ArticleBiochimica et biophysica acta2007
Inhibition of the CaaX proteases Rce1p and Ste24p by peptidyl (acyloxy)methyl ketones.
Article in Biochimica et biophysica acta, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 38 citations in OpenAlex.
- Targeted genetic and small molecule disruption of N-Ras CaaX cleavage alters its localization and oncogenic potential.Bioorganic chemistry · 2024Article
- Regulation of Small GTPase Prenylation in the Nervous System.Molecular neurobiology · 2020Review
- Concepts and advances in cancer therapeutic vulnerabilities in RAS membrane targeting.Seminars in cancer biology · 2019Review
- Isoprenoids and protein prenylation: implications in the pathogenesis and therapeutic intervention of Alzheimer's disease.Critical reviews in biochemistry and molecular biology · 2018Review
- Rce1: mechanism and inhibition.Critical reviews in biochemistry and molecular biology · 2018Review
- Human CaaX protease ZMPSTE24 expressed in yeast: Structure and inhibition by HIV protease inhibitors.Protein science : a publication of the Protein Society · 2017Article
- Ste24p Mediates Proteolysis of Both Isoprenylated and Non-prenylated Oligopeptides.The Journal of biological chemistry · 2016Article
- The renewed battle against RAS-mutant cancers.Cellular and molecular life sciences : CMLS · 2016Review
- 8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells.Bioorganic & medicinal chemistry · 2016Article
- A novel chemical screening strategy in zebrafish identifies common pathways in embryogenesis and rhabdomyosarcoma development.Development (Cambridge, England) · 2013Article
- Prenyltransferase Inhibitors: Treating Human Ailments from Cancer to Parasitic Infections.MedChemComm · 2013Article
- Cell-permeable, small-molecule activators of the insulin-degrading enzyme.Journal of biomolecular screening · 2012Article
- Biogenesis of the Saccharomyces cerevisiae pheromone a-factor, from yeast mating to human disease.Microbiology and molecular biology reviews : MMBR · 2012Review
- Photoaffinity labeling of Ras converting enzyme using peptide substrates that incorporate benzoylphenylalanine (Bpa) residues: improved labeling and structural implications.Bioorganic & medicinal chemistry · 2011Article
- Inhibition of Ras for cancer treatment: the search continues.Future medicinal chemistry · 2011Review
- Therapeutic strategies for targeting ras proteins.Genes & cancer · 2011Article
- Modulation of the inhibitor properties of dipeptidyl (acyloxy)methyl ketones toward the CaaX proteases.Bioorganic & medicinal chemistry · 2010Article
- Photoaffinity labeling of Ras converting enzyme 1 (Rce1p) using a benzophenone-containing peptide substrate.Bioorganic & medicinal chemistry · 2010Article
- Isoprenoids, small GTPases and Alzheimer's disease.Biochimica et biophysica acta · 2010Review
- Chemical inhibition of CaaX protease activity disrupts yeast Ras localization.Yeast (Chichester, England) · 2010Article
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Authors and funding
6 authors at 1 institution in 1 country.
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Abstract
The CaaX proteases Rce1p and Ste24p can independently promote a proteolytic step required for the maturation of certain isoprenylated proteins. Although functionally related, Rce1p and Ste24p are unrelated in primary sequence. They have distinct enzymatic properties, which are reflected in part by their distinct inhibitor profiles. Moreover, Rce1p 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 Rce1p 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 Rce1p to TPCK is substrate-dependent, which significantly alters the interpretation of certain reports having used TPCK sensitivity for mechanistic classification of Rce1p. Finally, we show that an AOMK inhibits the isoprenylcysteine carboxyl methyltransferase Ste14p. 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.
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