The discovery by Barker in 1958 of a biologically active cobalamin, required for the transformation of glutamate to-methylaspartate, heralded the discovery of a class of radical B12-dependent enzymes that catalyze isomerization reactions. 1 The stable cobalt (Co)-carbon bond of 5′-deoxyadenosylcobalamin (AdoCbl) or coenzyme B12 holds the key to the reactivity of AdoCbl and was revealed by the historical solution of the crystal structure of this cofactor by Hodgkin and co-workers in 1961. 2 AdoCbl is a portly member of the family of tetrapyrrolic-derived macrocyles (Figure 1). The corrin ring of cobalamin is more reduced and hence perhaps more ancient than its structural cousins, chlorin and heme, but it is more oxidized than the nickel-containing corphin ring. This affords the corrin ring some measure of flexibility that may be important in harnessing its reactivity in enzyme-catalyzed reactions. The cofactor, described as a “substance of frightening complexity”, 3 has several distinguishing structural attributes. Rings A and D are directly fused in the corrin ring instead of being bridged by a methylene group, and the biosynthetic pathway outfits the cofactor with an