Vitamin B12 is an essential vitamin for human health and lack of it leads to pernicious anaemia. This biological activity has attracted intense interest, and continues to do so; in addition, the complex architecture of the B12 molecule has fascinated chemists and biochemists since its discovery as the first natural organo-cobalt complex and the establishment of its structure by X-ray analysis. The organic ligand surrounding the cobalt displays many stereogenic centres around its periphery carrying reactive functional groups. This complexity led B12 to be rightly regarded as an extreme challenge to the synthetic chemist. Yet micro-organisms achieve this synthesis in vivo with complete control of regio- and stereochemistry. How do they do it? This Review tells the full remarkable story. Success in unravelling this biosynthetic puzzle came from a collaborative effort by biologists and chemists using the full range of approaches available from their disciplines. These extended from genetics at one end of the spectrum to synthesis and NMR at the other. This work can act as a guide for future research on the biosynthesis of yet more complex natural substances.
Department of Chemistry
University of Cambridge