If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Synonyms: anaerobic adenosylcobalamin biosynthesis, vitamin B12 biosynthesis
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Vitamins Biosynthesis → Cobalamin Biosynthesis → Adenosylcobalamin Biosynthesis|
Some taxa known to possess this pathway include : Bacillus megaterium , Chlorobaculum tepidum , Leptospira interrogans , Methanocaldococcus jannaschii , Methanothermobacter thermautotrophicus , Propionibacterium freudenreichii , Propionibacterium freudenreichii shermanii , Salmonella enterica enterica serovar Typhimurium
Vitamin B12 (also known as adenosylcobalamin or coenzyme B12) was discovered in the 1920s after Minot and Murphy reported that they could cure the symptoms of pernicious anaemia by feeding patients with crude liver extract [Minot26] (they received the Nobel prize in 1934 for this discovery). The unknown factor has been isolated and subsequently crystallized in 1948 [Smith48, Rickes48], and was given the name vitamin B12 and, as it was shown to contain a cobalt ion, cobalamin [Warren02].
Vitamin B12 is one of the most structurally complex small molecules made in Nature. It contains a contracted porphinoid ring with a cobalt ion ligated at its center and further held in place by a lower axial base (a dimethylbenzimidazole) and an upper methyl or adenosyl group. Its biosynthesis is similarly complex, and requires more than thirty genes. It's biosynthesis is confined to only some bacteria and archaea [Martens02].
Two main pathways are known for coenzyme B12 biosynthesis - an aerobic pathway (see adenosylcobalamin biosynthesis II (late cobalt incorporation)) and an anaerobic pathway (this pathway). The main differences between these pathways are the timing of the Co2+ ion insertion and the ring-contraction mechanism (for more about ring contraction, see [Rasetti81]). Co2+ is inserted early on in the anaerobic pathway, and rather late in the aerobic pathway. The two different routes then merge at cob(II)yrinate a,c-diamide, and the latter part of the pathway is identical, or at least very similar.
About This Pathway
The best characterized anaerobic pathway is the one from Salmonella enterica enterica serovar Typhimurium, although much of the early work was performed with the bacterium Propionibacterium freudenreichii shermanii and much of the more recent work was done with the bacterium Bacillus megaterium.
The biosynthesis of coenzyme B12 starts with the biosynthesis of the tetrapyrrole intermediate uroporphyrinogen-III, a common intermediate in the biosynthesis of several important compounds such as heme and chlorophyl. Uroporphyrinogen-III is converted to a corrin ring by a complex process that involves (among other things) the attachment of eight methyl groups, all derived from S-adenosyl-L-methionine (SAM). During the process the ring contracts via bonding of carbons C-1 and C-19, eliminating carbon C-20 from the ring. This contraction process converts the ring from a porphyrin ring to a corrin ring. Both the C-20 carbon and the added C-20 methyl group are lost in the form of acetaldehyde.
The intermediates formed prior to the formation of the corrin ring are called precorrins. The precorrins are numbered corresponding to the number of methyl groups that have been already introduced. If two different intermediates have the same number of methyl groups, they are also labeled by A or B (as in precorrin-6A). If there is still some uncertainty about an intermediate, it is given a temporary designation of X or Y.
There is indeed some uncertainty about the path from precorrin-2 to cobalt-precorrin-3. Early work, performed mostly with Salmonella enterica, suggested that this transition may be catalyzed in two steps - the insertion of cobalt into precorrin-2, which is catalyzed by cbiK, followed by methylation by cbiL. However, information gathered from multiple studies, most recently with the aerobic bacterium Bacillus megaterium that posseses a complete anaerobic pathway, suggests that this conversion may proceed through the oxidized factor intermediates, which is favored for the ease of cobalt insertion. Thus, precorrin-2 is first oxidized to sirohydrochlorin by cysG. Cobalt in then inserted (either by cbiK or cbiX), followed by methylation to cobalt-factor III and reduction to cobalt-precorrin-3 [Raux03, Frank07a, Frank05a, Leech03, Brindley03, Moore13].
The first intermediate with a corrin ring is cobyrinate. However, this intermediate still needs to be modified extensively. Successive amidation reactions transfer amide groups from two L-glutamine molecules to the carboxy groups a and c, resulting in cob(II)yrinate a,c-diamide. The Co2+ ion is then reduced to Co1+, and the molecule is adenosylated to form adenosyl-cobyrinate a,c-diamide. Additional amidation of the carboxyl groups b, d, e and g generates adenosylcobyrate. At this point the lower ligand base is synthesized and tethered to the corrin ring via a structure known as the nucleotide loop, which is composed of some form of (R)-1-aminopropan-2-ol and 5,6-dimethylbenzimidazole. More information about the biosynthesis of these side chains is provided at aminopropanol phosphate biosynthesis I and 5,6-dimethylbenzimidazole biosynthesis.
There is some uncertainty about the order in which some of the final reactions of the pathway occur. Depending on the order of the reactions, different intermediates may form. Recent findings suggest that (R)-1-amino-2-propanol O-2-phosphate is formed and added to adenosylcobyrate, forming |adenosyl-cobinamide phosphate, which is then phosphorylated by GTP to form adenosylcobinamide-GDP.
At least in Salmonella enterica enterica serovar Typhimurium α-ribazole 5'-phosphate, which is formed from 5,6-dimethylbenzimidazole, is then added, forming adenosylcobalamin 5'-phosphate [Zayas07a]. The last reaction in the pathway is the dephosphorylation of adenosylcobalamin 5'-phosphate to coenzyme B12.
coenzyme B12 biosynthesis in archaea
It is well documented that some archaebacteria synthesize and require cobamides to live. For example, methanogens contain extraordinarily high concentrations of cobamides, in the form of cobalt-factor III and Pseudo B12, which are required for methanogenesis from H2, CO2, acetate and methanol [Buan06, Yin06, Hagemeier06] (for a review see [DiMarco90]). Other archaea, such as the halophile Halobacterium sp. NRC-1 [Woodson03a], the sulfur metabolizing Acidianus ambivalens [Krautler88] and the thermophile Moorella thermoacetica [Das07] also require cobamides. Comparative genomics studies find cobalamin biosynthetic genes in many archaea [Rodionov03a]. However, at this point the actual pathways employed by archaebacteria are not well understood.
Subpathways: cob(II)yrinate a,c-diamide biosynthesis I (early cobalt insertion) , adenosylcobalamin biosynthesis from cobyrinate a,c-diamide I , tetrapyrrole biosynthesis I (from glutamate) , aminopropanol phosphate biosynthesis I , 5,6-dimethylbenzimidazole biosynthesis
Variants: adenosylcobalamin biosynthesis II (late cobalt incorporation) , adenosylcobalamin salvage from cobalamin , adenosylcobalamin salvage from cobinamide I , adenosylcobalamin salvage from cobinamide II
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