Cobalamin biosynthesis is the process by which bacteria and archea make cobalamin, vitamin B12. Many steps are involved in converting aminolevulinic acid via uroporphyrinogen III and adenosylcobyric acid to the final forms in which it is used by enzymes in both the producing organisms and other species, including humans who acquire it through their diet.
The feature which distinguishes the two main biosynthetic routes is whether the cobalt that is at the catalytic site in the coenzyme is incorporated early (in anaerobic organisms) or late (in aerobic organisms) and whether oxygen is required. In both cases, the macrocycle that will form a coordination complex with the cobalt ion is a corrin ring, specifically one with seven carboxylate groups called cobyrinic acid. Subsequently, amide groups are formed on all but one of the carboxylates, giving cobyric acid, and the cobalt is ligated by an adenosyl group. In the final part of the biosynthesis, common to all organisms, an aminopropanol sidechain is added to the one free carboxylic group and assembly of the nucleotide loop, which will provide the second ligand for the cobalt, is completed.
Many prokaryotic species cannot biosynthesize adenosylcobalamin, but can make it from cobalamin which they assimilate from external sources. In humans, dietary sources of cobalamin are bound after ingestion as transcobalamins and converted to the coenzyme forms in which they are used.
Cobalamin
Cobalamin (vitamin B12) is the largest and most structurally complex vitamin. It consists of a modified tetrapyrrole, a corrin, with a centrally chelated cobalt ion and is usually found in one of two biologically active forms: methylcobalamin and adenosylcobalamin. Most prokaryotes, as well as animals, have cobalamin-dependent enzymes that use it as a cofactor, whereas plants and fungi do not 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 certain mammals, cobalamin is obtained through the diet, and is required for methionine synthase and methylmalonyl-CoA mutase. In humans, it plays essential roles in folate metabolism and in the synthesis of the citric acid cycle intermediate, succinyl-CoA.
Overview 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 leading to cobyrinic acid, with seven carboxylate groups. In the anaerobic pathway this already contains cobalt but in the aerobic pathway the material formed at that stage is hydrogenobyrinic acid, without the bound cobalt. Insertion of cobalt, where not already present; formation of amides on all but one of the carboxylate groups to give cobyric acid; attachment of an adenosyl group as ligand to the cobalt; attachment of an aminopropanol sidechain to the one free carboxylic group and assembly of the nucleotide loop which will provide the second ligand for the cobalt. A further type of synthesis occurs through a salvage pathway, where outside corrinoids are absorbed to make B12. Species from the following genera and the following individual species are known to synthesize cobalamin: Propionibacterium shermanii, Pseudomonas denitrificans, Streptomyces griseus, Acetobacterium, Aerobacter, Agrobacterium, Alcaligenes, Azotobacter, Bacillus, Clostridium, Corynebacterium, Flavobacterium, Lactobacillus, Micromonospora, Mycobacterium, Nocardia, Proteus, Rhizobium, Salmonella, Serratia, Streptococcus and Xanthomonas.
Detail of steps up to formation of uroporphyrinogen III
In the early steps of the biosynthesis, a tetrapyrrolic structural framework is created by the enzymes deaminase and cosynthetase which transform aminolevulinic acid via porphobilinogen and hydroxymethylbilane to uroporphyrinogen III. The latter is the first macrocyclic intermediate common to haem, chlorophyll, sirohaem and cobalamin itself.