecule.

The total world production of vitamin B₁₂, by four companies (the French Sanofi-Aventis and three Chinese companies) in 2008 was 35 tonnes.

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

== Metabolism ==

The two bioactive forms of vitamin {{chem|B|12}} are [[methylcobalamin]] in [[cytosol]] and [[adenosylcobalamin]] in [[mitochondria]]. Multivitamins often contain cyanocobalamin, which is presumably converted to bioactive forms in the body. Both methylcobalamin and adenosylcobalamin are commercially available as supplement pills. The [[MMACHC]] gene product catalyzes the decyanation of cyanocobalamin as well as the dealkylation of alkylcobalamins including methylcobalamin and adenosylcobalamin. This function has also been attributed to [[Cyanocobalamin reductase (cyanide-eliminating)|cobalamin reductases]]. The MMACHC gene product and cobalamin reductases enable the interconversion of cyano- and alkylcobalamins.

Cyanocobalamin is added to fortify nutrition, including baby milk powder, breakfast cereals and [[energy drinks]] for humans, also animal feed for poultry, swine and fish. Vitamin {{chem|B|12}} becomes inactive due to [[hydrogen cyanide]] and [[nitric oxide]] in cigarette smoke. Vitamin {{chem|B|12}} also becomes inactive due to [[nitrous oxide]] {{chem|N|2|O}} commonly known as laughing gas, used for [[anaesthesia]] and as a recreational drug. Vitamin {{chem|B|12}} becomes inactive due to microwaving or other forms of heating.

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

=== In the cytosol ===

[[Methylcobalamin]] and [[5-methyltetrahydrofolate]] are needed by [[methionine synthase]] in the [[methionine]] cycle to transfer a methyl group from [[5-methyltetrahydrofolate]] to [[homocysteine]], thereby generating [[tetrahydrofolate]] (THF) and [[methionine]], which is used to make [[SAMe]]. [[SAMe]] is the universal methyl donor and is used for [[DNA methylation]] and to make [[lipid bilayer|phospholipid]] [[cell membrane|membranes]], [[choline]], [[sphingomyelin]], [[acetylcholine]], and other [[neurotransmitters]].

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

=== In mitochondria ===

[[File:Odd-chain FA oxydation.png|thumb|upright|Vitamin {{chem|B|12}} [[adenosylcobalamin]] in [[mitochondrion]]—cholesterol and protein metabolism]]

The enzymes that use {{chem|B|12}} as a built-in cofactor are [[methylmalonyl-CoA mutase]] ([[Protein Data Bank|PDB]] 4REQ) and [[methionine synthase]] ([[Protein Data Bank|PDB]] 1Q8J).

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

The metabolism of [[propionyl-CoA]] occurs in the mitochondria and requires Vitamin {{chem|B|12}} (as [[adenosylcobalamin]]) to make [[succinyl-CoA]]. When the conversion of propionyl-CoA to succinyl-CoA in the mitochondria fails due to Vitamin {{chem|B|12}} deficiency, elevated blood levels of [[methylmalonic acid]] (MMA) occur. Thus, elevated blood levels of [[homocysteine]] and MMA may both be indicators of [[vitamin B12 deficiency|vitamin {{chem|B|12}} deficiency]].

[[Adenosylcobalamin]] is needed as [[cofactor (biochemistry)|cofactor]] in [[methylmalonyl-CoA mutase]]—MUT enzyme. Processing of cholesterol and protein gives [[propionyl-CoA]] that is converted to [[methylmalonyl-CoA]], which is used by [[methylmalonyl-CoA mutase|MUT enzyme]] to make [[succinyl-CoA]]. Vitamin {{chem|B|12}} is needed to prevent anemia, since making [[porphyrin]] and [[heme]] in [[mitochondria]] for producing hemoglobin in red blood cells depends on [[succinyl-CoA]] made by vitamin {{chem|B|12}}.