- Cobalamin biosynthesis
CobD_Cbib Identifiers Symbol CobD_Cbib Pfam PF03186 InterPro IPR004485 Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary CobS Identifiers Symbol CobS Pfam PF02654 InterPro IPR003805 Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary CobT Identifiers Symbol CobT Pfam PF06213 InterPro IPR006538 Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary CobU adenosylcobinamide kinase/adenosylcobinamide phosphate guanylyltransferase (cobu) from salmonella typhimurium Identifiers Symbol CobU Pfam PF02283 Pfam clan CL0023 InterPro IPR003203 SCOP 1cbu Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary cobW yjia protein Identifiers Symbol cobW Pfam PF02492 Pfam clan CL0023 InterPro IPR003495 SCOP 1nij Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary CobW C terminal yjia protein Identifiers Symbol CobW_C Pfam PF07683 InterPro IPR011629 SCOP 1nij Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary CbiA dethiobiotin synthetase complexed with 7,8-diamino-nonanoic acid, 5'-adenosyl-methylene-triphosphate, and manganese Identifiers Symbol CbiA Pfam PF01656 Pfam clan CL0023 InterPro IPR002586 SCOP 1dts Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary CbiD structural genomics, 1.9a crystal structure of cobalamin biosynthesis protein (cbid) from archaeoglobus fulgidus Identifiers Symbol CbiD Pfam PF01888 InterPro IPR002748 Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary CbiG N terminus Identifiers Symbol CbiG_N Pfam PF11760 InterPro IPR021744 Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary CbiG central region Identifiers Symbol CbiG_mid Pfam PF11761 InterPro IPR021745 Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary CbiG C terminus Identifiers Symbol CbiG_C Pfam PF01890 InterPro IPR002750 Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary CbiJ Identifiers Symbol CbiJ Pfam PF02571 InterPro IPR003723 Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary CbiM Identifiers Symbol CbiM Pfam PF01891 Pfam clan CL0315 InterPro IPR002751 Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary CbiN Identifiers Symbol CbiN Pfam PF02553 InterPro IPR003705 TCDB 3.A.1 Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary CbiQ Identifiers Symbol CbiQ Pfam PF02361 InterPro IPR003339 TCDB 3.A.1 Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary CbiX crystal structure of hypothetical protein af0721 from archaeoglobus fulgidus Identifiers Symbol CbiX Pfam PF01903 Pfam clan CL0043 InterPro IPR002762 Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary CbiZ Identifiers Symbol CbiZ Pfam PF01955 InterPro IPR002808 Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary
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 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
There are at least two distinct cobalamin biosynthetic pathways in bacteria:
- 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 220.127.116.11. 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 an integral membrane protein which is involved in cobalamin synthesis, its exact function in unknown.
The cobalt transport protein CbiN is part of the active cobalt transport system involved in uptake of cobalt in to 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.
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