Recent discoveries in mono- and dinuclear nonheme iron enzymes: Emerging mechanisms and catalytic strategies

Nonheme iron enzymes encompass one of the most chemically versatile families of metalloenzymes, catalyzing an extraordinary range of oxidative transformations essential to metabolism, natural product biosynthesis, and environmental biodegradation. Despite their mechanistic diversity, these enzymes share a unifying principle: the controlled activation of molecular oxygen to drive selective substrate oxidation. Many mononuclear nonheme iron enzymes employ a conserved 2-His-1-carboxylate facial triad and frequently utilize 2-oxoglutarate (2OG) as a co-substrate to generate Fe(IV)O intermediates that mediate diverse C-H and CC bond oxidations. Organic cofactor-independent nonheme iron enzymes have been recognized for decades, with early examples including catechol dioxygenases and intradiol-cleaving enzymes. Structural and mechanistic advances over the past two decades have revealed that many of these cofactor-independent enzymes feature alternative 3-His or 4-His metal-binding motifs, which confer distinct electronic properties and enable oxygen activation pathways beyond those accessible to 2-His-1-carboxylate systems. Parallel advances in the study of dinuclear nonheme iron enzymes have illuminated equally rich mechanistic diversity, particularly within the ferritin-like (FDO) and heme-oxygenase-like (HDO) families. These diiron systems employ cooperative metal-metal interactions to form diiron-oxygen intermediates that enable multielectron oxidation chemistry beyond the reach of mononuclear centers. Structural and mechanistic studies of HDO-type enzymes involved in natural product biosynthetic pathways have revealed noncanonical coordination environments and substrate selectivity, underscoring the evolutionary and functional plasticity of nonheme iron catalysis. This review summarizes emerging insights into His-rich mononuclear enzymes and HDO-type diiron systems, highlighting their structural innovations, mechanistic principles, and collective contributions to expanding the frontiers of oxygen activation chemistry.