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Cobalamin biosynthesis Edit Wikipedia article
adenosylcobinamide kinase/adenosylcobinamide phosphate guanylyltransferase (cobu) from salmonella typhimurium
|CobW C terminal|
dethiobiotin synthetase complexed with 7,8-diamino-nonanoic acid, 5'-adenosyl-methylene-triphosphate, and manganese
structural genomics, 1.9a crystal structure of cobalamin biosynthesis protein (cbid) from archaeoglobus fulgidus
|CbiG N terminus|
|CbiG central region|
|CbiG C terminus|
crystal structure of hypothetical protein af0721 from archaeoglobus fulgidus
In molecular biology, cobalamin biosynthesis is the synthesis of cobalamin (vitamin B12).
Cobalamin (vitamin B12) is a structurally complex cofactor, consisting of a modified tetrapyrrole with a centrally chelated cobalt. Cobalamin is usually found in one of two biologically active forms: methylcobalamin and adocobalamin. Most prokaryotes, as well as animals, have cobalamin-dependent enzymes, whereas plants and fungi do not appear to use it. In bacteria and archaea, these enzymes include methionine synthase, ribonucleotide reductase, glutamate and methylmalonyl-CoA mutases, ethanolamine ammonia-lyase, and diol dehydratase. In mammals, cobalamin is obtained through the diet, and is required for methionine synthase and methylmalonyl-CoA mutase.
Pathways of cobalamin biosynthesis
- Aerobic pathway that requires oxygen and in which cobalt is inserted late in the pathway; found in Pseudomonas denitrificans and Rhodobacter capsulatus.
- Anaerobic pathway in which cobalt insertion is the first committed step towards cobalamin synthesis; found in Salmonella typhimurium, Bacillus megaterium, and Propionibacterium freudenreichii subsp. shermanii.
Either pathway can be divided into two parts:
- Corrin ring synthesis (differs in aerobic and anaerobic pathways)
- Adenosylation of corrin ring, attachment of aminopropanol arm, and assembly of the nucleotide loop (common to both pathways).
Proteins involved in cobalamin biosynthesis
There are about 30 enzymes involved in either pathway, where those involved in the aerobic pathway are prefixed Cob and those of the anaerobic pathway Cbi. Several of these enzymes are pathway-specific: CbiD, CbiG, and CbiK are specific to the anaerobic route of S. typhimurium, whereas CobE, CobF, CobG, CobN, CobS, CobT, and CobW are unique to the aerobic pathway of P. denitrificans.
Aerobic cobalt chelatase consists of three subunits, CobT, CobN and CobS. Cobalamin (vitamin B12) can be complexed with metal via the ATP-dependent reactions (aerobic pathway) (e.g., in P. denitrificans) or via ATP-independent reactions (anaerobic pathway) (e.g., in Salmonella typhimurium). The corresponding cobalt chelatases are not homologous. However, aerobic cobalt chelatase subunits CobN and CobS are homologous to Mg-chelatase subunits BchH and BchI, respectively. CobT, too, has been found to be remotely related to the third subunit of Mg-chelatase, BchD (involved in bacteriochlorophyll synthesis, e.g., in Rhodobacter capsulatus).
The CobS protein is a cobalamin-5-phosphate synthase that catyalzes the reactions:
- Adenosylcobinamide-GDP + alpha-ribazole-5'-P = adenosylcobalamin-5'-phosphate + GMP
- Adenosylcobinamide-GDP + alpha-ribazole = adenosylcobalamin + GMP
The protein product from these catalyses is associated with a large complex of proteins and is induced by cobinamide. CobS is involved in part III of cobalamin biosynthesis, one of the late steps in adenosylcobalamin synthesis that, together with CobU, CobT, and CobC proteins, defines the nucleotide loop assembly pathway.
CobU proteins are bifunctional cobalbumin biosynthesis enzymes which display cobinamide kinase and cobinamide phosphate guanyltransferase activity. The crystal structure of the enzyme reveals the molecule to be a trimer with a propeller-like shape.
CobW proteins are generally found proximal to the trimeric cobaltochelatase subunit CobN, which is essential for vitamin B12 (cobalamin) biosynthesis. They contain a P-loop nucleotide-binding loop in the N-terminal domain and a histidine-rich region in the C-terminal portion suggesting a role in metal binding, possibly as an intermediary between the cobalt transport and chelation systems. CobW might be involved in cobalt reduction leading to cobalt(I) corrinoids. CobW-like proteins include P47K, a Pseudomonas chlororaphis protein needed for nitrile hydratase expression, and urease accessory protein UreG, which acts as a chaperone in the activation of urease upon insertion of nickel into the active site.
The CbiA family of proteins consists of various cobyrinic acid a,c-diamide synthases. These include CbiA and CbiP from Salmonella typhimurium., and CobQ from Rhodobacter capsulatus. These amidases catalyse amidations to various side chains of hydrogenobyrinic acid or cobyrinic acid a,c-diamide in the biosynthesis of cobalamin (vitamin B12) from uroporphyrinogen III.
CbiD is an essential protein for cobalamin biosynthesis in both Salmonella typhimurium and Bacillus megaterium. A deletion mutant of CbiD suggests that this enzyme is involved in C-1 methylation and deacylation reactions required during the ring contraction process in the anaerobic pathway to cobalamin (similar role as CobF). The CbiD protein has a putative S-AdoMet binding site. CbiD has no counterpart in the aerobic pathway.
CbiG proteins are specific for anaerobic cobalamin biosynthesis. CbiG, which shows homology with CobE of the aerobic pathway, participates in the conversion of cobalt-precorrin 5 into cobalt-precorrin 6. CbiG is responsible for the opening of the delta-lactone ring and extrusion of the C2-unit. The aerobic pathway uses molecular oxygen to trigger the events at C-20 leading to contraction and expulsion of the C2-unit as acetic acid from a metal-free intermediate, whereas the anaerobic route involves the internal delivery of oxygen from a carboxylic acid terminus to C-20 followed by extrusion of the C2-unit as acetaldehyde, using cobalt complexes as substrates.
The CbiJ family of proteins includes the CobK and CbiJ precorrin-6x reductases EC 188.8.131.52. In the aerobic pathway, CobK catalyses the reduction of the macrocycle of precorrin-6X to produce precorrin-6Y; while in the anaerobic pathway CbiJ catalyses the reduction of the macrocycle of cobalt-precorrin-6X into cobalt-precorrin-6Y.
CbiM is a transmembrane cobalamin transporter.
The cobalt transport protein CbiN is part of the active cobalt transport system involved in uptake of cobalt into the cell involved with cobalamin biosynthesis (vitamin B12). It has been suggested that CbiN may function as the periplasmic binding protein component of the active cobalt transport system.
The CbiQ family consists of various cobalt transport proteins Most of which are found in Cobalamin (Vitamin B12) biosynthesis operons. In Salmonella the cbiN cbiQ (product CbiQ in this family) and cbiO are likely to form an active cobalt transport system.
The CbiX protein functions as a cobalt-chelatase in the anaerobic biosynthesis of cobalamin. It catalyses the insertion of cobalt into sirohydrochlorin. The structure of CbiX from Archaeoglobus fulgidus consists of a central mixed beta-sheet flanked by four alpha-helices, although it is about half the size of other Class II tetrapyrrole chelatases. The CbiX proteins found in archaea appear to be shorter than those found in eubacteria.
The CbiZ family of proteins includes CbiZ, which is involved in the salvage pathway of cobinamide in archaea. Archaea convert adenosylcobinamide (AdoCbi) into adenosylcobinamide phosphate (AdoCbi-P) in two steps. First, the amidohydrolase activity of CbiZ cleaves off the aminopropanol moiety of AdoCbi yielding adenosylcobyric acid (AdoCby); second, AdoCby is converted into AdoCbi-P by the action of adenosylcobinamide-phosphate synthase (CbiB). Adenosylcobyric acid is an intermediate of the de novo coenzyme B12 biosynthetic route.
- Rodionov DA, Vitreschak AG, Mironov AA, Gelfand MS (October 2003). "Comparative genomics of the vitamin B12 metabolism and regulation in prokaryotes". J. Biol. Chem. 278 (42): 41148â€“59. doi:10.1074/jbc.M305837200. PMID 12869542.
- Banerjee R (April 2006). "B12 trafficking in mammals: A for coenzyme escort service". ACS Chem. Biol. 1 (3): 149â€“59. doi:10.1021/cb6001174. PMID 17163662.
- Roessner CA, Santander PJ, Scott AI (2001). "Multiple biosynthetic pathways for vitamin B12: variations on a central theme". Vitam. Horm. 61: 267â€“97. doi:10.1016/s0083-6729(01)61009-4. PMID 11153269.
- Heldt D, Lawrence AD, Lindenmeyer M, Deery E, Heathcote P, Rigby SE, Warren MJ (August 2005). "Aerobic synthesis of vitamin B12: ring contraction and cobalt chelation". Biochem. Soc. Trans. 33 (Pt 4): 815â€“9. doi:10.1042/BST0330815. PMID 16042605.
- Roessner CA, Huang KX, Warren MJ, Raux E, Scott AI (June 2002). "Isolation and characterization of 14 additional genes specifying the anaerobic biosynthesis of cobalamin (vitamin B12) in Propionibacterium freudenreichii (P. shermanii)". Microbiology (Reading, Engl.) 148 (Pt 6): 1845â€“53. PMID 12055304.
- Raux E, Schubert HL, Warren MJ (December 2000). "Biosynthesis of cobalamin (vitamin B12): a bacterial conundrum". Cell. Mol. Life Sci. 57 (13-14): 1880â€“93. doi:10.1007/PL00000670. PMID 11215515.
- Woodson JD, Zayas CL, Escalante-Semerena JC (December 2003). "A new pathway for salvaging the coenzyme B12 precursor cobinamide in archaea requires cobinamide-phosphate synthase (CbiB) enzyme activity". J. Bacteriol. 185 (24): 7193â€“201. doi:10.1128/jb.185.24.7193-7201.2003. PMC 296239. PMID 14645280.
- Roth JR, Lawrence JG, Bobik TA (1996). "Cobalamin (coenzyme B12): synthesis and biological significance". Annu. Rev. Microbiol. 50: 137â€“81. doi:10.1146/annurev.micro.50.1.137. PMID 8905078.
- Fodje MN, Hansson A, Hansson M, Olsen JG, Gough S, Willows RD, Al-Karadaghi S (August 2001). "Interplay between an AAA module and an integrin I domain may regulate the function of magnesium chelatase". J. Mol. Biol. 311 (1): 111â€“22. doi:10.1006/jmbi.2001.4834. PMID 11469861.
- Maggio-Hall LA, Escalante-Semerena JC (October 1999). "In vitro synthesis of the nucleotide loop of cobalamin by Salmonella typhimurium enzymes". Proc. Natl. Acad. Sci. U.S.A. 96 (21): 11798â€“803. doi:10.1073/pnas.96.21.11798. PMC 18366. PMID 10518530.
- Maggio-Hall LA, Claas KR, Escalante-Semerena JC (May 2004). "The last step in coenzyme B(12) synthesis is localized to the cell membrane in bacteria and archaea". Microbiology (Reading, Engl.) 150 (Pt 5): 1385â€“95. doi:10.1099/mic.0.26952-0. PMID 15133100.
- Thompson TB, Thomas MG, Escalante-Semerena JC, Rayment I (May 1998). "Three-dimensional structure of adenosylcobinamide kinase/adenosylcobinamide phosphate guanylyltransferase from Salmonella typhimurium determined to 2.3 A resolution,". Biochemistry 37 (21): 7686â€“95. doi:10.1021/bi973178f. PMID 9601028.
- Hashimoto Y, Nishiyama M, Horinouchi S, Beppu T (October 1994). "Nitrile hydratase gene from Rhodococcus sp. N-774 requirement for its downstream region for efficient expression". Biosci. Biotechnol. Biochem. 58 (10): 1859â€“65. doi:10.1271/bbb.58.1859. PMID 7765511.
- Zambelli B, Musiani F, Savini M, Tucker P, Ciurli S (March 2007). "Biochemical studies on Mycobacterium tuberculosis UreG and comparative modeling reveal structural and functional conservation among the bacterial UreG family". Biochemistry 46 (11): 3171â€“82. doi:10.1021/bi6024676. PMID 17309280.
- Pollich M, Klug G (August 1995). "Identification and sequence analysis of genes involved in late steps in cobalamin (vitamin B12) synthesis in Rhodobacter capsulatus". J. Bacteriol. 177 (15): 4481â€“7. PMC 177200. PMID 7635831.
- Roth JR, Lawrence JG, Rubenfield M, Kieffer-Higgins S, Church GM (June 1993). "Characterization of the cobalamin (vitamin B12) biosynthetic genes of Salmonella typhimurium". J. Bacteriol. 175 (11): 3303â€“16. PMC 204727. PMID 8501034.
- Roessner CA, Williams HJ, Scott AI (April 2005). "Genetically engineered production of 1-desmethylcobyrinic acid, 1-desmethylcobyrinic acid a,c-diamide, and cobyrinic acid a,c-diamide in Escherichia coli implies a role for CbiD in C-1 methylation in the anaerobic pathway to cobalamin". J. Biol. Chem. 280 (17): 16748â€“53. doi:10.1074/jbc.M501805200. PMID 15741157.
- Raux E, Lanois A, Warren MJ, Rambach A, Thermes C (October 1998). "Cobalamin (vitamin B12) biosynthesis: identification and characterization of a Bacillus megaterium cobI operon". Biochem. J. 335 (1): 159â€“66. PMC 1219764. PMID 9742225.
- Scott AI, Roessner CA (August 2002). "Biosynthesis of cobalamin (vitamin B(12))". Biochem. Soc. Trans. 30 (4): 613â€“20. doi:10.1042/bst0300613. PMID 12196148.
- Kajiwara Y, Santander PJ, Roessner CA, PÃƒÂ©rez LM, Scott AI (August 2006). "Genetically engineered synthesis and structural characterization of cobalt-precorrin 5A and -5B, two new intermediates on the anaerobic pathway to vitamin B12: definition of the roles of the CbiF and CbiG enzymes". J. Am. Chem. Soc. 128 (30): 9971â€“8. doi:10.1021/ja062940a. PMID 16866557.
- Kim W, Major TA, Whitman WB (December 2005). "Role of the precorrin 6-X reductase gene in cobamide biosynthesis in Methanococcus maripaludis". Archaea 1 (6): 375â€“84. doi:10.1155/2005/903614. PMC 2685584. PMID 16243778.
- Shearer N, Hinsley AP, Van Spanning RJ, Spiro S (November 1999). "Anaerobic growth of Paracoccus denitrificans requires cobalamin: characterization of cobK and cobJ genes". J. Bacteriol. 181 (22): 6907â€“13. PMC 94164. PMID 10559155.
- Roth, J. R.; Lawrence, J. G.; Rubenfield, M.; Kieffer-Higgins, S.; Church, G. M. (1993). "Characterization of the cobalamin (vitamin B12) biosynthetic genes of Salmonella typhimurium". Journal of bacteriology 175 (11): 3303â€“3316. PMC 204727. PMID 8501034.
- Yin J, Xu LX, Cherney MM, Raux-Deery E, Bindley AA, Savchenko A, Walker JR, Cuff ME, Warren MJ, James MN (March 2006). "Crystal structure of the vitamin B12 biosynthetic cobaltochelatase, CbiXS, from Archaeoglobus fulgidus". J. Struct. Funct. Genomics 7 (1): 37â€“50. doi:10.1007/s10969-006-9008-x. PMID 16835730.
- Brindley AA, Raux E, Leech HK, Schubert HL, Warren MJ (June 2003). "A story of chelatase evolution: identification and characterization of a small 13-15-kDa "ancestral" cobaltochelatase (CbiXS) in the archaea". J. Biol. Chem. 278 (25): 22388â€“95. doi:10.1074/jbc.M302468200. PMID 12686546.
- Woodson JD, Escalante-Semerena JC (March 2004). "CbiZ, an amidohydrolase enzyme required for salvaging the coenzyme B12 precursor cobinamide in archaea". Proc. Natl. Acad. Sci. U.S.A. 101 (10): 3591â€“6. doi:10.1073/pnas.0305939101. PMC 373507. PMID 14990804.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
CbiX Provide feedback
The function of CbiX is uncertain, however it is found in cobalamin biosynthesis operons and so may have a related function. Some CbiX proteins contain a striking histidine-rich region at their C-terminus, which suggests that it might be involved in metal chelation .
Raux E, Lanois A, Warren MJ, Rambach A, Thermes C; , Biochem J 1998;335:159-166.: Cobalamin (vitamin B12) biosynthesis: identification and characterization of a Bacillus megaterium cobI operon. PUBMED:9742225 EPMC:9742225
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR002762
Cobalamin (vitamin B12) is a structurally complex cofactor, consisting of a modified tetrapyrrole with a centrally chelated cobalt. Cobalamin is usually found in one of two biologically active forms: methylcobalamin and adocobalamin. Most prokaryotes, as well as animals, have cobalamin-dependent enzymes, whereas plants and fungi do not appear to use it. In bacteria and archaea, these include methionine synthase, ribonucleotide reductase, glutamate and methylmalonyl-CoA mutases, ethanolamine ammonia lyase, and diol dehydratase [PUBMED:12869542]. In mammals, cobalamin is obtained through the diet, and is required for methionine synthase and methylmalonyl-CoA mutase [PUBMED:17163662].
There are at least two distinct cobalamin biosynthetic pathways in bacteria [PUBMED:11153269]:
- Aerobic pathway that requires oxygen and in which cobalt is inserted late in the pathway [PUBMED:16042605]; found in Pseudomonas denitrificans and Rhodobacter capsulatus.
- Anaerobic pathway in which cobalt insertion is the first committed step towards cobalamin synthesis [PUBMED:12055304, PUBMED:23922391]; found in Salmonella typhimurium, Bacillus megaterium, and Propionibacterium freudenreichii subsp. shermanii.
Either pathway can be divided into two parts: (1) corrin ring synthesis (differs in aerobic and anaerobic pathways) and (2) adenosylation of corrin ring, attachment of aminopropanol arm, and assembly of the nucleotide loop (common to both pathways) [PUBMED:11215515]. There are about 30 enzymes involved in either pathway, where those involved in the aerobic pathway are prefixed Cob and those of the anaerobic pathway Cbi. Several of these enzymes are pathway-specific: CbiD, CbiG, and CbiK are specific to the anaerobic route of S. typhimurium, whereas CobE, CobF, CobG, CobN, CobS, CobT, and CobW are unique to the aerobic pathway of P. denitrificans.
This entry represents the CbiX protein, which functions as a cobalt-chelatase in the anaerobic biosynthesis of cobalamin. It catalyses the insertion of cobalt into sirohydrochlorin. The structure of CbiX from Archaeoglobus fulgidus consists of a central mixed beta-sheet flanked by four alpha-helices, although it is about half the size of other Class II tetrapyrrole chelatases [PUBMED:16835730]. The CbiX proteins found in archaea appear to be shorter than those found in eubacteria [PUBMED:12686546].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||metal ion binding (GO:0046872)|
|lyase activity (GO:0016829)|
|Biological process||cobalamin biosynthetic process (GO:0009236)|
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Metallated tetrapyrroles are used as prosthetic groups in proteins involved in biologically important processes such as photosynthesis, oxygen transport, drug metabolism and nitric oxide synthesis. In living organisms, metallation is catalysed by a group of enzymes called chelatases. This clan contains ferrochelatase (heme) and cobalt chelatase .
The clan contains the following 3 members:CbiK CbiX Ferrochelatase
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|Seed source:||Enright A|
|Author:||Enright A, Ouzounis C, Bateman A|
|Number in seed:||68|
|Number in full:||16106|
|Average length of the domain:||101.70 aa|
|Average identity of full alignment:||29 %|
|Average coverage of the sequence by the domain:||60.71 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 80369284 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||13|
|Download:||download the raw HMM for this family|
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Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There is 1 interaction for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the CbiX domain has been found. There are 18 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
Loading structure mapping...