Disulfide Bond Formation in Prokaryotic Systems

Disulfide bond formation in prokaryotes secures the structural stability and function of many extra-cytoplasmic proteins. In Gram-negative bacteria this process is confined to the periplasm, where the thiol oxidase DsbA introduces disulfide bonds into nascent substrates and is re-oxidised by the membrane enzyme DsbB, which channels electrons into the respiratory chain. Mispaired disulfides are corrected by isomerases such as DsbC, itself maintained in a reduced state via DsbD. Gram-positive organisms exhibit a more diverse repertoire, with some lineages lacking canonical Dsb pathways but employing alternative oxidoreductases or cysteine exclusion strategies. These machineries are crucial for assembly of envelope components, virulence factors and stress sensors. Recent advances highlight auxiliary redox networks involving low-molecular-weight thiols (notably glutathione) that complement enzymatic catalysts under fluctuating oxidative conditions. Structural and biophysical studies have elucidated catalytic features such as proton-relay pathways and binding-site specificity, and these systems are emerging as promising targets for anti-virulence interventions.

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Disulfide Bond Formation in Prokaryotic Systems publication trend

The graph below shows the total number of articles in disulfide bond formation in prokaryotic systems across all publications each year (not limited to Nature Index journals).

Technical terms

Disulfide bond: A covalent linkage between the sulfur atoms of two cysteine residues that stabilises protein tertiary and quaternary structure.

Thiol-disulfide oxidoreductase: An enzyme that catalyses the formation, reduction or isomerisation of disulfide bonds to guide correct protein folding.

Periplasm: The compartment between the inner and outer membranes of Gram-negative bacteria where oxidative folding occurs.

DsbA: A periplasmic thiol oxidase in Gram-negative bacteria that introduces disulfide bonds into exported proteins.

Glutathione (GSH/GSSG): A low-molecular-weight thiol redox buffer, existing in reduced (GSH) and oxidised (GSSG) forms to maintain redox homeostasis.

References

1. The role of glutathione in periplasmic redox homeostasis and oxidative protein folding in Escherichia coli. Redox Biology (2023).
2. A cryptic oxidoreductase safeguards oxidative protein folding in Corynebacterium diphtheriae. Proceedings of the National Academy of Sciences of the United States of America (2023).
3. A Buried Water Network Modulates the Activity of the Escherichia coli Disulphide Catalyst DsbA. Antioxidants (2023).
4. Exploring the inhibitory potential of in silico-designed small peptides on Helicobacter pylori Hp0231 (DsbK), a periplasmic oxidoreductase involved in disulfide bond formation. Frontiers in Molecular Biosciences (2024).
5. Disulfide Bond Formation and Cysteine Exclusion in Gram-positive Bacteria* ♦. Journal of Biological Chemistry (2009).
6. Targeting Bacterial Dsb Proteins for the Development of Anti-Virulence Agents. Molecules (2016).
7. The Structure of the Bacterial Oxidoreductase Enzyme DsbA in Complex with a Peptide Reveals a Basis for Substrate Specificity in the Catalytic Cycle of DsbA Enzymes*. Journal of Biological Chemistry (2009).