Dipeptidyl Peptidase Enzymology in Periodontal Pathogens

Asaccharolytic Gram-negative bacteria such as Porphyromonas gingivalis and related species rely on proteolytic systems to harvest amino acids from host proteins. Central to this process are dipeptidyl peptidases (DPPs), a class of serine exopeptidases that sequentially remove dipeptides from the N-terminus of oligopeptides in the periplasm. Distinct DPP isoforms (for example DPP4, DPP5, DPP7 and DPP11) display complementary substrate specificities, enabling efficient liberation of dipeptides bearing proline, hydrophobic or acidic residues. Auxiliary exopeptidases such as acylpeptidyl-oligopeptidase and prolyl tripeptidyl-peptidase generate modified termini that feed into the DPP network. Released dipeptides are then imported across the inner membrane via proton-dependent oligopeptide transporters of the major facilitator superfamily. Beyond nutrient acquisition, certain DPPs modulate host-pathogen interactions and systemic processes; for instance, elevated DPP4 activity in periodontal sites has been linked to impaired incretin function in diabetes. Given their absence in mammals and their central role in both local tissue destruction and extra-oral effects, DPPs represent attractive targets for novel antimicrobial and anti-inflammatory strategies.

Research from Nature Portfolio

Recent studies have revealed that binding of substrates to bacterial DPP11 is driven primarily by increases in protein conformational entropy, with specific “entropy reservoir” regions unfolding to distinguish incoming peptides from reaction products. This thermodynamic signature offers a new paradigm for peptidase specificity. Building on structural data, fragment-based screening identified the first nonpeptidyl inhibitors targeting the S46 family enzyme DPP11, yielding lead compounds that selectively inhibit the enzyme and suppress Porphyromonas gingivalis growth. Complementary crystallographic analyses of DPP7 from diverse bacteria have uncovered a conserved hydrogen-bonding network at the S2 subsite, explaining an unexpected preference for asparagine in certain contexts and guiding the design of broad-spectrum S46 peptidase inhibitors.

Dipeptidyl Peptidase Enzymology in Periodontal Pathogens publication trend

The graph below shows the total number of articles in dipeptidyl peptidase enzymology in periodontal pathogens across all publications each year (not limited to Nature Index journals).

Technical terms

Dipeptidyl peptidase (DPP): A serine exopeptidase that cleaves dipeptides from the N-terminus of oligopeptides.

Exopeptidase: A protease that removes amino acids or peptides from the termini of protein substrates.

Periplasm: The compartment between the inner and outer membranes in Gram-negative bacteria where exopeptidase activity occurs.

Proton-dependent oligopeptide transporter (POT): A membrane protein that imports oligopeptides into the cytoplasm using a proton gradient.

S46 family: A subgroup of bacterial serine peptidases with distinct active-site features and substrate specificities, absent in mammals.

References

1. Dipeptidyl‐peptidases: Key enzymes producing entry forms of extracellular proteins in asaccharolytic periodontopathic bacterium Porphyromonas gingivalis. Molecular Oral Microbiology (2020).
2. A Porphyromonas gingivalis Periplasmic Novel Exopeptidase, Acylpeptidyl Oligopeptidase, Releases N-Acylated Di- and Tripeptides from Oligopeptides*. Journal of Biological Chemistry (2016).
3. Dipeptidyl-Peptidase-4 and Glucagon-like-Peptide-1, a Link in the Connection between Periodontitis and Diabetes Mellitus—What Do We Know So Far?—A Scoping Review. Journal of Clinical Medicine (2024).
4. Asp- and Glu-specific Novel Dipeptidyl Peptidase 11 of Porphyromonas gingivalis Ensures Utilization of Proteinaceous Energy Sources*. Journal of Biological Chemistry (2011).
5. Bacterial protease uses distinct thermodynamic signatures for substrate recognition. Scientific Reports (2017).
6. Fragment-based discovery of the first nonpeptidyl inhibitor of an S46 family peptidase. Scientific Reports (2019).
7. Structural basis for an exceptionally strong preference for asparagine residue at the S2 subsite of Stenotrophomonas maltophilia dipeptidyl peptidase 7. Scientific Reports (2021).