The Heme Oxygenase-Like Diiron Enzyme HrmI Reveals Altered Regulatory Mechanisms for Dioxygen Activation and Substrate N-Oxygenation
Year: 2025
Type: article
Abstract: Nonheme diiron enzymes activate dioxygen (O 2 ) to affect various biochemical outcomes. HrmI, a member of the recently discovered and functionally versatile heme oxygenase-like dimetal oxidase/oxygenase (HDO) superfamily, catalyzes the N-oxygenation of L -Lysine to yield 6-nitronorleucine for the biosynthesis of the antibiotic hormaomycin. Unlike other characterized HDO N-oxygenases that have an additional carboxylate ligand thought to be key for regulating dioxygen activation and ensuing N-oxygenation, the predicted primary coordination sphere of HrmI resembles those of HDOs that instead perform C–C fragmentation of substrates. We show that diferrous HrmI reacts with O 2 in a substrate-independent manner to form a presumptive μ-1,2 (Fe 3+ ) 2 peroxo (or P ) intermediate common to the catalytic scheme of many HDOs. P is rapidly converted to a second species with both optical and Mössbauer properties that resemble an activated peroxodiferric adduct ( P’ ). The substrate-dependent acceleration of P’ decay suggests that it, rather than P, initiates l -Lysine metabolism. X-ray crystallographic studies of HrmI in several redox and ligand-bound states provide a stepwise view of structural changes during catalysis and, together with analytical approaches, capture a hydroxylamino metabolic intermediate en route to 6-nitronorleucine formation. The activation of peroxo species provides a key strategy that enables functional adaptation within the widely distributed HDO structural scaffold.
DOI: 10.1021/jacs.5c08814
Institutions: North Carolina State University, Carnegie Mellon University
Language: English
Subfield: Inorganic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Awards: G1229526393, G2149517906, G2371548206, Interdisciplinary Biochemistry Graduate Program, G262532246, G2889594291, Divergence of Carboxylate-Bridged Diiron Enzymes for Natural Product Biosynthesis, G303061748, G315621713, G4235786860, G4581610328, G4654690619, G498139845, G5496315722, G5570207115, G7396808078, G7863156295, G8207748872, G8382000481, G8925327636, A Synchrotron Radiation Structural Biology Resource, Investigating the involvement of small intestine in metformin's effect on hepatic lipid metabolism, Dissect Mechanism of Iron(II)/2-Oxoglutarate Dependent Enzymes Catalyzed Halogenation in Nucleotide Biosynthesis, G969889393
OpenAlex ID: W4413051412