Calculated Mechanism of Cyanobacterial Aldehyde-Deformylating Oxygenase: Asymmetric Aldehyde Activation by a Symmetric Diiron Cofactor

Cyanobacterial aldehyde-deformylating oxygenase (cADO) is a nonheme diiron enzyme that catalyzes the conversion of aldehyde to alk(a/e)ne, an important transformation in biofuel research. In this work, we report a highly desired computational study for probing the mechanism of cADO. By combining our QM/MM results with the available ⁵⁷Fe Mössbauer spectroscopic data, the gained detailed structural information suggests construction of asymmetry from the symmetric diiron cofactor in an aldehyde substrate and O₂ activation. His₁₆₀, one of the two iron-coordinate histidine residues in cADO, plays a pivotal role in this asymmetric aldehyde activation process by unprecedented reversible dissociation from the diiron cofactor, a behavior unknown in any other nonheme dinuclear or mononuclear enzymes. The revealed intrinsically asymmetric interactions of the substrate/O₂ with the symmetric cofactor in cADO are inspirational for exploring diiron subsite resolution in other nonheme diiron enzymes.