The original coenzymes were small organic molecules that activated enzymes and participated directly in catalyzing enzymatic reactions. Most of them were derived from vitamins and were known as biologically “activated” forms of vitamins such as niacin, riboflavin, thiamine, and pyridoxal. Heme was in a separate category, perhaps because of its widespread biological role as an oxygen carrier, and because it was not a vitamin, it was not widely regarded as a coenzyme. However, heme was clearly an enzymatic prosthetic group in enzymes such as peroxidases and catalase, and it was known to participate in catalysis. Today, heme takes its place among the coenzymes. Other, more recently discovered metallic cofactors round out this chapter on metallocoenzymes. Most of the detailed mechanisms of metallocoenzyme-dependent reactions are not known. Hypothetical mechanisms can often be written, and some of them are supported by a few experiments. Emerging principles are emphasized here for several of the more extensively studied metallocoenzymes. In other cases, the detailed mechanisms that we include in figures and schemes must be regarded as conjectural. We do not regard them as fanciful, but they have not been proved and are referred to as “a mechanism for” in recognition that other possible mechanisms have not been excluded. Space does not permit all conceivable mechanisms to be aired, and we hope that those shown here will stimulate discussion and experimentation. Vitamin B12 coenzymes may be regarded as transitional from traditional coenzymes, in that the parent cyanocobalamin is a true vitamin, and its biologically activated forms adenosylcobalamin and methylcobalamin, with their covalent cobalt-carbon bonds, are organometallic compounds. For these reasons, we begin by discussing the vitamin B12 coenzymes. The structure in fig. 4-1 is that of adenosylcobalamin, the first B12 coenzyme to be discovered. The molecule consists of the tetradentate corrin ring, cobalt in its 3+ oxidation state held within the corrin ring, the lower axial dimethylbenzimidazole α-ribotide ligand linked by a phosphodiester group to the corrin, and the 5'-deoxyadenosyl moiety covalently bonded to cobalt. The corrin ring is structurally and biosynthetically related to heme, but it differs in a number of respects, including that it is more highly reduced and incorporates extensive stereochemistry.