Purification, Characterization, and Sequence Analysis of a Potential Virulence Factor from Porphyromonas gingivalis , Peptidylarginine Deiminase
Open accessAbstract
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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Citrullination of arginine occurs via the action of peptidyl arginine deiminase, an enzyme found in both humans and P gingivalis.
“Citrullination of arginine occurs via the action of peptidyl arginine deiminase, an enzyme found in both humans and P gingivalis.211”
From The oral microbiome: Role of key organisms and complex networks in oral health and disease (2021) · cites this paper as [211]
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Harvey, G., Fitzsimmons, T. R., Dhamarpatni, A. A. S. S. K., Marchant, C. L., Haynes, D. R., & Bartold, P. M. (2012) · Journal of Periodontal Research · doi:10.1111/jre.12002 · Cited by 164 · see citing works
“Although the expression of PAD by PPAD has been well documented (9) this was not examined in the present study because of the current lack of availability of commercial antibodies to PPAD.”
Kharlamova, N., Jiang, X., Sherina, N., Potempa, B. A., Israelsson, L., Quirke, A., Eriksson, K., Yucel‐Lindberg, T., Venables, P. J., Potempa, J., et al. (2015) · Arthritis & Rheumatology · doi:10.1002/art.39491 · Cited by 163 · see citing works
“PPAD, which can citrullinate both bacterial and human proteins after degradation by Rgp (29), could therefore potentially contribute to the generation of de novo epitopes and the formation of autoantigens in RA.”
BackgroundInfluentialSelf-citationRelationship between Periodontitis and Rheumatoid Arthritis: Review of the Literature
Araújo, V. M. A., de Melo, I. M., & Lima, V. (2015) · Mediators of Inflammation · doi:10.1155/2015/259074 · Cited by 160 · see citing works
How the microbiota shapes rheumatic diseases
de Wiele, T. V., Praet, J. T. V., Marzorati, M., Drennan, M. B., & Elewaut, D. S. (2016) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2016.85 · Cited by 159 · see citing works
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“gingivalis has been implicated as a potentially even more interesting link between periodontitis and RA when it was found that it expresses a bacterial PAD, typically referred to as PPAD, to distinguish it from the human isoforms [114].”
BackgroundHLA-Disease Associations in Rheumatoid Arthritis
van Drongelen, V., & Holoshitz, J. (2017) · Rheumatic Disease Clinics of North America · doi:10.1016/j.rdc.2017.04.003 · Cited by 128 · see citing works
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“P. gingivalis is unique among periodontal pathogens in that it possesses a peptidyl arginine deiminase(McGraw et al., 1999, Wegner et al., 2010), which can citrullinate host peptides that in turn may elicit an anti-citrulline autoimmune response among genetically susceptible individuals.”
The autoimmunity–oral microbiome connection
Nikitakis, N. G., Papaioannou, W., Sakkas, L. I., & Kousvelari, E. E. (2016) · Oral Diseases · doi:10.1111/odi.12589 · Cited by 132 · see citing works
Espina, M. D. T., Gabarrini, G., Harmsen, H. J. M., Westra, J., Winkelhoff, A. J. V., & van Dijl, J. M. (2018) · FEMS Microbiology Reviews · doi:10.1093/femsre/fuy035 · Cited by 130 · see citing works
An Overview of the Intrinsic Role of Citrullination in Autoimmune Disorders
Alghamdi, M. A., Alasmari, D., Assiri, A., Mattar, E. H., Aljaddawi, A. A., Alattas, S. G., & Redwan, E. M. M. M. (2019) · Journal of Immunology Research · doi:10.1155/2019/7592851 · Cited by 126 · see citing works
Gómez-Bañuelos, E., Mukherjee, A., Darrah, E., & Andrade, F. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8091309 · Cited by 124 · see citing works
“Indeed, the data from some animal models of arthritis strongly suggest that P. gingivalis may exacerbate or induce disease by mechanisms independent of ACPA production, which may involve the activity of PPAD as a virulence factor targeting either free L-citrulline or protein substrates [131].”
BackgroundInfluentialKinloch, A. J., Alzabin, S., Brintnell, W. C., Wilson, E., Barra, L., Wegner, N., Bell, D., Cairns, E., & Venables, P. J. (2011) · Arthritis & Rheumatism · doi:10.1002/art.30639 · Cited by 123 · see citing works
Lappin, D. F., Apatzidou, D. A., Quirke, A., Oliver-Bell, J., Butcher, J. P., Kinane, D. F., Riggio, M. P., Venables, P. J., McInnes, I. B., & Culshaw, S. (2013) · Journal Of Clinical Periodontology · doi:10.1111/jcpe.12138 · Cited by 121 · see citing works
“…autoantigens central to initiation of arthritis since P. gingivalis is unique among human parasitic prokaryotic organisms in its expression of peptidylarginine deiminase (pPAD), which posttranslationally citrullinates proteins (McGraw et al. 1999, Rosenstein et al. 2004, Lundberg et al. 2010).”
BackgroundFebles, J. G., & Sanz, M. (2021) · Periodontology 2000 · doi:10.1111/prd.12385 · Cited by 121 · see citing works
Okada, M., Kobayashi, T., Ito, S., Yokoyama, T., Abe, A., Murasawa, A., & Yoshie, H. (2013) · Journal of Periodontology · doi:10.1902/jop.2013.130079 · Cited by 120 · see citing works
Periodontal disease and periodontal bacteria as triggers for rheumatoid arthritis
Cheng, Z., Meade, J. L., Mankia, K. S., Emery, P., & DeVine, D. (2017) · Best Practice & Research Clinical Rheumatology · doi:10.1016/j.berh.2017.08.001 · Cited by 120 · see citing works
Kriebel, K., Hieke, C., Müller-Hilke, B., Nakata, M., & Kreikemeyer, B. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.00053 · Cited by 118 · see citing works
“In contrast to human PADs, PPAD Frontiers in Microbiology | www.frontiersin.org 8 January 2018 | Volume 9 | Article 53 does not require calcium ion for its activity of citrullination of C-terminal arginine residues (Rodriguez et al., 2009; McGraw et al., 1999).”
BackgroundResultGully, N. J., Bright, R., Marino, V., Marchant, C. L., Cantley, M. D., Haynes, D. R., Butler, C. A., Dashper, S. G., Reynolds, E. C., & Bartold, P. M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0100838 · Cited by 118 · see citing works
“inflammation and development of rheumatoid arthritis [9,15].”
BackgroundDetection of oral bacterial DNA in synovial fluid
Reichert, S., Haffner, M., Keyßer, G., Schäfer, C., Stein, J. M., Schaller, H., Wienke, A., Strauss, H., Heide, S., & Schulz, S. (2013) · Journal Of Clinical Periodontology · doi:10.1111/jcpe.12102 · Cited by 118 · see citing works
“2004 hypothesized that a microbial enzyme produced by Porphyromonas gingivalis, peptidylarginine deiminase (PAD), is not only a virulence factor for periodontitis (McGraw et al. 1999) but could also be responsible for autoimmune reactions against joint tissues.”
BackgroundA novel superfamily of enzymes that catalyze the modification of guanidino groups
Shirai, H., Blundell, T. L., & Mizuguchi, K. (2001) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(01)01906-5 · Cited by 120 · see citing works
Citrullination in the periodontium—a possible link between periodontitis and rheumatoid arthritis
Laugisch, O., Wong, A., Sroka, A., Kantyka, T., Kozieł, J., Neuhaus, K. W., Sculean, A., Venables, P. J., Potempa, J., Möller, B., et al. (2015) · Clinical Oral Investigations · doi:10.1007/s00784-015-1556-7 · Cited by 115 · see citing works
“gingivalis is the only human pathogen, which produces the unique PAD (PPAD) [17, 18], also considered as a virulence factor.”
Self-citationThe association between rheumatoid arthritis and periodontitis
Leech, M. T., & Bartold, P. M. (2015) · Best Practice & Research Clinical Rheumatology · doi:10.1016/j.berh.2015.03.001 · Cited by 115 · see citing works
Nakada, Y., & Itoh, Y. (2003) · Microbiology · doi:10.1099/mic.0.26009-0 · Cited by 115 · see citing works
“Within a region between residues 60 and 361, AguA is weakly homologous (23 % identity and 38 % similarity) to the corresponding region of the peptidylarginine deiminase of Porphyromonas gingivalis (McGraw et al., 1999).”
BackgroundLiao, F., Li, Z., Wang, Y., Shi, B., Gong, Z., & Cheng, X. (2009) · Medical Hypotheses · doi:10.1016/j.mehy.2008.12.040 · Cited by 115 · see citing works
“gingivalis is recognized to be a major pathogenic organism in PD and is the only bacteria known to express a PAD enzyme [31].”
BackgroundNakayama, K. (2014) · Journal of Periodontal Research · doi:10.1111/jre.12255 · Cited by 114 · see citing works
“gingivalis, promotes the growth of the pathogen in the periodontal pocket by enhancing the survivability of this bacterium and mediating the circumvention of host humoral defenses (64).”
BackgroundManipulation of Neutrophils by Porphyromonas gingivalis in the Development of Periodontitis
Sochalska, M., & Potempa, J. (2017) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2017.00197 · Cited by 113 · see citing works
“P. gingivalis peptidyl arginine deiminase (PPAD) is another enzyme unique to P. gingivalis, which converts proteins Arg residues, usually present at the carboxy terminus, into citrulline (McGraw et al., 1999).”
BackgroundSelf-citationMankia, K. S., Cheng, Z., Do, T., Hunt, L. H., Meade, J. L., Kang, J. X., Clerehugh, V., Speirs, A., Tugnait, A., Hensor, E. M. A., et al. (2019) · JAMA Network Open · doi:10.1001/jamanetworkopen.2019.5394 · Cited by 112 · see citing works
Review: Preclinical Rheumatoid Arthritis: Progress Toward Prevention
Mankia, K. S., & Emery, P. (2016) · Arthritis & Rheumatology · doi:10.1002/art.39603 · Cited by 111 · see citing works
Wu, C., Yang, H., & Lai, J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21114015 · Cited by 112 · see citing works
“gingivalis is a pathogen capable of citrullinating peptides into a unique pattern due to the expression of its own PAD [96].”
BackgroundMangat, P., Wegner, N., Venables, P. J., & Potempa, J. (2010) · Arthritis Research & Therapy · doi:10.1186/ar3000 · Cited by 111 · see citing works
“Th e localization and functions of each of the human PAD enzymes are summarized in Table 1. Homologous amino acid sequences for some or all of these PADs exist in other eukaryotic species, such as the mouse, chicken, frog, and bony fi sh. Among prokaryotic species, PAD activity has, to date, been described in Porphyro…”
BackgroundResultInfluentialSelf-citationKonig, M. F., Paracha, A. S., Moni, M., Bingham, C. O., & Andrade, F. (2014) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2014-205385 · Cited by 107 · see citing works
Peripheral education of the immune system by the colonic microbiota
Kuhn, K. A., & Stappenbeck, T. S. (2013) · Seminars in Immunology · doi:10.1016/j.smim.2013.10.002 · Cited by 104 · see citing works
Johansson, L., Sherina, N., Kharlamova, N., Potempa, B. A., Larsson, B., Israelsson, L., Potempa, J., Rantapää‐Dahlqvist, S., & Lundberg, K. (2016) · Arthritis Research & Therapy · doi:10.1186/s13075-016-1100-4 · Cited by 105 · see citing works
“PAD interacts with another major virulence factor, arginine gingipainB (RgpB), an arginine-specific extra-cellular protease expressed on the surface of the bacterial outer membrane [24, 25].”
BackgroundSelf-citationMicroRNAs in rheumatoid arthritis
Ceribelli, A., Nahid, M. A., Satoh, M., & Chan, E. K. L. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.05.020 · Cited by 104 · see citing works
“Furthermore, it is known that the specificity of bacterial PAD is largely restricted to citrullination of terminal-arginine residues which are the same as citrullinated residues as in CCP or citrullinated peptides generated from mammalian PAD enzymes [63].”
Nakao, R., Takashiba, S., Kosono, S., Yoshida, M., Watanabe, H., Ohnishi, M., & Senpuku, H. (2013) · Microbes and Infection · doi:10.1016/j.micinf.2013.10.005 · Cited by 104 · see citing works
Goulas, T., Mizgalska, D., Garcia-Ferrer, I., Kantyka, T., Guevara, T., Szmigielski, B., Sroka, A., Millán, C., Usón, I., Veillard, F., et al. (2015) · Scientific Reports · doi:10.1038/srep11969 · Cited by 104 · see citing works
Self-citationPeptidyl Arginine Deiminase from Porphyromonas gingivalis Abolishes Anaphylatoxin C5a Activity
Bielecka, E., Scavenius, C., Kantyka, T., Jusko, M., Mizgalska, D., Szmigielski, B., Potempa, B. A., Enghild, J. J., Prossnitz, E. R., Blom, A. M., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.c114.617142 · Cited by 103 · see citing works
“gingivalis (4), it is tempting to speculate that paralysis of bactericidal activity of murine macrophages is induced not by the native anaphylatoxin crosstalk but by generated in situ C-terminally modified C5a.”
BackgroundSelf-citationPeriodontitis and rheumatoid arthritis: An update 2012‐2017
Bartold, P. M., & Lopez‐Oliva, I. (2020) · Periodontology 2000 · doi:10.1111/prd.12300 · Cited by 102 · see citing works
The lung in ACPA-positive rheumatoid arthritis: an initiating site of injury?
Perry, E. S., Kelly, C. A., Eggleton, P., Soyza, A. D., & Hutchinson, D. G. (2014) · Lara D. Veeken · doi:10.1093/rheumatology/keu195 · Cited by 101 · see citing works
How Autoantibodies Regulate Osteoclast Induced Bone Loss in Rheumatoid Arthritis
Steffen, U., Schett, G. A., & Bözec, A. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01483 · Cited by 103 · see citing works
“In addition, the bacterium Porphyromonas gingivalis (which is involved in periodontitis) releases PAD (19).”
BackgroundInfluentialGorasia, D. G., Veith, P. D., Hanssen, E. G., Glew, M. D., Sato, K., Yukitake, H., Nakayama, K., & Reynolds, E. C. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005820 · Cited by 98 · see citing works
Olsen, I., Singhrao, S. K., & Potempa, J. (2018) · Journal of Oral Microbiology · doi:10.1080/20002297.2018.1487742 · Cited by 97 · see citing works
“arginine residues [11,21], which are activated following an influx of calcium ions from the extracellular environment or from the cytosol [22].”
BackgroundSelf-citationPorphyromonas gingivalis and rheumatoid arthritis
Perricone, C., Ceccarelli, F., Saccucci, M., Carlo, G. D., Bogdanos, D. P., Lucchetti, R., Pilloni, A., Valesini, G., Polimeni, A., & Conti, F. (2019) · Current Opinion in Rheumatology · doi:10.1097/bor.0000000000000638 · Cited by 96 · see citing works
Periodontitis, Porphyromonas, and the pathogenesis of rheumatoid arthritis
Farquharson, D., Butcher, J. P., & Culshaw, S. (2012) · Mucosal Immunology · doi:10.1038/mi.2011.66 · Cited by 96 · see citing works
The Link Between Periodontitis and Rheumatoid Arthritis: A Periodontist’s Perspective
Payne, J. B., Golub, L. M., Thiele, G. M., & Mikuls, T. R. (2014) · Current Oral Health Reports · doi:10.1007/s40496-014-0040-9 · Cited by 94 · see citing works
Cheng, Z., Do, T., Mankia, K. S., Meade, J. L., Hunt, L. H., Clerehugh, V., Speirs, A., Tugnait, A., Emery, P., & DeVine, D. (2020) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2020-216972 · Cited by 93 · see citing works
de Pablo, P., Dietrich, T., Chapple, I., Milward, M. R., Chowdhury, M., Charles, P. J., Buckley, C. D., & Venables, P. J. (2013) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2012-202701 · Cited by 90 · see citing works
Okada, M., Kobayashi, T., Ito, S., Yokoyama, T., Komatsu, Y., Abe, A., Murasawa, A., & Yoshie, H. (2011) · Journal of Periodontology · doi:10.1902/jop.2011.110020 · Cited by 88 · see citing works
Rheumatoid arthritis is linked to oral bacteria: etiological association
Öğrendik, M. (2009) · Modern Rheumatology · doi:10.1007/s10165-009-0194-9 · Cited by 88 · see citing works
Engström, M., Eriksson, K., Lee, L., Hermansson, M., Johansson, A. S., Nicholas, A. P., Gerasimčik, N., Lundberg, K., Klareskog, L., Catrina, A. I., et al. (2018) · Journal of Translational Medicine · doi:10.1186/s12967-018-1588-2 · Cited by 86 · see citing works
“gingivalis-derived peptidylarginine deiminase (PPAD), which may, together with host’s endogenous PADs, contribute to local citrullination [4, 10, 11].”
BackgroundA Secreted Bacterial Peptidylarginine Deiminase Can Neutralize Human Innate Immune Defenses
Stobernack, T., Espina, M. D. T., Mulder, L. M., Medina, L. M. P., Piebenga, D., Gabarrini, G., Zhao, X., Janssen, K. M. J., Hulzebos, J., Brouwer, E., et al. (2018) · mBio · doi:10.1128/mbio.01704-18 · Cited by 89 · see citing works
Łasica, A. M., Goulas, T., Mizgalska, D., Zhou, X., de Diego, I., Książęk, M., Madej, M., Guo, Y., Guevara, T., Nowak, M., et al. (2016) · Scientific Reports · doi:10.1038/srep37708 · Cited by 86 · see citing works
“…encodes 32 putative CTD-containing proteins, which include PorU and important virulence factors such as the gingipain cysteine peptidases RgpA, RgpB, and Kgp 20,21 ; carboxypeptidase D ( alias Cpg70 22 ); 35-kDa heme-binding protein (HBP35 23,24 ) and peptidylarginine deiminase (PPAD 25,26 ).”
BackgroundSelf-citationKobayashi, T., Okada, M., Ito, S., Kobayashi, D., Ishida, K., Kojima, A., Narita, I., Murasawa, A., & Yoshie, H. (2013) · Journal of Periodontology · doi:10.1902/jop.2013.120696 · Cited by 83 · see citing works
Cosgarea, R., Tristiu, R., Dumitru, R. B., Arweiler, N. B., Rednic, S., Sirbu, C. I., Lascu, L. M., Sculean, A., & Eick, S. (2018) · Clinical Oral Investigations · doi:10.1007/s00784-018-2420-3 · Cited by 83 · see citing works
“gingivalis-peptidylarginine deiminase [36] which citrullinates fibrinogen and α-enolase (major autoantigens in RA) [37], P.”
BackgroundBello-Gualtero, J. M., Lafaurie, G. I., Hoyos, L. X., Castillo, D. M., Ávila, J. D., Niño, J. C. M., Puin, S. R. U., Londoño, J. D., Valle‐Oñate, R., & Romero‐Sánchez, C. (2015) · Journal of Periodontology · doi:10.1902/jop.2015.150455 · Cited by 82 · see citing works
The Infectious Basis of ACPA-Positive Rheumatoid Arthritis
Sakkas, L. I., Daoussis, D., Liossis, S. C., & Bogdanos, D. P. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.01853 · Cited by 81 · see citing works
“P. gingivalis has two unique enzymes, peptidylarginine deiminase (PPAD) and arginine ginpains (Rgps) which are expressed on the bacterial outer membrane and can also be secreted (Potempa et al., 1995; McGraw et al., 1999).”
BackgroundMontgomery, A. B., Kopec, J., Shrestha, L., Thézénas, M., Burgess-Brown, N., Fischer, R., Yue, W. W., & Venables, P. J. (2015) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2015-207656 · Cited by 80 · see citing works
Chou, Y., Lai, K., Chen, D., Lin, C., & Chen, H. (2015) · PLoS ONE · doi:10.1371/journal.pone.0139693 · Cited by 78 · see citing works
“A promising hypothesis to interpret the relationship between RA and PD is the autoimmune response to citrullinated proteins produced by PPAD [13].”
BackgroundInfluential
- Authors
- McGraw, W. T., Potempa, J., Farley, D., & Travis, J.
- Affiliations
- University of Georgia (US)
- Jagiellonian University (PL)
- <!--label omitted: 3-->Department of Arthritis Biology, Novartis Pharmaceuticals, Summit, New Jersey 07901,3 and
- 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
- 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
- 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 › Health Professions › Pharmacy › 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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