New intermediates in the B12 pathway

Vitamin B12 has a complex structure which represents one of the most challenging biosynthetic problems in Nature. Exciting progress has been made by combining the techniques, approaches and strengths of chemistry, spectroscopy and biology. Most of the advances until recently came from experiments based either on labelling simpler precursors with radioactive isotopes followed by controlled degradation of the labelled products, or on the use of stable isotopes, 13C in particular, because it can be detected and its environment can be studied by NMR spectroscopy. These experiments imposed heavy demands on synthesis which provided the specifically labelled starting materials. More recently, the powerful methods of genetics and molecular biology have been added to the armoury, leading to another massive surge forward by allowing the preparation, through gene overexpression, of large quantities of the enzymes of the biosynthetic pathway. Equally important has been the generation of mutant forms of B12-producing organisms in which the biosynthetic pathway is blocked at specific points. Here I focus on the latest advances. The structures of the newly discovered intermediates are described and some of the chemistry involved is explored. In conclusion, the presently known pathway to vitamin B12 is reviewed.