7od0

Publication Abstract from PubMed

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 degrees 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 microM), 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.

Latency, thermal stability, and identification of an inhibitory compound of mirolysin, a secretory protease of the human periodontopathogen Tannerella forsythia.,Zak KM, Bostock MJ, Waligorska I, Thogersen IB, Enghild JJ, Popowicz GM, Grudnik P, Potempa J, Ksiazek M J Enzyme Inhib Med Chem. 2021 Dec;36(1):1267-1281. doi:, 10.1080/14756366.2021.1937619. PMID:34210221^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.