Implications of Porphyromonas gingivalis peptidyl arginine deiminase and gingipain R in human health and diseases

Abstract

Porphyromonas gingivalis is a major pathogenic bacterium involved in the pathogenesis of periodontitis. Citrullination has been reported as the underlying mechanism of the pathogenesis, which relies on the interplay between two virulence factors of the bacterium, namely gingipain R and the bacterial peptidyl arginine deiminase. Gingipain R cleaves host proteins to expose the C-terminal arginines for peptidyl arginine deiminase to citrullinate and generate citrullinated proteins. Apart from carrying out citrullination in the periodontium, the bacterium is found capable of citrullinating proteins present in the host synovial tissues, atherosclerotic plaques and neurons. Studies have suggested that both virulence factors are the key factors that trigger distal effects mediated by citrullination, leading to the development of some non-communicable diseases, such as rheumatoid arthritis, atherosclerosis, and Alzheimer's disease. Thus, inhibition of these virulence factors not only can mitigate periodontitis, but also can provide new therapeutic solutions for systematic diseases involving bacterial citrullination. Herein, we described both these proteins in terms of their unique structural conformations and biological relevance to different human diseases. Moreover, investigations of inhibitory actions on the enzymes are also enumerated. New approaches for identifying inhibitors for peptidyl arginine deiminase through drug repurposing and virtual screening are also discussed.

Keywords: Porphyromonas gingivalis; citrullination; gingipain R; inhibitors; peptidyl arginine deiminase; systemic disease.

Figure 1

Link between P. gingivalis, an oral pathogen, with various systemic diseases.

Figure 2

Mechanism of action of P. gingivalis virulence factors – Rgp and PPAD. P. gingivalis invades by secreting gingipains, which shred and degrade different cell receptors and ECM components. This disrupts signaling pathways and promotes tissue damage. PPAD and human PAD then citrullinate the liberated peptides. These citrullinated peptide antigens are recognized by antigen-presenting cells, resulting in the generation of anti-citrullinated protein antibodies (ACPAs) by the B cells. These ACPAs are associated with an increased risk of RA.

Figure 3

3D representation of Porphyromonas gingivalis Rgp with co-crystallized ligand, D-Phe-Phe-Arg-chloromethylketone, labelled H37 501 (PDB ID: 1CVR). Highlighted in orange: crown (catalytic domain), blue: root (IgSF domain).

Figure 4

3D representation of Porphyromonas gingivalis PPAD with co-crystallized ligand, Asp-Gln dipeptide (substrate-mimic complex) (PDB ID: 4YTB). Highlighted in orange: crown (catalytic domain), blue: root (IgSF domain).

Figure 5

3D representation of Porphyromonas gingivalis PPAD with co-crystallized ligand, Met-Arg dipeptide (substrate complex) (PDB ID: 4YTG). Highlighted in orange: crown (catalytic domain), blue: root (IgSF domain).