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  • neuraminidase inhibitors Initially DPP DPP and prolyl tripep

    2023-09-18

    Initially, DPP4, DPP7, and prolyl tripeptidyl peptidase A (PtpA) were the only exopeptidases identified in P. gingivalis. These share substrates according to their altered specificities, as DPP4 is highly specific for Pro at the penultimate position from the N-terminus (P1 position), though it accepts Ala to a lesser extent [18,19], DPP7 is preferential to P1 hydrophobic amino acids [20], and PtpA liberates tripeptides with P1-position Pro, an activity that is able to compensate DPP4 and DPP7, which are unable to accept oligopeptides with Pro at the third position [21]. Although these three exopeptidases could not sufficiently explain the entire metabolism of extracellular oligopeptides, no other members were added to the list of P. gingivalis exopeptidases for a period of 10 years. Even though Asp and Glu are located in central routes of metabolism in P. gingivalis[10,15,22] (Fig. 1), oligopeptides with acidic amino neuraminidase inhibitors residues do not seem to be efficiently produced. Moreover, none of DPPs [19,21,23] and PtpA [20] are incapable of utilizing N-terminally blocked polypeptides, such as the various serum proteins present in gingival crevicular fluid. The majority of these disadvantages have been overcome by recent discoveries such as a novel Asp/Glu-specific DPP, DPP11 [23], DPP5, which is specific for hydrophobic P1 amino acid [24], and AOP in P. gingivalis[25]. Furthermore, we demonstrated that gingipains are able to produce dipeptides from oligopeptides [24]. These peptidases with various substrate specificities benefit P. gingivalis for colonization in nutrition-limited subgingival environments.
    Peptidases involved in degradation of extracellular proteinaceous nutrients
    Subcellular localization and comparison of enzymatic properties among exopeptidases All four DPP and AOP activities have been detected in P. gingivalis cells, though not in culture medium, indicating that they are present as so-called cell-associated forms. Furthermore, subcellular fractionation demonstrated that DPP5 and DPP11 are localized in the periplasmic space of the cell (Fig. 1) [23,24]. Indeed, DPPs do not have the C-terminal domain, which is required for outer membrane localization of Rgp and Kgp mediated by the type IX secretion system [57]. Periplasmic localization of P. gingivalis DPPs, PtpA, and AOP has also been suggested based on proteome analysis [58]. The differing subcellular localization between DPPs and gingipains seems to be compatible with the process of extracellular polypeptide processing. We determined and compared the enzymatic parameters of recombinant forms of DPPs and AOP (Table 1). The kcat/Km values for the best substrates for their respective peptidases were the highest in DPP4 followed by DPP11, while DPP5 and DPP7 possessed moderate values, and AOP had the lowest. Interestingly, this order was in parallel with substrate confinement in these exopeptidases, from Pro-specific DPP4, to Asp/Glu-specific DPP11, hydrophobic P1- and P2-specific DPP7, hydrophobic P1-specific DPP5, and the most relaxed hydrophobic P1-specific AOP. This coincidence is reasonable, because DPP4 may fold into the most specific steric structures for its substrate, whereas AOP, which is able to liberate di- and tri-peptides with and without N-terminal modification, may fold into a more open structure that is able to accept several types of substrates.
    All four DPP activities have been detected in P. gingivalis strains ATCC 33277, ATCC 49417, W83, W50, HW24D1, HNA99, HG1690, and 16-1 [50], and the exopeptidases discussed in this article contribute to bacterial growth. The findings presented here suggest that the activities of these exopeptidases influence both bacterial colonization in the oral cavity and clearance from the cardiovascular system after entering the blood circulation from a periodontal lesion. It has been reported that P. gingivalis DPP4 promotes the degradation of collagen and gelatin mediated by host proteases, and also inhibits binding between gingival fibroblasts and fibronectin [43]. In addition, DPP4 is involved in biofilm formation by P. gingivalis, which is closely related to bacterial virulence [44]. Hence, it is reasonable to postulate that other DPPs also contribute to biofilm formation and mixed-species colonization in subgingival plaque. Furthermore, evaluation of the roles of P. gingivalis DPPs in systemic diseases, especially type-2 diabetes mellitus and cardiovascular diseases, would be interesting. Our preliminary data indicate that the human peptide hormone incretin GLP-1, which induces secretion of insulin from the pancreas, is degraded by P. gingivalis bacterial cells and DPP4 in vitro. This is now an important point of focus for further studies.