Cobalt - An Essential Element for Life

Cobalt appears centrally in the periodic table, and with its neighbours, iron, manganese, nickel and copper, has a vital rôle in a number of biochemical metalloenzyme reactions.

The disease, pernicious anæmia, was first described in 1821, and was invariably fatal. In 1926 Minot and Murphy, following Whipple's observation that anæmic dogs could be cured by feeding them raw liver, discovered that pernicious anæmia could also be treated by supplementing the human diet with liver. An intensive search for the "liver factor" was started. However cobalt's vital status was not proved until after World War II, in 1948, when the 'anti-pernicious anæmia factor', which became called Vitamin B12, was finally purified and isolated as crystals by Folkers and his co-workers at Merck Laboratories, and by Smith and Parker at Glaxo Laboratories. Small red crystals of Vitamin B12 were then grown by Lester Smith and given to Dorothy Hodgkin for X-ray crystal structure analysis. All that was known at this stage was that the approximate empirical formula was C61-64H84-90N14O 13-14PCo.

A crystal structure on a molecule of this size and complexity had never been attempted before, it was a huge and complex task, since crystal structure determinations were not the routine tasks that they are today, and the techniques were still being developed, both the X-ray and the computer equipment were tedious and difficult to use. Thus the X-ray crystal structure which emerged from this study between 1950 the early 1960s was the first determination of a chemical formula by X-ray diffraction, and the first determination of the structure of a metalloenzyme. It was a triumph for Dorothy Hodgkin and her Oxford X-ray crystallography group, inspiring many young crystallographers, and pointing them to biochemistry as an exciting new subject for their endevours. The structure work also caused Woodward (at Harvard) and Eschenmoser (at the Swiss Federal Institute of Technology) to start synthetic work on Vitamin B12. The synthesis took 11 more years, and involved more than 90 separate reactions performed by over 100 co-workers. The sterochemical puzzles involved in the synthesis led to the Woodward-Hoffman rules. This all adds up to three Nobel prizes in chemistry and one in medicine!

  1. Whipple(California), Minot and Murphy (Massachusetts) : (Physiology and Medicine) : the discovery of "anti-pernicious anæmia factor", now called Vitamin B12
  2. Dorothy Crowfoot Hodgkin (Oxford) : (Chemistry) : determinations by X-ray techniques of the structures of important biochemical substances.
  3. R.B.Woodward (Harvard) : (Chemistry) : outstanding achievements in the art of organic synthesis
  4. K.Fukui (Kyoto) and R.Hoffman (Cornell) : (Chemistry) : "for their theories, developed independently, concerning the course of chemical reactions" i.e. quantum mechanical studies of chemical reactivity.

The advances made during the past 50 years in Vitamin B12 research have been spectacular and are ongoing. In 1994 details of the binding site of methionine synthase from Escherichia coli were revealed. Thus, during the next 10 years, it is very likely that the three-dimensional structure of all the B12-dependent enzymes and their binding proteins will be resolved by either X-ray crystallography or by NMR spectroscopy. Indeed the numbers of papers published per year relating to B12 is nearly at the level seen in the early days of the research in the late1950s and early 1960s.