We two alone will sing: the two-substrate α-keto acid-dependent oxygenases

4-Hydroxyphenylpyruvate dioxygenase (HPPD) and hydroxymandelate synthase (HMS) are the only two known members of the α-keto acid-dependent oxygenases that adopt the fold common to the vicinal oxygen chelate superfamily of enzymes. All other oxygenases of this type have a jellyroll fold. Despite a clearly different ancestry, the salient details of HPPD and HMS catalysis are the same as all α-keto acid-dependent oxygenases. All α-keto acid-dependent oxygenases use reducing equivalents from an α-keto acid to reduce dioxygen via an active site ferrous ion mediator and then catalyze decarboxylation of the α-keto acid to promote the formation of a high valence iron-oxo species. The most common purpose of which is to then hydroxylate the substrate. This mini-review summarizes the structural and mechanistic data assembled in recent years for HPPD and HMS in the context of both their roles in nature and the vicinal oxygen chelate and α-keto acid-dependent oxygenases superfamilies.