Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0031099 (periodontitis)
 12,489 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Small, cysteine-rich, beta-sheet peptide antibiotics are found throughout the Animalia. Though broad spectrum in potential, they may exert selective antimicrobial effects under certain conditions. We have explored the antimicrobial properties of two families of beta-sheet peptide antibiotics, defensins and protegrins, against periodontopathic bacteria. The rabbit defensin NP-1 was active against facultative Gram-negative bacteria associated with early onset periodontitis, including Actinobacillus actinomycetemcomitans and the Capnocytophaga spp. Porcine protegrins showed even greater activity against those organisms, as well as against anaerobic bacteria associated with adult periodontitis, including Porphyromonas gingivalis Prevotella intermedia and Fusobacterium nucleatum. Based on these observations, we believe that protegrin-like beta-sheet peptide antibiotics may be useful dental therapeutics.
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PMID:Beta-sheet antibiotic peptides as potential dental therapeutics. 957 96

Porphyromonas gingivalis has been associated with the development of adult periodontitis and cysteine proteinases with Arg- and Lys-specific activity have been implicated as major virulence factors. In a cell sonicate of P. gingivalis W50, a complex of non-covalently associated proteins has been previously characterized. This complex is composed of a 45 kDa Arg-specific, calcium-stabilized cysteine proteinase (PrtR45), a 48 kDa Lys-specific cysteine proteinase (PrtK48) and seven sequence-related adhesins designated PrtR44, PrtR15, PrtR17, PrtR27, PrtK39, PrtK15 and PrtK44, with all proteins being encoded by the two genes prtR and prtK. It has been proposed that these non-covalently associated complexes form extracellularly after autolytic processing of the PrtR and PrtK polyproteins, with the adhesins binding to the proteinases (PrtR45 and PrtK48) and autoaggregating. Another form of the cell-associated, Arg-specific, calcium-stabilized cysteine proteinase is described here. Designated PrtRII50, it is a discrete 50 kDa protein with no adhesin-association and has enzymic characteristics and an inhibitor/activator profile almost identical to PrtR45. The PrtRII50 proteinase is encoded as a preproprotein by a second gene, prtRII, with high sequence similarity to PrtR except that it lacks the C-terminal adhesin domains. A comparison of the deduced amino acid sequence of PrtRII50 with that of the adhesin-associated proteinases PrtR45 and PrtK48 revealed that PrtRII50 does not contain a C-terminal motif that is conserved in PrtR45 and PrtK48. Related motifs are also found in the adhesin domains of PrtR and PrtK. It is proposed that this conserved motif is an adhesin-binding motif (ABM) involved in association of the PrtR and PrtK proteinases and adhesins into large complexes, as the PrtR-PrtK proteinase-adhesin complex inactivated by N-alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) was shown to bind specifically to a synthetic peptide corresponding to the conserved motif in a competitive binding assay.
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PMID:Characterization of a second cell-associated Arg-specific cysteine proteinase of Porphyromonas gingivalis and identification of an adhesin-binding motif involved in association of the prtR and prtK proteinases and adhesins into large complexes. 963 29

The oral anaerobic bacterium Porphyromonas gingivalis, a major pathogen of advanced adult periodontitis, produces a novel class of cysteine proteinases in both cell-associated and secretory forms. A lysine-specific cysteine proteinase (Lys-gingipain, KGP), as well as an arginine-specific cysteine proteinase (Arg-gingipain), is a major trypsin-like proteinase of the organism. Recent studies indicate that the secreted KGP is implicated in the destruction of periodontal tissue and the disruption of host defense mechanisms. In this study, we have constructed a KGP-deficient mutant to determine whether the cell-associated KGP is important for pathophysiology of the organism. Although the mutant retained the strong ability to disrupt the bactericidal activity of polymorphonuclear leukocytes, its hemagglutination activity was reduced to about one-half that observed with the wild-type strain. More important, the mutant did not form black-pigmented colonies on blood agar plates, indicating the defect of hemoglobin adsorption and heme accumulation. Immunoblot analysis showed that the expression of a 19-kDa hemoglobin receptor protein, which is thought to be responsible for hemoglobin binding by the organism, was greatly retarded in this mutant. The mutant also showed a marked decrease in the ability to degrade fibrinogen. These results suggest the possible involvement of KGP in the hemoglobin binding and heme accumulation of the organism and in the bleeding tendency in periodontal pockets.
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PMID:Involvement of a lysine-specific cysteine proteinase in hemoglobin adsorption and heme accumulation by Porphyromonas gingivalis. 969 80

The salivary peptide histatin 5 has been reported to be an inhibitor of the Arg- and Lys-specific proteinases of Porphyromonas gingivalis, an oral pathogen associated with periodontitis. In this study a purified P. gingivalis proteinase preparation consisting of a complex of the Arg- and Lys-specific proteinases and adhesins was assayed using chromogenic substrates in the presence of histatin 5. Histatin 5 produced a concentration-dependent decrease in the initial rate of hydrolysis of the chromogenic substrates by both proteinases. However, pre-incubation of histatin 5 with the purified proteinase preparation or a P. gingivalis cell sonicate for 10 min prior to assay with the chromogenic substrates showed that under these conditions the salivary peptide did not decrease the initial rate of chromogen release. Mass spectrometric analysis revealed rapid degradation of histatin 5 at all four lysyl and all three arginyl residues by the P. gingivalis proteinases. This study demonstrates that histatin 5 is a substrate for the P. gingivalis extracellular Arg- and Lys-specific cysteine proteinases and not an inhibitor.
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PMID:Histatin 5 is a substrate and not an inhibitor of the Arg- and Lys-specific proteinases of Porphyromonas gingivalis. 975 56

Gingipains are the major cysteine proteinases synthesized by Porphyromonas gingivalis which, in soluble form, are able to initially convert IL-8 (77 amino acid residues) to a more potent species truncated at the amino terminus, followed by slow degradation and destruction of chemokine biological activity. In contrast, the same enzymes when associated with bacterial outer-membrane blebs (vesicles), instantly degrade this chemokine. This division of enhancing and inactivating activity between soluble and membrane-bound gingipains can cause the compartmentalization of pro- and anti-inflammatory reactions to distal and proximal positions from bacterial plaque, respectively, which may explain why, despite the massive neutrophil accumulation at periodontitis sites, there is no elimination of infection.
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PMID:Modulation of interleukin-8 activity by gingipains from Porphyromonas gingivalis: implications for pathogenicity of periodontal disease. 987 87

The anti-resorptive properties of tetracyclines (TCs) and their non-antimicrobial, chemically modified analogues (CMTs) have enormous therapeutic potential in medicine and dentistry. Osseous destructive diseases associated with excessive mammalian collagenase (matrix metalloproteinase) activity and collagen breakdown include malignancy, arthritis, and periodontitis. However, apart from the significant antimatrix metalloproteinase effects of TCs, TCs/CMTs are also potent inhibitors of osteoclast function (i.e., anti-resorptive). Thus, TCs can affect several parameters of osteoclast function and consequently inhibit bone resorption by (1) altering intracellular calcium concentration and interacting with the putative calcium receptor; (2) decreasing ruffled border area; (3) diminishing acid production; (4) diminishing the secretion of lysosomal cysteine proteinases (cathepsins); (5) inducing cell retraction by affecting podosomes; (6) inhibiting osteoclast gelatinase activity; (7) selectively inhibiting osteoclast ontogeny or development; and (8) inducing apoptosis or programmed cell death of osteoclasts. TCs/CMTs, as anti-resorptive drugs, may act similarly to bisphosphonates and primarily affect osteoclast function.
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PMID:Effects of tetracyclines on bone metabolism. 997 23

In order to determine the effect of bacterial proteinases on activation of the protein C system, a negative regulator of blood coagulation, two arginine-specific cysteine proteinases (gingipains R) from Porphyromonas gingivalis, a causative bacterium of adult periodontitis, were examined. Each enzyme activated human protein C in a dose- and incubation time-dependent manner. Interestingly, the form of enzyme being composed of a non-covalent complex containing both catalytic and adhesion domains (RgpA) produced activated protein C 14-fold more efficiently than RgpB which contained the catalytic domain alone. The kcat/Km value of RgpA was 18-fold higher than that of RgpB and comparable to that of the thrombin-thrombomodulin complex, the physiological activator of protein C. RgpA catalyzed protein C activation was augmented 1.4-fold by phospholipids, ubiquitous cell membrane components. Furthermore, RgpA, but not RgpB, could activate protein C in plasma and this resulted in a decrease of the protein C concentration in plasma, which is often observed in patients with sepsis during the development of disseminated intravascular coagulation (DIC). These data indicate that RgpA is a more potent activator of protein C than RgpB and suggest that only the former enzyme can cause protein C activation in vivo. The present study further suggests that bacterial proteinases may possibly contribute to the consumption of plasma protein C which predisposes to DIC and/or promotes a thrombotic tendency towards DIC in sepsis.
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PMID:Activation of protein C by arginine-specific cysteine proteinases (gingipains-R) from Porphyromonas gingivalis. 1006 39

Porphyromonas gingivalis, a gram-negative oral anaerobic bacterium, has been implicated in the onset and development of periodontitis. The P. gingivalis fimbriae which mediate bacterial adherence to host oral sites and induce host inflammatory responses have been suggested as a potential antigen candidate. for vaccine development. This study was undertaken to generate Streptococcus gordonii vectors expressing the major subunit protein (FimA) of P. gingivalis fimbriae for testing as a potential live vaccine against periodontitis. We report here the expression of the C-terminal saliva-binding epitopes of P. gingivalis FimA on the surface of S. gordonii and demonstrate that domains containing free cysteine residues are poorly expressed on the surface of S. gordonii.
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PMID:Expression of saliva-binding epitopes of the Porphyromonas gingivalis FimA protein on the surface of Streptococcus gordonii. 1022 64

Cysteine proteinases have been emphasized in the virulence of Porphyromonas gingivalis in chronic periodontitis. These hydrolases may promote the degradation of extracellular matrix proteins and disrupt components of the immune system. In this study it was shown that purified Arg-gingipain and Lys-gingipain inhibited expression of class II major histocompatibility complex (MHC) proteins in response to the stimulation of endothelial cells with human gamma interferon (IFN-gamma). Treatment with the cysteine proteinases resulted in a rapid shift in the apparent molecular size of IFN-gamma from 17 to 15 kDa, as shown by Western blot analysis, a response which also occurred in the presence of serum. Further, glycosylated natural IFN-gamma from human leukocytes and unglycosylated recombinant IFN-gamma from Escherichia coli were both digested by the cysteine proteinases. Immunoblot analysis indicated that cleavage within the carboxyl terminus of recombinant IFN-gamma correlated with the loss of induction of MHC class II expression as monitored by analytical flow cytometry. No hydrolysis of MHC class II molecules or human IFN-gamma receptor by these proteinases was detected by Western blot analysis. These findings suggest that P. gingivalis cysteine proteinases may alter the cytokine network at the point of infection through the cleavage of IFN-gamma. Degradation of IFN-gamma could have important consequences for the recruitment and activation of leukocytes and therefore may contribute significantly to the destruction of the periodontal attachment.
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PMID:Modulation of major histocompatibility complex protein expression by human gamma interferon mediated by cysteine proteinase-adhesin polyproteins of Porphyromonas gingivalis. 1033 9

Gingipains are cysteine proteinases acting as key virulence factors of the bacterium Porphyromonas gingivalis, the major pathogen in periodontal disease. The 1.5 and 2.0 A crystal structures of free and D-Phe-Phe-Arg-chloromethylketone-inhibited gingipain R reveal a 435-residue, single-polypeptide chain organized into a catalytic and an immunoglobulin-like domain. The catalytic domain is subdivided into two subdomains comprising four- and six-stranded beta-sheets sandwiched by alpha-helices. Each subdomain bears topological similarities to the p20-p10 heterodimer of caspase-1. The second subdomain harbours the Cys-His catalytic diad and a nearby Glu arranged around the S1 specificity pocket, which carries an Asp residue to enforce preference for Arg-P1 residues. This gingipain R structure is an excellent template for the rational design of drugs with a potential to cure and prevent periodontitis. Here we show the binding mode of an arginine-containing inhibitor in the active-site, thus identifying major interaction sites defining a suitable pharmacophor.
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PMID:Crystal structure of gingipain R: an Arg-specific bacterial cysteine proteinase with a caspase-like fold. 1052 90


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