Enzymatic Mechanisms in Electron Transport Complexes

Electron transport complexes are multisubunit assemblies that couple redox chemistry to proton or ion translocation, thereby driving ATP synthesis and maintaining cellular redox balance. Central to their function are enzyme-bound cofactors—including flavin adenine dinucleotide (FAD), iron-sulfur clusters and haem groups—that mediate sequential one- or two-electron transfers. Substrate oxidation or reduction occurs at distinct catalytic sites, often separated by tens of ångströms, with intervening cofactors forming defined pathways for electron flow. Structural rearrangements and auxiliary assembly factors guide cofactor insertion and stabilise reaction intermediates, ensuring directional electron transfer and minimising deleterious side reactions such as reactive oxygen species formation. Advances in cryo-electron microscopy, X-ray crystallography and spectroscopic analysis have begun to resolve the atomic details of these mechanisms, revealing how conformational dynamics, cofactor binding sites and interdomain interactions underpin both physiological function and the molecular basis of disease-linked malfunctions.

Research from Nature Portfolio

High-resolution cryo-electron microscopy of a trimeric succinate dehydrogenase from Mycobacterium smegmatis has delineated two spatially distinct quinone-binding cavities and defined the electron-proton transfer pathway linking the FAD centre to the membrane-embedded quinone sites. The work uncovers a small membrane-anchored subunit that occludes the canonical quinone site and reveals a secondary distal pocket formed at protomer interfaces, offering a refined model for substrate access and drug targeting.

A captured assembly intermediate of Escherichia coli complex II has illuminated the mechanism of covalent flavinylation. Structural comparison with mature enzyme shows large-scale domain rotations and loop rearrangements that create a transient tunnel to the active site. An accessory protein modulates conformational equilibria, disfavouring turnover of succinate/fumarate and promoting flavin attachment, thereby orchestrating maturation of the holoenzyme.

Structural studies on the quinol:fumarate reductase from Desulfovibrio gigas have identified a bound menaquinone molecule proximate to a b-haem within the membrane subunit. This unexpected cofactor location suggests a supplementary redox centre that participates in proton-coupled electron transfer across the lipid bilayer, challenging previous models and highlighting species-specific adaptations in anaerobic respiratory chains.

Enzymatic Mechanisms in Electron Transport Complexes publication trend

The graph below shows the total number of articles in enzymatic mechanisms in electron transport complexes across all publications each year (not limited to Nature Index journals).

Technical terms

Flavoprotein: An enzyme subunit harbouring a flavin adenine dinucleotide cofactor that mediates two-electron transfers.

Iron-sulfur cluster: A prosthetic group composed of iron and inorganic sulphide ligands, serving as one-electron relay centres within proteins.

Quinone-binding site: A pocket within membrane subunits where ubiquinone or menaquinone accepts or donates electrons, often coupled to proton translocation.

Covalent flavinylation: The enzymatic attachment of a flavin cofactor to a protein via a permanent covalent bond, essential for catalytic competence in certain dehydrogenases.

Proton-coupled electron transfer (PCET): A mechanism where electron transfer is directly linked to proton movement, ensuring charge neutrality and efficient energy conversion.

References

1. Cryo-EM structure of trimeric Mycobacterium smegmatis succinate dehydrogenase with a membrane-anchor SdhF. Nature Communications (2020).
2. Crystal structure of an assembly intermediate of respiratory Complex II. Nature Communications (2018).
3. Structural insights into the electron/proton transfer pathways in the quinol:fumarate reductase from Desulfovibrio gigas. Scientific Reports (2018).
4. The unassembled flavoprotein subunits of human and bacterial complex II have impaired catalytic activity and generate only minor amounts of ROS. Journal of Biological Chemistry (2018).
5. Crystallographic Studies of the Escherichia coliQuinol-Fumarate Reductase with Inhibitors Bound to the Quinol-binding Site*. Journal of Biological Chemistry (2002).
6. The Iron-Sulfur Clusters in Escherichia coli Succinate Dehydrogenase Direct Electron Flow*. Journal of Biological Chemistry (2006).