Abstract
Protein prenylation involves the post-translational modification of specific protein-derived cysteine residues with farnesyl or geranylgeranyl groups through thioether linkages. Because a large number of proteins that participate in signal transduction processes require this modification, there has been intense interest in developing inhibitors of these enzymes and in clarifying the biological function of prenylation. Isoprenoid analogues have proven to be versatile tools for probing the mechanism and structure of prenyltransferases. Mechanistic probes have been created to investigate the stereochemical course and substituent effects in prenyltransferase catalyzed reactions. They have also been used to measure kinetic isotope effects and search for possible cationic intermediates. Photoaffinity labeling analogues containing either diazotrifluoropropionate or benzophenone units have been used to identify the location of isoprenoid binding sites in these enzymes. Biophysical probes incorporating fluorescent moieties or isotopic labels have been used to measure isoprenoid dissociation constants or prenyl group conformation when bound to the enzyme. Analogues containing noncognate alkene isomers or bulky substituents have also contributed to an understanding of isoprenoid recognition. Most recently, photoactive and isomeric isoprenylated analogues are providing insights into the function of protein prenylation.
Keywords: farnesyl, geranylgeranyl, diphosphate, prenylation, isoprenoid, prenyltransferase, stereochemistry, photoaffinity labeling
Current Topics in Medicinal Chemistry
Title: Use of Synthetic Isoprenoid Analogues for Understanding Protein Prenyltransferase Mechanism and Structure
Volume: 3 Issue: 10
Author(s): Tamara A. Kale, Shih-an J. Hsieh, Matt W. Rose and Mark D. Distefano
Affiliation:
Keywords: farnesyl, geranylgeranyl, diphosphate, prenylation, isoprenoid, prenyltransferase, stereochemistry, photoaffinity labeling
Abstract: Protein prenylation involves the post-translational modification of specific protein-derived cysteine residues with farnesyl or geranylgeranyl groups through thioether linkages. Because a large number of proteins that participate in signal transduction processes require this modification, there has been intense interest in developing inhibitors of these enzymes and in clarifying the biological function of prenylation. Isoprenoid analogues have proven to be versatile tools for probing the mechanism and structure of prenyltransferases. Mechanistic probes have been created to investigate the stereochemical course and substituent effects in prenyltransferase catalyzed reactions. They have also been used to measure kinetic isotope effects and search for possible cationic intermediates. Photoaffinity labeling analogues containing either diazotrifluoropropionate or benzophenone units have been used to identify the location of isoprenoid binding sites in these enzymes. Biophysical probes incorporating fluorescent moieties or isotopic labels have been used to measure isoprenoid dissociation constants or prenyl group conformation when bound to the enzyme. Analogues containing noncognate alkene isomers or bulky substituents have also contributed to an understanding of isoprenoid recognition. Most recently, photoactive and isomeric isoprenylated analogues are providing insights into the function of protein prenylation.
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Cite this article as:
Kale A. Tamara, Hsieh J. Shih-an, Rose W. Matt and Distefano D. Mark, Use of Synthetic Isoprenoid Analogues for Understanding Protein Prenyltransferase Mechanism and Structure, Current Topics in Medicinal Chemistry 2003; 3 (10) . https://dx.doi.org/10.2174/1568026033452087
DOI https://dx.doi.org/10.2174/1568026033452087 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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