Abstract:
:Mirolysin is a secretory protease of Tannerella forsythia, a member of the dysbiotic oral microbiota responsible for periodontitis. In this study, we show that mirolysin latency is achieved by a "cysteine-switch" mechanism exerted by Cys23 in the N-terminal profragment. Mutation of Cys23 shortened the time needed for activation of the zymogen from several days to 5 min. The mutation also decreased the thermal stability and autoproteolysis resistance of promirolysin. Mature mirolysin is a thermophilic enzyme and shows optimal activity at 65 °C. Through NMR-based fragment screening, we identified a small molecule (compound (cpd) 9) that blocks promirolysin maturation and functions as a competitive inhibitor (Ki = 3.2 µM), binding to the S1' subsite of the substrate-binding pocket. Cpd 9 shows superior specificity and does not interact with other T. forsythia proteases or Lys/Arg-specific proteases.
journal_name
J Enzyme Inhib Med Chemjournal_title
Journal of enzyme inhibition and medicinal chemistryauthors
Zak KM,Bostock MJ,Waligorska I,Thøgersen IB,Enghild JJ,Popowicz GM,Grudnik P,Potempa J,Ksiazek Mdoi
10.1080/14756366.2021.1937619keywords:
["NMR-based fragment screening","Periodontitis","Tannerella forsythia","protease inhibitors","proteolysis"]subject
Has Abstractpub_date
2021-12-01 00:00:00pages
1267-1281issue
1eissn
1475-6366issn
1475-6374journal_volume
36pub_type
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