ArticleThe Journal of biological chemistry2005
The isoprenoid substrate specificity of isoprenylcysteine carboxylmethyltransferase: development of novel inhibitors.
Article in The Journal of biological chemistry, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 37 citations in OpenAlex.
- ICMT supports BRAFProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Post-translational modifications and their implications in cancer.Frontiers in oncology · 2023Review
- Article
- Article
- Isoprenyl carboxyl methyltransferase inhibitors: a brief review including recent patents.Amino acids · 2017Review
- Mutational analysis of the integral membrane methyltransferase isoprenylcysteine carboxyl methyltransferase (ICMT) reveals potential substrate binding sites.The Journal of biological chemistry · 2014Article
- Diazirine-containing photoactivatable isoprenoid: synthesis and application in studies with isoprenylcysteine carboxyl methyltransferase.The Journal of organic chemistry · 2014Article
- Identification of methylated proteins in the yeast small ribosomal subunit: a role for SPOUT methyltransferases in protein arginine methylation.Biochemistry · 2012Article
- Evaluation of substrate and inhibitor binding to yeast and human isoprenylcysteine carboxyl methyltransferases (Icmts) using biotinylated benzophenone-containing photoaffinity probes.Biochemical and biophysical research communications · 2012Article
- S-Farnesyl-Thiopropionic Acid (FTPA) Triazoles as Potent Inhibitors of Isoprenylcysteine Carboxyl Methyltransferase.ACS medicinal chemistry letters · 2012Article
- Amide-modified prenylcysteine based Icmt inhibitors: Structure-activity relationships, kinetic analysis and cellular characterization.Bioorganic & medicinal chemistry · 2012Article
- Lipid and sulfur substituted prenylcysteine analogs as human Icmt inhibitors.Bioorganic & medicinal chemistry letters · 2011Article
- Inhibition of isoprenylcysteine carboxylmethyltransferase induces autophagic-dependent apoptosis and impairs tumor growth.Oncogene · 2010Article
- Chemical inhibition of CaaX protease activity disrupts yeast Ras localization.Yeast (Chichester, England) · 2010Article
- Functional oligomerization of the Saccharomyces cerevisiae isoprenylcysteine carboxyl methyltransferase, Ste14p.The Journal of biological chemistry · 2010Article
- Heterologous expression studies of Saccharomyces cerevisiae reveal two distinct trypanosomatid CaaX protease activities and identify their potential targets.Eukaryotic cell · 2009Article
- Solid-phase synthesis of prenylcysteine analogs.The Journal of organic chemistry · 2009Article
- Article
- A potent HIV protease inhibitor, darunavir, does not inhibit ZMPSTE24 or lead to an accumulation of farnesyl-prelamin A in cells.The Journal of biological chemistry · 2008Article
- Small-molecule inhibitors of the Rce1p CaaX protease.Journal of biomolecular screening · 2007Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Isoprenylcysteine carboxylmethyltransferase (Icmt) is an integral membrane protein localized to the endoplasmic reticulum of eukaryotic cells that catalyzes the post-translational alpha-carboxylmethylesterification of CAAX motif proteins, including the oncoprotein Ras. Prior to methylation, these protein substrates all contain an isoprenylcysteine residue at the C terminus. In this study, we developed a variety of substrates and inhibitors of Icmt that vary in the isoprene moiety in order to gain information about the nature of the lipophilic substrate binding site. These isoprenoid-modified analogs of the minimal Icmt substrate N-acetyl-S-farnesyl-L-cysteine (AFC) were synthesized from newly and previously prepared farnesol analogs. Using both yeast and human Icmt enzymes, these compounds were found to vary widely in their ability to act as substrates, supporting the isoprenoid moiety as a key substrate recognition element for Icmt. Compound 3 is a competitive inhibitor of overexpressed yeast Icmt (K(I) = 17.1 +/- 1.7 microm). Compound 4 shows a mix of competitive and uncompetitive inhibition for both the yeast and the human Icmt proteins (yeast K(IC) = 35.4 +/- 3.4 microm, K(IU) = 614.4 +/- 148 microm; human K(IC) = 119.3 +/- 18.1 microm, K(IU) = 377.2 +/- 42.5 microm). These data further suggest that differences in substrate specificity exist between the human and yeast enzymes. Biological studies suggest that inhibition of Icmt results in Ras mislocalization and loss of cellular transformation ability, making Icmt an attractive and novel anticancer target. Further elaboration of the lead compounds synthesized and assayed here may lead to clinically useful higher potency inhibitors.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.