Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 18, Issue 17, Pages 6230-6237Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2010.07.041
Keywords
Ras converting enzyme (Rce1p); Sterile mutant 24 (Ste24p); (Acyloxy)methyl ketone; Protease; Ras; CaaX protein; Post-translational modification
Funding
- Georgia Cancer Coalition Distinguished Cancer Clinician
- National Institutes of Health [GM067092]
- NSF
- University of Georgia (UGA)
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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. (C) 2010 Elsevier Ltd. All rights reserved.
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