Variations of the 2-His-1-carboxylate theme in mononuclear non-heme FeII oxygenases.

A facial triad of two histidine side chains and one aspartate or glutamate side chain forms the canonical metal-coordinating motif in the catalytic centers of various mononuclear non-heme Fe(II) enzymes. Although these active sites are based on totally unrelated protein folds and bring about a wide range of chemical transformations, most of them share the ability to couple dioxygen reduction with the oxygenation of an organic substrate. With the increasing number of protein structures now solved, it has become clear that the 2-His-1-carboxylate signature is less of a paradigm for non-heme Fe(II) active sites than had long been thought and that it can be replaced by alternative metal centers in various oxygenases, the structure-function relationships and proposed catalytic mechanisms of which are reviewed here. Metal coordination through three histidines and one glutamate constitutes the classical motif described for enzyme members of the cupin protein superfamily, such as aci-reductone dioxygenase and quercetin dioxygenase, multiple metal forms of which (including the Fe(II) type) are found in nature. Cysteine dioxygenase and diketone dioxygenase, which are strictly Fe(II)-dependent oxygenases based on the cupin fold, bind the catalytic metal through the homologous triad of histidines, but lack the fourth glutamate ligand. An alpha-ketoglutarate-dependent Fe(II) halogenase shows metal coordination by two histidines as the only protein-derived ligands, whilst carotene oxygenase, from a different protein fold family, features an Fe(II) site consisting of four histidine side chains. These recently discovered metallocenters are discussed with respect to their metal-binding properties and the reaction coordinates of the O(2)-dependent conversions they catalyze.