Biosynthesis Vitamin B12 is derived from a tetrapyrrolic structural framework 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 heme, chlorophyll, siroheme and B12 itself. Later steps, especially the incorporation of the additional methyl groups of its structure, were investigated using 13C methyl-labelled S-adenosyl methionine. It was not until a genetically engineered strain of Pseudomonas denitrificans was used, in which eight of the genes involved in the biosynthesis of the vitamin had been overexpressed, that the complete sequence of methylation and other steps could be determined, thus fully establishing all the intermediates in the pathway. Species from the following genera and the following individual species are known to synthesize B12: 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. Industrial Industrial production of B12 is achieved through fermentation of selected microorganisms. Streptomyces griseus, a bacterium once thought to be a fungus, was the commercial source of vitamin B12 for many years. The species Pseudomonas denitrificans and Propionibacterium freudenreichii subsp. shermanii are more commonly used today. These are grown under special conditions to enhance yield. Rhone-Poulenc improved yield via genetic engineering P. denitrificans. Propionibacterium, the other commonly used bacteria, produce no exotoxins or endotoxins and are generally recognized as safe (have been granted GRAS status) by the Food and Drug Administration of the United States. The total world production of vitamin B12 in 2008 was 35,000 kg (77,175 lb). Laboratory The complete laboratory synthesis of B12 was achieved by Robert Burns Woodward and Albert Eschenmoser in 1972. The work required the effort of 91 postdoctoral fellows (mostly at Harvard) and 12 PhD students (at ETH Zurich) from 19 nations. The synthesis constitutes a formal total synthesis, since the research groups only prepared the known intermediate cobyric acid, whose chemical conversion to vitamin B12 was previously reported. This synthesis of vitamin B12 is of no practical consequence due to its length, taking 72 chemical steps and giving an overall chemical yield well under 0.01%. Although there have been sporadic synthetic efforts since 1972, the Eschenmoser–Woodward synthesis remains the only completed (formal) total synthesis. History Descriptions of deficiency effects Between 1849 and 1887, Thomas Addison described a case of pernicious anemia, William Osler and William Gardner first described