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 chelatedcobalt. 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.[1] In mammals, cobalamin is obtained through the diet, and is required for methionine synthase and methylmalonyl-CoA mutase.[2]
There are at least two distinct cobalamin biosynthetic pathways in bacteria[3]:
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).[6]
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.
The CbiB or CobD protein converts cobyric acid to cobinamide by the addition of aminopropanol on the F carboxylic group. It is part of the cob operon.[7]
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).[8][9] 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.[9] 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).[9]
The CobS protein is a cobalamin-5-phosphate synthase that catyalzes the reactions:
The proteinproduct 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.[10][11]
CobW proteins are generally found proximal to the trimeric cobaltochelatase subunit CobN, which is essential for vitamin B12 (cobalamin) biosynthesis.[1] 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,[13] and urease accessory protein UreG, which acts as a chaperone in the activation of urease upon insertion of nickel into the active site.[14]
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.[19] CbiG is responsible for the opening of the delta-lactone ring and extrusion of the C2-unit.[20] 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.[20]
The CbiJ family of proteins includes the CobK and CbiJ precorrin-6x reductases EC1.3.1.54. 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.[21][22]
CbiM is an intergral membrane protein which is involved in cobalamin synthesis, its exact function in unknown.
The cobalttransportprotein CbiN is part of the active cobalt transport system involved in uptake of cobalt in to the cell involved with cobalaminbiosynthesis (vitamin B12). It has been suggested that CbiN may function as the periplasmic binding protein component of the active cobalt transport system.[16]
References
^ abRodionov DA, Vitreschak AG, Mironov AA, Gelfand MS (2003). "Comparative genomics of the vitamin B12 metabolism and regulation in prokaryotes". J. Biol. Chem. 278 (42): 41148–59. doi:10.1074/jbc.M305837200. PMID12869542. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
^Banerjee R (2006). "B12 trafficking in mammals: A for coenzyme escort service". ACS Chem. Biol. 1 (3): 149–59. doi:10.1021/cb6001174. PMID17163662. {{cite journal}}: Unknown parameter |month= ignored (help)
^Roessner CA, Santander PJ, Scott AI (2001). "Multiple biosynthetic pathways for vitamin B12: variations on a central theme". Vitam. Horm. 61: 267–97. PMID11153269.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^Heldt D, Lawrence AD, Lindenmeyer M, Deery E, Heathcote P, Rigby SE, Warren MJ (2005). "Aerobic synthesis of vitamin B12: ring contraction and cobalt chelation". Biochem. Soc. Trans. 33 (Pt 4): 815–9. doi:10.1042/BST0330815. PMID16042605. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^Roessner CA, Huang KX, Warren MJ, Raux E, Scott AI (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): 1845–53. PMID12055304. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^Raux E, Schubert HL, Warren MJ (2000). "Biosynthesis of cobalamin (vitamin B12): a bacterial conundrum". Cell. Mol. Life Sci. 57 (13–14): 1880–93. PMID11215515. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^Roth JR, Lawrence JG, Bobik TA (1996). "Cobalamin (coenzyme B12): synthesis and biological significance". Annu. Rev. Microbiol. 50: 137–81. doi:10.1146/annurev.micro.50.1.137. PMID8905078.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ abcFodje MN, Hansson A, Hansson M, Olsen JG, Gough S, Willows RD, Al-Karadaghi S (2001). "Interplay between an AAA module and an integrin I domain may regulate the function of magnesium chelatase". J. Mol. Biol. 311 (1): 111–22. doi:10.1006/jmbi.2001.4834. PMID11469861. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^Maggio-Hall LA, Claas KR, Escalante-Semerena JC (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): 1385–95. PMID15133100. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^Thompson TB, Thomas MG, Escalante-Semerena JC, Rayment I (1998). "Three-dimensional structure of adenosylcobinamide kinase/adenosylcobinamide phosphate guanylyltransferase from Salmonella typhimurium determined to 2.3 A resolution,". Biochemistry. 37 (21): 7686–95. doi:10.1021/bi973178f. PMID9601028. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^Hashimoto Y, Nishiyama M, Horinouchi S, Beppu T (1994). "Nitrile hydratase gene from Rhodococcus sp. N-774 requirement for its downstream region for efficient expression". Biosci. Biotechnol. Biochem. 58 (10): 1859–65. PMID7765511. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^Zambelli B, Musiani F, Savini M, Tucker P, Ciurli S (2007). "Biochemical studies on Mycobacterium tuberculosis UreG and comparative modeling reveal structural and functional conservation among the bacterial UreG family". Biochemistry. 46 (11): 3171–82. doi:10.1021/bi6024676. PMID17309280. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^Roessner CA, Williams HJ, Scott AI (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): 16748–53. doi:10.1074/jbc.M501805200. PMID15741157. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
