期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
卷 1773, 期 6, 页码 853-862出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2007.03.004
关键词
ras; protease; CaaX protein; post-translational modification; isoprenylation; (acyloxy)methyl ketone
资金
- NIGMS NIH HHS [R01 GM067092, R01 GM067092-02S1, R01 GM067092-02] Funding Source: Medline
The CaaX proteases Rce 1p and Ste24p can independently promote a proteolytic step required for the maturation of certain isoprenylated proteins. Although functionally related, Rce 1p and Ste24p are unrelated in primary sequence. They have distinct enzymatic properties, which are reflected in part by their distinct inhibitor profiles. Moreover, Rce 1p has an undefined catalytic mechanism, whereas Ste24p is an established zinc-dependent metalloprotease. This study demonstrates that both enzymes are inhibited by peptidyl (acyloxy)methyl ketones (AOMKs), making these compounds the first documented dual specificity inhibitors of the CaaX proteases. Further investigation of AOMK-mediated inhibition reveals that varying the peptidyl moiety can significantly alter the inhibitory properties of AOMKs toward Rce 1p and Ste24p and that these enzymes display subtle differences in sensitivity to AOMKs. This observation suggests that this compound class could potentially be engineered to be selective for either of the CaaX proteases. We also demonstrate that the reported sensitivity of Rce 1p to TPCK is substrate-dependent, which significantly alters the interpretation of certain reports having used TPCK sensitivity for mechanistic classification of Rce 1p. Finally, we show that an AOMK inhibits the isoprenylcysteine carboxyl methyltransferase Stel4p. In sum, our observations raise important considerations regarding the specificity of agents targeting enzymes involved in the maturation of isoprenylated proteins, some of which are being developed as anti-cancer therapeutic agents. (c) 2007 Elsevier B.V. All rights reserved.
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