Mechanism of electron transfers mediated by cytochromes and in mitochondria and endoplasmic reticulum: classical and murburn perspectives.

We explore the mechanism of electron transfers mediated by cytochrome , a soluble protein involved in mitochondrial oxidative phosphorylation and cytochrome , a microsomal membrane protein acting as a redox aide in xenobiotic metabolism. We found minimal conservation in the sequence and surface amino acid residues of cytochrome proteins among divergent species. Therefore, we question the evolutionary logic for electron transfer (ET) occurring through affinity binding via recognition of specific surface residues/topography. Also, analysis of putative protein-protein interactions in the crystal structures of these proteins and their redox partners did not point to any specific interaction logic. A comparison of the kinetic and thermodynamic constants of wildtype vs. mutants did not provide strong evidence to support the binding-based ET paradigm, but indicated support for diffusible reactive species (DRS)-mediated process. Topographically divergent cytochromes from one species have been substituted for reaction with proteins from other species, implying the involvement of non-specific interactions. We provide a viable alternative (murburn concept) to classical protein-protein binding-based long range ET mechanism. To account for the promiscuity of interactions and solvent-accessible hemes, we propose that the two proteins act as non- specific redox capacitors, mediating one-electron redox equilibriums involving DRS and unbound ions.Communicated by Ramaswamy H. Sarma.