Abstract:
:We studied the mode of regulation of the activity of mature cathepsin B (CB) by L-cysteine and some related thiols. The activity of CB with Z-Arg-Arg-NHMec as substrate was gradually inhibited over a range of increasing concentration of Cys, Cys methyl ester (CysOMe), Cys ethyl ester (CysOEt), N-acetyl-Cys (N-AcCys) and 3-mercaptopropionic acid. However, the inhibition of CB peaked at a definite value of [Cys], [CysOMe], [CysOEt] and [N-AcCys] and was gradually reversed over a range of higher concentrations of Cys and its esters. The maximum inhibitory concentrations of Cys, CysOME, CysOEt and N-AcCys showed a positive relationship to the pKa(RSH) values of the thiols and those of CysOEt and Cys decreased with increasing pH. The capability of the thiols to overcome their own inhibitory effect on CB was dependent on the concentration of their thiolate anion (RS-). However, the preincubation-dilution experiments showed that Cys and N-AcCys did not interact with active CB via a covalent mode. The inhibition of CB by N-AcCys was competitive and could be reversed by CysOMe. This activity-recovering effect of CysOMe was concentration-dependent and obeyed the Michaelis-Menten saturation kinetics over a profound increase of [RS-]. CB reacting in an environment of concurrently decreasing [RS-] and increasing [RSH], which was achieved by means of carboxylesterase-catalyzed deesterification of CysOEt to Cys, was progressively inhibited. Cys and N-AcCys also inhibited the fragmentation of histone H4 by CB and their concentration-dependent inhibitory profiles were qualitatively similar to those observed with Z-Arg-Arg-NHMec. Taken together, the results indicate that the RSH form of Cys and related thiols inhibits the activity of CB while the RS- form of these thiols counteracts or reverses the inhibitory action of the RSH form. This previously unrecognized thiol-thiolate anion regulation mechanism might be involved in a dynamic regulation of CB activity in endosomes and lysosomes and at the sites of lysosome-driven pericellular proteolysis.
journal_name
Biol Chemjournal_title
Biological chemistryauthors
Krepela E,Procházka J,Kárová Bdoi
10.1515/BC.1999.069keywords:
subject
Has Abstractpub_date
1999-05-01 00:00:00pages
541-51issue
5eissn
1431-6730issn
1437-4315journal_volume
380pub_type
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