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

Abstract

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- (FeA) and tetra-coordinations (FeB) 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 FeA(II)-•OH + FeB(II)-•OOH, the addition of H+/e forming FeA(II)-water, the O–O bond dissociation assisted by a hydrogen transfer from FeA(II)-water to FeB-bound oxygen to form a unique triple-hydroxyl intermediate of FeA(II)-•OH + FeB(II)-(•OH)2, a hydrogen transfer inside FeB(II)-(•OH)2 resulting in a FeA(II)-•OH and a high-valent FeB(IV)═O, the respective abstraction of the C9- and C10-hydrogens of substrates by FeB(IV)═O and FeA(II)-•OH producing alkene, and the regeneration of FeB(II)-•OH to FeB(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.