Modulation of the inhibitor properties of dipeptidyl (acyloxy)methyl ketones toward the CaaX proteases |
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Authors: | Anne-Marie R Dechert James P MacNamara Sarah R Breevoort Emily R Hildebrandt Ned W Hembree Adam C Rea Duncan E McLain Stephen B Porter Walter K Schmidt Timothy M Dore |
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Institution: | 1. Department of Chemistry, University of Georgia, Athens, GA 30602-2556, United States;2. Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602-7229, United States |
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Abstract: | Dipeptidyl (acyloxy)methyl ketones (AOMKs) have been identified as mechanism-based inhibitors of certain cysteine proteases. These compounds are also inhibitors of the integral membrane proteins Rce1p and Ste24p, which are proteases that independently mediate a cleavage step associated with the maturation of certain isoprenylated proteins. The enzymatic mechanism of Rce1p is ill-defined, whereas Ste24p is a zinc metalloprotease. Rce1p is required for the proper processing of the oncoprotein Ras and is viewed as a potential target for cancer therapy. In this study, we synthesized a small library of dipeptidyl AOMKs to investigate the structural elements that contribute to the inhibitor properties of this class of molecules toward Rce1p and Ste24p. The compounds were evaluated using a fluorescence-based in vitro proteolysis assay. The most potent dipeptidyl AOMKs contained an arginine residue and the identity of the benzoate group strongly influenced potency. A ‘warhead’ free AOMK inhibited Rce1p and Ste24p. The data suggest that the dipeptidyl AOMKs are not mechanism-based inhibitors of Rce1p and Ste24p and corroborate the hypothesis that Rce1p is not a cysteine protease. |
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