Cited by 378Oral microbiology and periodontitis researchOral and gingival health researchBacterial biofilms and quorum sensing

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Purification, Characterization, and Sequence Analysis of a Potential Virulence Factor from Porphyromonas gingivalis , Peptidylarginine Deiminase

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McGraw, Walker T., Potempa, Jan, Farley, David, Travis, James·1999·Infection and Immunity

DOI 10.1128/iai.67.7.3248-3256.1999PMC PMC116503

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Abstract

The initiation and progression of adult-onset periodontitis has been associated with infection of the gingival sulcus by Porphyromonas gingivalis . This organism utilizes a multitude of virulence factors to evade host defenses as it establishes itself as one of the predominant pathogens in periodontal pockets. A feature common to many other oral pathogens is the production of ammonia due to its protective effect during acidic cleansing cycles in the mouth. Additionally, ammonia production by P. gingivalis has been proposed as a virulence factor due to its negative effects on neutrophil function. In this study, we describe the first purification of a peptidylarginine deiminase (PAD) from a prokaryote. PAD exhibits biochemical characteristics and properties that suggest that it may be a virulence agent. PAD deiminates the guanidino group of carboxyl-terminal arginine residues on a variety of peptides, including the vasoregulatory peptide-hormone bradykinin, to yield ammonia and a citrulline residue. The soluble protein has an apparent mass of 46 kDa, while the DNA sequence predicts a full-length protein of 61.7 kDa. PAD is optimally active at 55°C, stable at low pH, and shows the greatest activity above pH 9.0. Interestingly, in the presence of stabilizing factors, PAD is resistant to limited proteolysis and retains significant activity after short-term boiling. We propose that PAD, acting in concert with arginine-specific proteinases from P. gingivalis , promotes the growth of the pathogen in the periodontal pocket, initially by enhancing its survivability and then by assisting the organism in its circumvention of host humoral defenses.

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The activity of bacterial peptidylarginine deiminase is important during formation of dual-species biofilm by periodontal pathogen Porphyromonas gingivalis and opportunistic fungus Candida albicans
Karkowska‐Kuleta, J., Bartnicka, D., Zawrotniak, M., Zielińska, G., Kieronska‐Rudek, A., Bocheńska, O., Ciastoń, I., Kozieł, J., Potempa, J., Baster, Z., et al. (2018) · Pathogens and Disease · doi:10.1093/femspd/fty033 · Cited by 47
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Pros and cons of causative association between periodontitis and rheumatoid arthritis
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The Contribution of Macrophage Plasticity to Inflammatory Arthritis and Their Potential as Therapeutic Targets
Kulakova, K. A., Lawal, T. R., McCarthy, E. M., & Floudas, A. (2024) · Cells · doi:10.3390/cells13181586 · Cited by 55
“The bacteria induce autoimmune responses by the citrullination of host peptides catalysed by protein arginine deiminase (PAD) enzymes [20].”
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Effects of clarithromycin in patients with active rheumatoid arthritis
Öğrendik, M. (2007) · Current Medical Research and Opinion · doi:10.1185/030079906x167642 · Cited by 46
Microbe-metabolite-host axis, two-way action in the pathogenesis and treatment of human autoimmunity
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Antibodies to a Citrullinated Porphyromonas gingivalis Epitope Are Increased in Early Rheumatoid Arthritis, and Can Be Produced by Gingival Tissue B Cells: Implications for a Bacterial Origin in RA Etiology
Sherina, N., de Vries, C., Kharlamova, N., Sippl, N., Jiang, X., Brynedal, B., Kindstedt, E., Hansson, M., Mathsson‐Alm, L., Israelsson, L., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.804822 · Cited by 45
“PAD show autocitrullination (14, 15, 37), similar to human PAD enzymes (38).”
BackgroundInfluential
Lessons to be learned from periodontitis
Janssen, K. M. J., Vissink, A., de Smit, M. J., Westra, J., & Brouwer, E. (2013) · Current Opinion in Rheumatology · doi:10.1097/bor.0b013e32835d833d · Cited by 44
“gingivalis PAD is able to citrullinate its endogenous proteins [38].”
Background
Significant association of periodontal disease with anti-citrullinated peptide antibody in a Japanese healthy population – The Nagahama study
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Dropping anchor: attachment of peptidylarginine deiminase via A-LPS to secreted outer membrane vesicles of Porphyromonas gingivalis
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“In particular, the role of Porphyromonas gingivalis, a well-known periodontopathogenic bacterium, has been widely highlighted, because this oral bacterium has an endogenous peptidylarginine deiminase enzyme [22].”
Background
There's no place like OM: Vesicular sorting and secretion of the peptidylarginine deiminase of Porphyromonas gingivalis
Gabarrini, G., Medina, L. M. P., Stobernack, T., Prins, R. C., Espina, M. D. T., Kuipers, J., Chlebowicz, M. A., Rossen, J. W. A., Winkelhoff, A. J. V., & van Dijl, J. M. (2018) · Virulence · doi:10.1080/21505594.2017.1421827 · Cited by 43
“Porphyromonas gingivalis is a Gram-negative, anaerobic bacterium and a keystone oral pathogen [1,2].”
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Peptidylarginine deiminase from Porphyromonas gingivalis contributes to infection of gingival fibroblasts and induction of prostaglandin E 2 ‐signaling pathway
Gawron, K., Bereta, G. P., Nowakowska, Z., Łazarz‐Bartyzel, K., Łazarz, M., Szmigielski, B., Mizgalska, D., Buda, A., Kozieł, J., Oruba, Z., et al. (2014) · Molecular Oral Microbiology · doi:10.1111/omi.12081 · Cited by 41
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Is there a link between carbamylation and citrullination in periodontal disease and rheumatoid arthritis?
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“gingivalis and is not evolutionarily related to the mammalian family of PAD enzymes [36].”
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The Role of Anti-Cyclic Citrullinated Peptide Antibody in Periodontal Disease
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Induced Apoptosis of Chondrocytes by Porphyromonas gingivalis as a Possible Pathway for Cartilage Loss in Rheumatoid Arthritis
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Salivary IgA antibodies to cyclic citrullinated peptides (CCP) in rheumatoid arthritis
Svärd, A., Kastbom, A., Sommarin, Y., & Skogh, T. (2012) · Immunobiology · doi:10.1016/j.imbio.2012.04.011 · Cited by 40
“Salivary IgA ACPA in RA 9”
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The Role of the Microbiome in Driving RA-Related Autoimmunity
Rooney, C. M., Mankia, K. S., & Emery, P. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.538130 · Cited by 41
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PPAD Activity Promotes Outer Membrane Vesicle Biogenesis and Surface Translocation by Porphyromonas gingivalis
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“terminus of peptides, which PPAD can then citrullinate (23, 24).”
Periodontal disease and influence of periodontal treatment on disease activity in patients with rheumatoid arthritis and spondyloarthritis
Białowąs, K., Radwan‐Oczko, M., Duś‐Ilnicka, I., Korman, L., & Świerkot, J. (2019) · Rheumatology International · doi:10.1007/s00296-019-04460-z · Cited by 38
Immunoreactive antigens recognized in serum samples from mice intranasally immunized with Porphyromonas gingivalis outer membrane vesicles
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Periodontitis prevalence and serum antibody reactivity to periodontal bacteria in primary Sjögren's syndrome: a pilot study
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Citrullination mediated by PPAD constrains biofilm formation in P. gingivalis strain 381
Vermilyea, D. M., Ottenberg, G. K., & Davey, M. E. (2019) · npj Biofilms and Microbiomes · doi:10.1038/s41522-019-0081-x · Cited by 35
Monoclonal Antibody Against Citrullinated Peptides Obtained From Rheumatoid Arthritis Patients Reacts With Numerous Citrullinated Microbial and Food Proteins
Tsuda, R., Ozawa, T., Kobayashi, E., Hamana, H., Taki, H., Tobe, K., Sugiyama, E., Iwamoto, M., Imura, J., Kishi, H., et al. (2015) · Arthritis & Rheumatology · doi:10.1002/art.39161 · Cited by 34
“Recent studies suggest that periodontitis and the presence of Porphyromonas gingivalis are risk factors for RA because P gingivalis expresses the bacterial PAD enzyme that induces citrullination of bacterial and human proteins (9,43,48,49).”
Background
Periodontal pathogens and the association between periodontitis and rheumatoid arthritis in Korean adults
Kim, J.-H., Choi, I. A., Lee, J. Y., Kim, K.-H., Kim, S., Koo, K., Kim, T., Seol, Y., Ku, Y., Rhyu, I., et al. (2018) · Journal of Periodontal & Implant Science · doi:10.5051/jpis.2018.48.6.347 · Cited by 34
“Citrullination occurs through the activity of an enzyme family known as peptidylarginine deiminases (PAD), of which Pg produces a variant [9].”
Background
The P. gingivalis Autocitrullinome Is Not a Target for ACPA in Early Rheumatoid Arthritis
Muñoz-Atienza, E., Flak, M. B., Sirr, J., Paramonov, N. A., Aduse‐Opoku, J., Pitzalis, C., & Curtis, M. A. (2020) · Journal of Dental Research · doi:10.1177/0022034519898144 · Cited by 34
“1998) and because PPAD is expressed mainly on the surface of this bacterium (McGraw et al. 1999; Quirke et al. 2014), PPAD activity at sites of periodontal inflammation can be inferred.”
BackgroundInfluential
Evolutionarily conserved antigens in autoimmune disease: Implications for an infective aetiology
Wegner, N., Wait, R., & Venables, P. J. (2008) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2008.09.012 · Cited by 34
Structure, function, and inhibition of a genomic/clinical variant of Porphyromonas gingivalis peptidylarginine deiminase
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“PPAD-T1 was described to efficiently citrullinate arginines within dipeptide benzoylglycylarginine and peptides derived from bradykinin.(9) Further substrates were epidermal growth factor and anaphylatoxin C5a, as well as peptides derived from α-enolase, fibrinogen, and bacterial cell-envelope proteins resulting from…”
Self-citation
Cardiovascular Diseases and Periodontitis
Hansen, P. R., & Holmstrup, P. (2022) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-96881-6_14 · Cited by 33
Interplay of Microbiota and Citrullination in the Immunopathogenesis of Rheumatoid Arthritis
Alghamdi, M. A., & Redwan, E. M. M. M. (2021) · Probiotics and Antimicrobial Proteins · doi:10.1007/s12602-021-09802-7 · Cited by 31
“Although the amino acid sequence of PPAD differs from that of human PAD, it can efficiently citrullinated the arginine residues of target proteins [45].”
Background
Association between anti-Porphyromonas gingivalis antibody, anti-citrullinated protein antibodies, and rheumatoid arthritis
Bae, S., & Lee, Y. H. (2017) · Zeitschrift für Rheumatologie · doi:10.1007/s00393-017-0328-y · Cited by 34
“gingivalis to citrullinate peptides, because PPAD can convert peptidylarginine into peptidyl-citrulline, only after degradationbyRgpB [48].”
Background
Disease mechanisms in preclinical rheumatoid arthritis: A narrative review
Romão, V. C., & Fonseca, J. E. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.689711 · Cited by 30
“Of note, antibodies against PPAD-citrullinated vimentin were recently reported in patients with preclinical and early RA (63).”
BackgroundInfluential
Periodontitis increases rheumatic factor serum levels and citrullinated proteins in gingival tissues and alter cytokine balance in arthritic rats
Corrêa, M. G., Sacchetti, S., Ribeiro, F. V., Pimentel, S. P., Casarin, R. C. V., Cirano, F. R., & Casati, M. Z. (2017) · PLoS ONE · doi:10.1371/journal.pone.0174442 · Cited by 29
Conserved Citrullinating Exoenzymes in Porphyromonas Species
Gabarrini, G., Chlebowicz, M. A., Quiroz, M. E. V., Veloo, A. C. M., Rossen, J. W. A., Harmsen, H. J. M., Laine, M. L., van Dijl, J. M., & Winkelhoff, A. J. V. (2018) · Journal of Dental Research · doi:10.1177/0022034517747575 · Cited by 33
“gingivalis (in short PPAD) was thus far the only known prokaryotic enzyme of this type (McGraw et al. 1999; Konig et al. 2014).”
BackgroundResult
A Lesson in Survival, by Giardia lamblia
Ropolo, A. S., & Touz, M. C. (2010) · The Scientific World JOURNAL · doi:10.1100/tsw.2010.200 · Cited by 30
“However, it has been observed that the bacterium Porphyromonas gingivalis, associated with the initiation and progression of adult-onset periodontitis, releases a PAD (pPAD), a virulence factor that prevents acidic cleansing cycles in the mouth[86].”
Background
Association of levels of antibodies against citrullinated cyclic peptides and citrullinated α-enolase in chronic and aggressive periodontitis as a risk factor of Rheumatoid arthritis: a case control study
Reichert, S., Schlumberger, W., Dähnrich, C., Hornig, N., Altermann, W., Schaller, H., & Schulz, S. (2015) · Journal of Translational Medicine · doi:10.1186/s12967-015-0625-7 · Cited by 30
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BackgroundInfluential
Citrullination and Proteolytic Processing of Chemokines by Porphyromonas gingivalis
Moelants, E. A. V., Loozen, G., Mortier, A., Martens, E., Opdenakker, G., Mizgalska, D., Szmigielski, B., Potempa, J., Damme, J. V., Teughels, W., et al. (2014) · Infection and Immunity · doi:10.1128/iai.01624-14 · Cited by 29
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Conservative Mechanisms of Extracellular Trap Formation by Annelida Eisenia andrei: Serine Protease Activity Requirement
Homa, J., Ortmann, W., & Kołaczkowska, E. (2016) · PLoS ONE · doi:10.1371/journal.pone.0159031 · Cited by 29
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Background
Metabolomics analysis in saliva from periodontally healthy, gingivitis and periodontitis patients
Alamri, M. M., Williams, B., Guennec, A. D. L., Mainas, G., Santamaria, P., Moyes, D. L., & Nibali, L. (2023) · Journal of Periodontal Research · doi:10.1111/jre.13183 · Cited by 28
Arginine deiminase inhibits Porphyromonas gingivalis surface attachment
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Glycobiology of the oral pathogen Porphyromonas gingivalis and related species
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Active matrix metalloproteinase‐8 and periodontal bacteria depending on periodontal status in patients with rheumatoid arthritis
Kirchner, A., Jäger, J., Krohn-Grimberghe, B., Patschan, S. A., Kottmann, T., Schmalz, G., Mausberg, R. F., Haak, R., & Ziebolz, D. (2017) · Journal of Periodontal Research · doi:10.1111/jre.12443 · Cited by 28
The Keystone‐Pathogen Hypothesis Updated: The Role of Porphyromonas gingivalis in Periodontitis
Curtis, M. A., Garnett, J. A., & Darveau, R. P. (2025) · Journal of Periodontal Research · doi:10.1111/jre.70050 · Cited by 33
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Authors: McGraw, W. T., Potempa, J., Farley, D., & Travis, J.
Affiliations: University of Georgia (US)
Jagiellonian University (PL)
Department of Arthritis Biology, Novartis Pharmaceuticals, Summit, New Jersey 07901,3 and
ORCID: Potempa, Jan
Travis, James
Venue: Infection and Immunity
Publisher: American Society for Microbiology
Published: 1999-07
Volume: 67
Issue: 7
Pages: 3248-3256
ISSN: 0019-9567 (ISSN-L)
1098-5522
DOI: 10.1128/iai.67.7.3248-3256.1999
PMC: PMC116503
OpenAlex: W1943338444
Cited by: 378
References: 47
Citations by year: 2026: 9 · 2025: 13 · 2024: 12 · 2023: 15 · 2022: 19 · 2021: 15 · 2020: 16 · 2019: 30 · 2018: 24 · 2017: 37 · 2016: 26 · 2015: 28 · 2014: 22 · 2013: 27 · 2012: 20
FWCI: 1.60
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Infection and Immunity (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
Health Sciences › Dentistry › Periodontics › Oral and gingival health research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bacterial biofilms and quorum sensing
Keywords: Porphyromonas gingivalis, peptidylarginine deiminase, virulence factors, periodontitis, ammonia synthesis, bradykinin, citrullination, protein purification, protein stability, host defense evasion, periodontal pockets
MeSH terms: Protein-Arginine Deiminases, Protein-Arginine Deiminase Type 4, Amino Acid Sequence, Base Sequence, Enzyme Activation, Humans, Hydrolases, Molecular Sequence Data, Periodontitis, Virulence, Bacteroidaceae Infections, Porphyromonas gingivalis, Sequence Analysis

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Purification, Characterization, and Sequence Analysis of a Potential Virulence Factor from Porphyromonas gingivalis , Peptidylarginine Deiminase

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