From cobalt-precorrin-5B to acid a,c-diamide The steps from cobalt-precorrin-5B to acid a,c-diamide in the anaerobic pathway are essentially chemically identical to those in the aerobic sequence. The intermediates are called cobalt-precorrin-6A, cobalt-precorrin-6B, cobalt-precorrin-8 and cobyrinic acid. The enzymes in sequence are CbiD; Cobalt-precorrin-6A reductase (CbiJ, ); CbiT, Cobalt-precorrin-8 methylmutase (CbiC, ) and CbiA. The final enzyme forms acid a,c-diamide as the two pathways converge. Detail of steps from acid a,c-diamide to adenosylcobalamin Aerobic and anaerobic organisms share the same chemical pathway beyond acid a,c-diamide and this is illustrated for the cob gene products. From acid a,c-diamide to adenosylcobyric acid The cobalt(II) is reduced to by the enzyme CobR and then the enzyme CobO attaches an adenosyl ligand to the metal. Next, the enzyme CobQ converts all the carboxylic acids, except the propionic acid on ring D, to their primary amides. From adenosylcobyric acid to adenosylcobinamide phosphate In aerobic organisms, the enzyme CobCD now attaches (R)-1-amino-2-propanol (derived from threonine) to the propionic acid, forming adenosylcobinamide and the enzyme CobU phosphorylates the terminal hydroxy group to form adenosylcobinamide phosphate. The same final product is formed in anaerobic organisms by direct reaction of adenosylcobyric acid with (R)-1-amino-2-propanol O-2-phosphate (derived from threonine-O-phosphate by the enzyme CobD) catalysed by the enzyme CbiB. From adenosylcobinamide phosphate to adenosylcobalamin In a separate branch of the pathway, 5,6-dimethylbenzimidazole is biosynthesised from flavin mononucleotide by the enzyme 5,6-dimethylbenzimidazole synthase and converted by CobT to alpha-ribazole 5' phosphate. Then the enzyme CobU activates adenosylcobinamide phosphate by formation of adenosylcobinamide-GDP and CobV links the two substrates to form Adenosylcobalamin-5'-phosphate. In the final step to the coenzyme, CobC removes the 5' phosphate group: Adenosylcobalamin-5'-phosphate + H2O adenosylcobalamin + phosphate The complete biosynthetic route involves a long linear path that requires about 25 contributing enzyme steps. Other pathways of cobalamin metabolism Salvage pathways in prokaryotes Many prokaryotic species cannot biosynthesize adenosylcobalamin, but can make it from cobalamin. These organisms are capable of cobalamin transport into the cell and its conversion to the required coenzyme form. Even organisms such as Salmonella typhimurium that can make cobalamin also assimilate it from external sources when available. Uptake into cells is facilitated by ABC transporters which absorb the cobalamin through the cell membrane. Cobalamin metabolism in humans In humans, dietary sources of cobalamin are bound after ingestion as transcobalamins. They are then converted to the coenzyme forms in which they are used. Methylmalonic aciduria and homocystinuria type