Identification and Characterization of Prokaryotic Dipeptidyl-peptidase 5 from Porphyromonas gingivalis

Ohara‐Nemoto, Yuko; Rouf, Shakh M. A.; Naito, Mariko; Yanase, Amie; Tetsuo, Fumi; Ono, Toshio; Kobayakawa, Takeshi; Shimoyama, Yu; Kimura, Shigenobu; Nakayama, Koji; Saiki, Keitarou; Kawai, Kiyoshi; Nemoto, Takayuki

doi:10.1074/jbc.m113.527333

Cited by 39 publications

(99 citation statements)

References 49 publications

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“…Together with the present and previous observations of PgDPP4, including the kinetic parameters of enzymatic reactions, optimal pH, inhibitor profiles, and substrate preference for Pro and less for Ala (15,18,31), our results led us to conclude that the enzymatic properties of bacterial DPP4 substantially resemble those of the human entity (28,38). In fact, the present findings revealed release of the N-terminal dipeptide from the incretin peptides GLP-1 and GIP by bacterial DPP4.…”

Section: Discussionsupporting

confidence: 53%

“…In fact, the dpp4-disrupted P. gingivalis strain NDP200 completely lost its activity, and Streptococcus mutans, a pathogen causing dental caries and which does not possess the dpp4 gene, showed no hydrolyzing activity either. In contrast, the activity was increased in P. gingivalis KDP136 (Δkgp-rgpA-rgpB) as reported previously (15).…”

Section: Resultsmentioning

confidence: 42%

“…Bacterial DPP4 activity was cell associated, while no activity was detected in the culture supernatants of the three microorganisms. Our previous studies of DPP5 (15), DPP11 (14), and AOP (16) indicated that these exopeptidases are localized as soluble forms in the periplasmic space. Hence, PgDPP4 seems to be also located in the periplasmic space.…”

Section: Discussionmentioning

confidence: 99%

“…PgDPP4 potently hydrolyzes Gly-Pro-4-methylcoumaryl-7-amide (MCA) and Lys-Ala-MCA as well at a much lower level of activity (31), the same manner as mammalian DPP4, and that activity is efficiently suppressed by hDPP4 inhibitors (15). These similarities between PgDPP4 and hDPP4 led us to speculate that PgDPP4 mimics the role of hDPP4 in glycemic control during recurrent bacteremia in periodontal patients, which may explain the link between severe periodontitis and diabetes mellitus.…”

mentioning

confidence: 99%

“…We recently identified novel dipeptide-producing exopeptidases in P. gingivalis, including DPP11, which specifically releases Xaa-Asp and Xaa-Glu (14); DPP5, with preference for the penultimate Ala and hydrophobic residues from the N terminus (15); and acylpeptidyl oligopeptidase (AOP), with preference mainly for the P1 position hydrophobic residue (16). Moreover, P. gingivalis expresses two additional DPPs and gingipains: DPP4 releases mainly Xaa-Pro but also Xaa-Ala and His-Ser (17,18), DPP7 preferentially cleaves dipeptides with both P1 and P2 hydrophobic residues (19,20), and Lys and Arg gingipains (Kgp and Rgp, respectively) exhibit Lysand Arg-specific dipeptidyl peptidase activities as well as endopeptidase activities (15). These peptidases are thought to cover most combinations of P2 and P1 amino acid residues and, therefore, efficiently produce N-terminal dipeptides from polypeptides (21).…”

mentioning

confidence: 99%

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Degradation of Incretins and Modulation of Blood Glucose Levels by Periodontopathic Bacterial Dipeptidyl Peptidase 4

et al. 2017

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Severe periodontitis is known to aggravate diabetes mellitus, though molecular events related to that link have not been fully elucidated. Porphyromonas gingivalis, a major pathogen of periodontitis, expresses dipeptidyl peptidase 4 (DPP4), which is involved in regulation of blood glucose levels by cleaving incretins in humans. We examined the enzymatic characteristics of DPP4 from P. gingivalis as well as two other periodontopathic bacteria, Tannerella forsythia and Prevotella intermedia, and determined whether it is capable of regulating blood glucose levels. Cellassociated DPP4 activity was found in those microorganisms, which was effectively suppressed by inhibitors of human DPP4, and molecules sized 73 kDa in P. gingivalis, and 71 kDa in T. forsythia and P. intermedia were immunologically detected. The k cat /K m values of recombinant DPP4s ranged from 721 Ϯ 55 to 1,283 Ϯ 23 M Ϫ1 s Ϫ1 toward Gly-Pro-4-methylcoumaryl-7-amide (MCA), while those were much lower for His-Ala-MCA. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis showed His/Tyr-Ala dipeptide release from the N termini of incretins, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide, respectively, with the action of microbial DPP4. Moreover, intravenous injection of DPP4 into mice decreased plasma active GLP-1 and insulin levels, accompanied by a substantial elevation in blood glucose over the control after oral glucose administration. These results are the first to show that periodontopathic bacterial DPP4 is capable of modulating blood glucose levels the same as mammalian DPP4; thus, the incidence of periodontopathic bacteremia may exacerbate diabetes mellitus via molecular events of bacterial DPP4 activities.

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