A new era for electron bifurcation

Abstract

Electron bifurcation, or the coupling of exergonic and endergonic oxidation-reduction reactions, was discovered by Peter Mitchell and provides an elegant mechanism to rationalize and understand the logic that underpins the Q cycle of the respiratory chain. Thought to be a unique reaction of respiratory complex III for nearly 40 years, about a decade ago Wolfgang Buckel and Rudolf Thauer discovered that flavin-based electron bifurcation is also an important component of anaerobic microbial metabolism. Their discovery spawned a surge of research activity, providing a basis to understand flavin-based bifurcation, forging fundamental parallels with Mitchell's Q cycle and leading to the proposal of metal-based bifurcating enzymes. New insights into the mechanism of electron bifurcation provide a foundation to establish the unifying principles and essential elements of this fascinating biochemical phenomenon.

Figure 1.

The electron transport chain illustrating the electron transfer from the unifying currency of reducing equivalents in biology NADH and FADH₂ through three proton translocating respiratory complexes, I, III, and IV from the mitochondrial matrix (M) into the intermembrane space IM resulting in the eventual reduction of oxygen to water and the generation of proton motive force that is harnessed to drive ATP synthesis through an ATPase.

Figure 2.

Electron transfer in respiratory complex III and the “Q cycle” illustrating the transfer of electrons from QH₂ simultaneously to an FeS cluster and a b-type cytoctrome in an electron bifurcation reaction. The electron transferred to the FeS cluster is on path to the eventual reduction of cytochrome c (the substrate for complex IV). The electron transferred to cytochrome b will be coupled with an additional electron from the subsequent round of the Q cycle to reduce Q to QH₂. The link between the Q cycle and the generation of proton motif force is the oxidation of QH₂ and the release of protons in the intermembrane space (IM) and the reduction and consumption of protons in the matrix (M). On the right are the structures of the Q, SQ, and QH₂ states.

Figure 3.

Left: Nfn structure showing cofactor arrangements along pathways and distances between cofactors. Right: Redox potential (E) landscape for bifurcating Nfn. After bifurcation at L-FAD, the first electron flows uphill (red relay) eventually to NAD⁺, and the second electron flows downhill (blue relay), on a different physical pathway, to ferredoxin (Fd).

Figure 4.

The HydABC scaffold of proposed metal-site bifurcating enzymes (right) where the M site is the H cluster, the [NiFe]-site or the W/Mo-pyranopterin catalytic site (left) of the [FeFe]-hydrogenase, [NiFe]-hydrogenase or formate dehydrogenase, respectively.