From Alkane to Alkene: The Inert Aliphatic C-H Bond Activation Presented by Binuclear Iron Stearoyl-CoA Desaturase with a Long di-Fe Distance of 6 Å

The desaturation of inert aliphatic C-H bonds from alkane to alkene, the initial step in biological fatty acid metabolism, can be catalyzed by a nonheme di-iron (NHFe₂) stearoyl-CoA desaturase (SCD1) with the longest di-Fe distance of >6 Å known in NHFe₂ enzymes. The SCD1 di-iron core is devised by nine histidines with penta- (Fe_A) and tetra-coordinations (Fe_B) mixed. Utilizing density functional theory calculations, we demonstrate that SCD1 employs a mechanism unknown previously in other NHFe₂ enzymes, which involves the binding of O₂/water leading to Fe_A(II)-^•OH + Fe_B(II)-^•OOH, the addition of H⁺/e forming FeA(II)-water, the O-O bond dissociation assisted by a hydrogen transfer from Fe_A(II)-water to Fe_B-bound oxygen to form a unique triple-hydroxyl intermediate of Fe_A(II)-^•OH + Fe_B(II)-(^•OH)₂, a hydrogen transfer inside Fe_B(II)-(^•OH)₂ resulting in a Fe_A(II)-^•OH and a high-valent Fe_B(IV)=O, the respective abstraction of the C₉- and C₁₀-hydrogens of substrates by Fe_B(IV)=O and Fe_A(II)-^•OH producing alkene, and the regeneration of Fe_B(II)-^•OH to Fe_B(II)-(OH₂)₂ with another H⁺/e added. The remote di-iron mixed with penta- and tetra-coordinations cooperates closely and achieves a good reactivity balance between O-O dissociation and hydrogen abstraction. The activity order of various Fe-containing species in the aliphatic C-H bond activation was obtained. Other important mechanistic characteristics and chemistry were also revealed. Our investigation lays a foundation for the design of low-cost and easily synthesized biomimetic catalysts for the aliphatic C-H bond activation, such as homogeneous di-Fe(II) complexes with pure N-containing ligands and heterogeneous porous Fe(II)-N metal-organic frameworks.