This lesson addresses the curious case of why CoA makes a brief cameo in the citric acid cycle during the formation of succinyl CoA only to leave again in the next step. We dig into the chemistry underlying the high-energy thioester bond that CoA forms with acyl groups, which explains more broadly one of the key roles of sulfur in energy metabolism. We conclude by looking at how the appearance of CoA allows us to harness energy released during the decarboxylation of alpha-ketoglutarate to form ATP directly during “substrate-level phosphorylation,” or, alternatively, to use energy from ATP to invest in the synthesis of heme.