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Mammalian-like type II glutaminyl cyclases in Porphyromonas gingivalis and other oral pathogenic bacteria as targets for treatment of periodontitis
The development of a targeted therapy would significantly improve the treatment of periodontitis and its associated diseases including Alzheimer’s disease, rheumatoid arthritis, and cardiovascular diseases. Glutaminyl cyclases (QCs) from the oral pathogens Porphyromonas gingivalis, Tannerella forsyt...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948796/ https://www.ncbi.nlm.nih.gov/pubmed/33837744 http://dx.doi.org/10.1016/j.jbc.2021.100263 |
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author | Taudte, Nadine Linnert, Miriam Rahfeld, Jens-Ulrich Piechotta, Anke Ramsbeck, Daniel Buchholz, Mirko Kolenko, Petr Parthier, Christoph Houston, John A. Veillard, Florian Eick, Sigrun Potempa, Jan Schilling, Stephan Demuth, Hans-Ulrich Stubbs, Milton T. |
author_facet | Taudte, Nadine Linnert, Miriam Rahfeld, Jens-Ulrich Piechotta, Anke Ramsbeck, Daniel Buchholz, Mirko Kolenko, Petr Parthier, Christoph Houston, John A. Veillard, Florian Eick, Sigrun Potempa, Jan Schilling, Stephan Demuth, Hans-Ulrich Stubbs, Milton T. |
author_sort | Taudte, Nadine |
collection | PubMed |
description | The development of a targeted therapy would significantly improve the treatment of periodontitis and its associated diseases including Alzheimer’s disease, rheumatoid arthritis, and cardiovascular diseases. Glutaminyl cyclases (QCs) from the oral pathogens Porphyromonas gingivalis, Tannerella forsythia, and Prevotella intermedia represent attractive target enzymes for small-molecule inhibitor development, as their action is likely to stabilize essential periplasmic and outer membrane proteins by N-terminal pyroglutamination. In contrast to other microbial QCs that utilize the so-called type I enzymes, these oral pathogens possess sequences corresponding to type II QCs, observed hitherto only in animals. However, whether differences between these bacteroidal QCs and animal QCs are sufficient to enable development of selective inhibitors is not clear. To learn more, we recombinantly expressed all three QCs. They exhibit comparable catalytic efficiencies and are inhibited by metal chelators. Crystal structures of the enzymes from P. gingivalis (PgQC) and T. forsythia (TfQC) reveal a tertiary structure composed of an eight-stranded β-sheet surrounded by seven α-helices, typical of animal type II QCs. In each case, an active site Zn ion is tetrahedrally coordinated by conserved residues. Nevertheless, significant differences to mammalian enzymes are found around the active site of the bacteroidal enzymes. Application of a PgQC-selective inhibitor described here for the first time results in growth inhibition of two P. gingivalis clinical isolates in a dose-dependent manner. The insights gained by these studies will assist in the development of highly specific small-molecule bacteroidal QC inhibitors, paving the way for alternative therapies against periodontitis and associated diseases. |
format | Online Article Text |
id | pubmed-7948796 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-79487962021-03-19 Mammalian-like type II glutaminyl cyclases in Porphyromonas gingivalis and other oral pathogenic bacteria as targets for treatment of periodontitis Taudte, Nadine Linnert, Miriam Rahfeld, Jens-Ulrich Piechotta, Anke Ramsbeck, Daniel Buchholz, Mirko Kolenko, Petr Parthier, Christoph Houston, John A. Veillard, Florian Eick, Sigrun Potempa, Jan Schilling, Stephan Demuth, Hans-Ulrich Stubbs, Milton T. J Biol Chem Research Article The development of a targeted therapy would significantly improve the treatment of periodontitis and its associated diseases including Alzheimer’s disease, rheumatoid arthritis, and cardiovascular diseases. Glutaminyl cyclases (QCs) from the oral pathogens Porphyromonas gingivalis, Tannerella forsythia, and Prevotella intermedia represent attractive target enzymes for small-molecule inhibitor development, as their action is likely to stabilize essential periplasmic and outer membrane proteins by N-terminal pyroglutamination. In contrast to other microbial QCs that utilize the so-called type I enzymes, these oral pathogens possess sequences corresponding to type II QCs, observed hitherto only in animals. However, whether differences between these bacteroidal QCs and animal QCs are sufficient to enable development of selective inhibitors is not clear. To learn more, we recombinantly expressed all three QCs. They exhibit comparable catalytic efficiencies and are inhibited by metal chelators. Crystal structures of the enzymes from P. gingivalis (PgQC) and T. forsythia (TfQC) reveal a tertiary structure composed of an eight-stranded β-sheet surrounded by seven α-helices, typical of animal type II QCs. In each case, an active site Zn ion is tetrahedrally coordinated by conserved residues. Nevertheless, significant differences to mammalian enzymes are found around the active site of the bacteroidal enzymes. Application of a PgQC-selective inhibitor described here for the first time results in growth inhibition of two P. gingivalis clinical isolates in a dose-dependent manner. The insights gained by these studies will assist in the development of highly specific small-molecule bacteroidal QC inhibitors, paving the way for alternative therapies against periodontitis and associated diseases. American Society for Biochemistry and Molecular Biology 2021-01-08 /pmc/articles/PMC7948796/ /pubmed/33837744 http://dx.doi.org/10.1016/j.jbc.2021.100263 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Taudte, Nadine Linnert, Miriam Rahfeld, Jens-Ulrich Piechotta, Anke Ramsbeck, Daniel Buchholz, Mirko Kolenko, Petr Parthier, Christoph Houston, John A. Veillard, Florian Eick, Sigrun Potempa, Jan Schilling, Stephan Demuth, Hans-Ulrich Stubbs, Milton T. Mammalian-like type II glutaminyl cyclases in Porphyromonas gingivalis and other oral pathogenic bacteria as targets for treatment of periodontitis |
title | Mammalian-like type II glutaminyl cyclases in Porphyromonas gingivalis and other oral pathogenic bacteria as targets for treatment of periodontitis |
title_full | Mammalian-like type II glutaminyl cyclases in Porphyromonas gingivalis and other oral pathogenic bacteria as targets for treatment of periodontitis |
title_fullStr | Mammalian-like type II glutaminyl cyclases in Porphyromonas gingivalis and other oral pathogenic bacteria as targets for treatment of periodontitis |
title_full_unstemmed | Mammalian-like type II glutaminyl cyclases in Porphyromonas gingivalis and other oral pathogenic bacteria as targets for treatment of periodontitis |
title_short | Mammalian-like type II glutaminyl cyclases in Porphyromonas gingivalis and other oral pathogenic bacteria as targets for treatment of periodontitis |
title_sort | mammalian-like type ii glutaminyl cyclases in porphyromonas gingivalis and other oral pathogenic bacteria as targets for treatment of periodontitis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948796/ https://www.ncbi.nlm.nih.gov/pubmed/33837744 http://dx.doi.org/10.1016/j.jbc.2021.100263 |
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