Prolyl Tripeptidylpeptidase
Yoshitaka Nakajima, ... Tadashi Yoshimoto, in Handbook of Proteolytic Enzymes (Third Edition), 2013
Biological Aspects
Porphyromonas gingivalis is a Gram-negative anaerobic bacteriumand is considered to be a major pathogen associated with periodontitis. Since this bacterium is known to be a very poor carbohydrate utilizer and cannot take up free amino acids, it only utilizes short oligopeptides as carbon and energy sources. P. gingivalis produces gingipains R and K, collagenase, DPP-4, and aminopeptidase B. Since type I collagen has a -(Gly-Xaa- Pro)n- sequence, PTP must be important for degradation of collagens as nutrients and it is likely to be co-working with other peptidases.
Platelets as Mediators of the Vascular Response to Infection
Dermot Cox, in Vascular Responses to Pathogens, 2016
Secreted products
secretes gingipains, which are proteases that can directly activate platelets. This is due to activation of protease-activated receptors on the platelet surface.51,52 Peptidoglycan has also been shown toinduce platelet aggregation and inflammation in conjunction with antibodies in an FcγRIIa-dependent manner.53,54 Lipopolysaccharide(LPS), while not directly activating platelets, is thought to increase the interactions of platelets with leucocytes in a TLR 4-dependent manner55–57 and is thought to play a role in activation of other cells in sepsis.58 Lipotechoic acid has been shown to mediate bacterial activation of platelets in a TLR 2-dependent manner.59 S. aureussecretes the enzyme staphylothrombin, which indirectly leads to the activation of platelets.60
Carbohydrates, Nucleosides & Nucleic Acids
Amirreza Faridmoayer, Mario F. Feldman, in Comprehensive Natural Products II, 2010
6.12.4.5 Glycosylation in Porphyromonas gingivalis
Porphyromonas gingivalis, a black-pigmented, Gram-negative anaerobe, populates the subgingival crevice of the mouth. It is known to undergo a transition from its commensal status in healthy individuals to a highly invasive intracellular pathogen in human patients suffering from periodontal disease.133 Porphyromonas gingivalis is known to produce a unique class of cysteine proteinases, termed gingipains. They consist of Arg-gingipain (Rgp) and Lys-gingipain (Kgp) that exist in both cell-associated and secreted forms which play a central role in the virulence of this organism. These enzymes are produced as large pre-proproteins and are subject to elaborate, yet not fully understood, secretion, glycosylation, activation, and maturation processes.134
A MAb raised against one of the isoforms of the Rgps purified from P. gingivalis, named MAb1B5, did not react with the corresponding recombinant form of the protein chain expressed in E. coli but was immunoreactive with a P. gingivalis polysaccharides.12 Chemical deglycosylation abolished immunoreactivity with MAb1B5 and caused a reduction in the size of the membrane-associated enzymes, suggesting that the gingipains are glycosylated. Further work showed that gingipains are O-glycosylated.12 However, the carbohydrates bound to gingipains are not fully characterized yet. Monosaccharide analysis showed that the different forms of the gingipains can contain 14–30% carbohydrate by weight of protein.135 The sugars are attached to multiple sites on the proteins, presumably at the C-terminal region. Interestingly, differences in the monosaccharide compositions of the oligosaccharides bound to the gingipains were found, indicating that these protease isoforms are modified at different extents with diverse sugars. The variable nature of these additions may have a significant effect on the structure, stability, and immune recognition of these protease glycoproteins.135
Unglycosylated gingipains are not catalytically active. However, the molecular basis of the inactivity is not known. Evidence suggesting that other proteins are also glycosylated in P. gingivalis has been presented.136 Recently, glycosylation of several proteins has been described in a closely related bacterium, Bacteroides fragilis, which is a commensal in humans.137 Further work will be needed to understand the glycosylation process in both systems, which can lead to a better understanding of the potential role of these systems in pathogenesis and commensalism.
Passive Immunization
Harold Marcotte, Lennart Hammarström, in Mucosal Immunology (Fourth Edition), 2015
Porphyromonas gingivalis
, a gram-negative anaerobe present in subgingival plaque, was identified as a major etiologic agent of chronic periodontitis(Marcotte and Lavoie, 1998). The factors by which Po. gingivalismight express its virulence include lipopolysaccharides, hemagglutinin, fimbriae, and the Arg-X-specific (Rgp) and Lys-X-specific (Kgp) cysteine proteinases (the gingipains) (Andrian et al., 2004).
Immunoglobulin Y against the Po. gingivalis 40-kD outer membrane protein and hemagglutinin (HagA) were found to inhibit aggregation and hemagglutination in vitro (Hamajima et al., 2007; Tezuka et al., 2006). Egg yolk antibodies against Po. gingivalisgingipains decreased bacterial adhesion and hydrolytic activityin vitro (Yokoyama et al., 2007b) and reduced levels of Po. gingivaliswhen applied to the teeth of periodontitis patients (Yokoyama et al., 2007a).
The anti-Po. gingivalis mAb 61BG1.3 is reactive with the adhesion-associated epitope contained in the beta fragment of gingipain RgpA and has been shown to inhibit hemagglutination of human red blood cells by Po. gingivalis (Booth and Lehner, 1997). Topical application of the mAb in patients with periodontitis prevented recolonization with Po. gingivalis for up to 9 months (Booth et al., 1996). Modified lactobacilli expressing scFv derived from 61BG1.3 on the cell surface were also shown to aggregate Po. gingivalis and inhibit its growth in vitro (Marcotte et al., 2006).
Gingipain R
Ky-Anh Nguyen, Jan Potempa, in Handbook of Proteolytic Enzymes (Third Edition), 2013
Name and History
Porphyromonas gingivalis, an opportunistic oral pathogen, produces substantial quantities of cysteine peptidases that cleave synthetic substrates with Arg and/or Lys residues at the P1 position [1]. Since 1984, these proteinases have become targets for purification and several seemingly related proteins have been separated and referred to as ‘trypsin-like proteinases’. More recently, acronyms were given to the rediscovered enzymes. Shah et al. (1990) were first to propose the name gingivain [2]. Alternatively, the term gingipain (P. gingivalis+clostripain) was suggested [3], since the purified enzyme shared some properties with clostripain, including a similar molecular mass, requirements of calcium for stability and narrow specificity limited to Arg↓Xaa peptide bonds. Both acronyms, with prefixes added, were later adopted to designate Lys- and Arg-specific enzymes [4–6]. In addition to gingivain and gingipain, the term argingipain has been introduced to describe an Arg-specific enzyme [7]. Therefore, in 1995, to avoid redundancies in nomenclature and in line with a recommendation by the IUBMB, the names gingipain R (EC3.4.22.37) and gingipain K (Chapter 523), abbreviated Rgp and Kgp, were suggested to account for the unique specificity of two major cysteine proteinases of P. gingivalis [8]. This nomenclature was eventually accepted by other authors who had previously championed alternative names for gingipains [9].
Advances in cloning, sequencing and Southern blot analysis of P. gingivalis genes encoding ‘trypsin-like’ proteinases revealed that various molecular mass forms of Arg-specific proteinases were derived from initial translation products of two very closely related genes (rgpA and rgpB, formerly referred to as rgp-1 and rgp-2) [10–14]. The gingipains R heterogeneity is further complicated by proteolytic processing of the nascent gene translation products, their glycosylation, and/or their assembly into multi-domain noncovalent complexes with adhesins as either soluble or membrane-associated forms. Taking these combinations into account, five forms of gingipains R can be distinguished, two derived from the rgpB gene and three derived from the rgpA gene translation product (Figure 522.1).
Figure 522.1. Schematic representation of the post-translational processing of the initial translation products of the rgpA and rgpB genes (center) and generation of different isoforms of RgpA and RgpB. The translation products of each gene (prepro-RgpA and prepro-RgpB) are targeted for export through the inner membrane by an N-terminal signal peptide and export through the outer membrane by a C-terminal domain (CTD). These regions are cleaved (white arrows) along with the propeptide domain during the maturation process to be converted into membrane-bound forms (mt-HRgpA and mt-RgpB) by post-translational processing. In addition, three other secreted forms (HRgpA, RgpAcat and RgpB) are also produced. Proteolytic processing (white arrows) of various adhesin domains (HA1 to 4) gives rise to more complex formation of RgpA isoforms. Small hexagons indicate glycan modifications, arbitrarily located.
Genetic Predisposition to Autoimmune Diseases Conferred by the Major Histocompatibility Complex
Veena Taneja, ... Chella S. David, in The Autoimmune Diseases (Fifth Edition), 2014
Porphyromonas Gingivalis and Rheumatoid Arthritis
(P. gingivalis), a Gram-negative facultative anaerobe, is the major cause of an inflammatory condition of oral cavity called periodontitis(McGraw et al., 1999). Smoking has been shown to be the leading susceptibility factor for periodontitis (Klareskog et al., 2006; Lundberg et al., 2010). Further, an association between the presence of HLA-DR4 and periodontitis has been described indicating similarities with RA. P. gingivalis is present in more than 80% of RA patients. Recent epidemiology studies have shown an association between periodontal disease and RA (Farquharson et al., 2012). Antibodies to P. gingivalis are increased in RA patients and correlate with anti-citrullinated peptide antibodies (ACPAs). The potential role of P. gingivalis in RA pathogenesis has been suggested to be due to the presence of the bacterial peptidyl arginine deiminase (PAD) enzyme, even though there is no similarity with human PAD (Farquharson et al., 2012). These enzymes can deiminate an arginine residue to citrulline in antigens thus changing their binding affinity to HLA molecules. Further, more than 40% of RA patients are positive for antibodies to an immunodominant peptide, citrullinated alpha-enolase peptide 1, which bears sequence similarity and cross-reactivity with enolase from P. gingivalis(Lundberg et al., 2010). These studies suggest that molecular mimicry and immune response to a bacterial epitope may result in production of antibodies. Recent studies have shown that bacterial PAD enzyme can deiminate host fibrinogen peptides (Wegner et al., 2010), which may lead to the generation of new epitopes, so triggering an immune response in a genetically predisposed individual.
Smoking and Autoimmunity
Several retrospective and prospective studies have shown the association between cigarette smoking and susceptibility to a number of autoimmune diseases such as RA, MS, type 1 diabetes, thyroiditis, primary biliary cirrhosis, and Crohn’s disease (Wingerchuk, 2012). This has led to the emergence of smoking as a risk factor linked to the onset and clinical development of these autoimmune diseases in genetically predisposed individuals. Although these studies show an association, there is no experimental proof of a direct link between smoking and autoimmune diseases, RA, and MS. Numerous studies have provided evidence suggesting an association of smoking with development of RA. Smoking has been associated with extra-articular features of RA-like nodules and lung disease which is the third major reason for mortality in arthritis patients (Harel-Meir et al., 2007). An interaction between smoking and DRB1 alleles has been suggested to confer an increased risk of ACPA positive RA. An increase in the presence of citrulline-modified proteins observed in the lungs of smokers may be due to an increase in the PAD enzyme (Makrygiannakis et al., 2008). Although the mechanism of interaction between the RA susceptible class II alleles and environmental factors like smoking has not been elucidated, it is thought that RA onset may occur later in life (median age for RA onset is around 60 years) but the process of autoreactivity starts earlier. This is supported by the fact that autoantibodies in shared epitope positive individuals precede clinical disease, suggesting a role for smoking in triggering antibody production. A recent study using the multinational QUEST-RA database showed no significant differences in the clinical profile of RA patients who are smokers and non-smokers except for an increase in the presence of nodules in the smoker group (Naranjo et al., 2010). A study with a 3-year follow-up of patients with current smokers showed fewer swollen joints and no difference in radiologic damage, suggesting smoking may be contributing to disease by the production of autoantibodies (Harrison et al., 2001). Cigarette smoking is the most characterized environmental factor associated with pathogenesis of RA and suggests that the onset of RA may begin at a site other than joints.
Cigarette smoke can interact with other environmental factors such as EBV to increase the risk of MS, as smokers were twice as likely to have MS with high titers of anti-EBNA antibody compared to non-smokers (Simon et al., 2010). Smoking can increase risk of MS through a number of pathways such as (1) modulation of systemic immune response; (2) increasing the blood–brain barrierpermeability; and (3) direct injury to CNS by neurotoxic chemicals present in smoke.
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