Mammalian-like type II glutaminyl cyclases in Porphyromonas gingivalis and other oral pathogenic bacteria as targets for treatment of periodontitis
| Autor: | Miriam Linnert, Stephan Schilling, Hans-Ulrich Demuth, Mirko Buchholz, Jens-Ulrich Rahfeld, John A. Houston, Christoph Parthier, Florian Veillard, Nadine Taudte, Anke Piechotta, Milton T. Stubbs, Petr Kolenko, Jan Potempa, Daniel Ramsbeck, Sigrun Eick |
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| Přispěvatelé: | Publica |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
glutaminyl cyclase periodontal disease TRH thyrotropin-releasing hormone Crystallography X-Ray Biochemistry Prevotella intermedia Catalytic Domain bacterial pathogens Tannerella forsythia 610 Medicine & health ACAP auto-antibodies against citrullinated peptides Bibliographie chemistry.chemical_classification biology Chemistry Aminoacyltransferases Glutaminyl cyclase Enzyme structure Pyrrolidonecarboxylic Acid enzyme structure AD Alzheimer's disease Bacterial outer membrane Porphyromonas gingivalis Research Article crystal structure drug design PPAD P. gingivalis peptidylarginine deiminase FRIL freeze-fracture replica immunolabeling 03 medical and health sciences ORF open reading frame medicine GnRH gonadotropin-releasing hormone Humans Periodontitis Molecular Biology 030102 biochemistry & molecular biology Cell Biology Periplasmic space NMM N-methylmorpholine medicine.disease biology.organism_classification Protein Structure Tertiary 030104 developmental biology Enzyme |
| Zdroj: | The Journal of Biological Chemistry 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 (2021). Mammalian-like type II glutaminyl cyclases in Porphyromonas gingivalis and other oral pathogenic bacteria as targets for treatment of periodontitis. The journal of biological chemistry, 296, p. 100263. American Society for Biochemistry and Molecular Biology 10.1016/j.jbc.2021.100263 |
| DOI: | 10.1016/j.jbc.2021.100263 |
| Popis: | 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 ��-sheet surrounded by seven ��-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. |
| Databáze: | OpenAIRE |
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