Story of the Week  

Modeling Coenzyme B12


Nature transforms one chemical species into another by chemical reactions. These reactions in human body occur in the presence of some specific compounds called catalysts. Vitamins serve as catalysts and are required by all animals and human beings. Food constitutes one of the major sources of vitamins. B12 is one such vitamin whose biochemistry is very fascinating. It is largest of all vitamins and is the only vitamin which contains in it a metal ion, cobalt. It is apparently the only vitamin which requires a special mechanism for absorption into the body from the gut. There are fewer molecules of vitamin B12 in a man than there are red blood cells. An adult human body contains 4-5 mg of vitamin B12 of which 1mg is in the liver alone. Vitamin B12 deficiency leads to a variety of diseases which can now be cured easily by administering adequate amounts of vitamin B12. It catalyses a number of unusual reactions of which some are still without analogy in organic chemistry. The past five decades have recorded a very significant progress in vitamin B12 chemistry and biochemistry.

The study began in 1821 with a mysterious disease now known as pernicious anaemia, caused by B12 deficeiency. It took almost one hundered years to gain knowledge into the signs of the disease and it still remained uncurable. Following a lead from W. Whipple in California (1925), physians W. P. Murphy and G. R. Minot in Boston (1926) reported a remarkeble improvement in patients fed on a diet of raw liver. All three were awarded noble prize in physiology and medicine in 1934 for their discovery concerning liver therapy against anaemia.

The first phase of research was to isolate the compound (liver therapy factor) that was present in liver in a concentration of only 1 ppm. Glaxo and Merck scientists islated this red crystalline material which they named it as vitamin B12. It was extremly active against pernicious anaemia.

The second phase of reaserch was to elucidate the structure of B12 by chemical and physical methods and to evolve methods for large scale production. Dorothy Hodgkin of Oxford was awarded the noble prize in 1964 for elucidating the structure of this molecule. The work was an exciting episode in the history of X-ray crystallography because B12 was the largest structure studied successfully upto that time.

The third phase of research activity was aimed at the synthesis, properties, reactions and their precise role in enzymatic reactions. The total synthesis of this molecule with the correct number of substituents and stereochemistry was acheived in 1976. It took 11 years and a dedicated contribution of 100 chemists in a collaborative effort directed by R. B. Woodward, the noble laureate (Harvard) and A. Eichenmoser (Zurich).

So, coenzyme B 12 has long fascinated chemists due to its complex structure and because it offers the only biological instance of a stable organometallic bond. Its unique property arises from the different catalytic activity of two different coenzymes. How the CoC bond is activated towards homolysis or heterolysis is an enduring subject of research. Studies on model compounds have continued to complement those on the more complex cobalamin and B12 -based proteins. The chemistry and molecular structure of cobaloximes, RCo(dioxime) 2 B, have been of great interest to chemists because of two reasons. First, these are used as model compounds for the study of B12 coenzyme and second, the co-ordination chemistry of these complexes is far-reaching, with almost unlimited possibilities for substituents in the axial position and variation in the equatorial ligands. The recently available crystallographic data on cobalamins suggests that the structural effects of changes in R are similar to those found in cobaloximes and sometimes can be related to their chemical behavior. Our research on cobaloximes have furnished some insight into the factors that affect homolysis of the Co-C bond and have allowed in-depth analysis of the variation in the geometry of R-Co-B fragment (in terms of electronic and steric properties of R and B).

Professor B D Gupta
Department of Chemistry

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